{"gene":"SERPINC1","run_date":"2026-04-28T20:42:07","timeline":{"discoveries":[{"year":1989,"finding":"Point mutations in the reactive center of antithrombin III (ATIII) impair serine protease reactivity: ATIII Charleville (Ala384Pro) and ATIII Avranches (Arg393His) were identified as reactive-site mutations that abolish thrombin inhibition, while Pro41Leu and Arg47Cys mutations impair heparin binding.","method":"PCR amplification of gene exons followed by allele-specific oligonucleotide dot blot and direct sequencing; functional classification by protease reactivity and heparin binding assays","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 1 — direct sequencing with functional classification; multiple mutations and phenotypes characterized in one study, replicated across multiple variant families","pmids":["2794060"],"is_preprint":false},{"year":1991,"finding":"Arg406 in the conserved C-terminal core region near the reactive site of antithrombin III is critical for biological function; mutation Arg406Met (AT-III Kyoto) results in reduced antigen, progressive activity, and heparin cofactor activity, demonstrating the functional importance of this conserved region.","method":"PCR followed by direct DNA sequencing; functional assays for antigen level, progressive activity, and heparin cofactor activity","journal":"Thrombosis research","confidence":"Medium","confidence_rationale":"Tier 2 — sequencing with multiple functional assays in a single patient, single lab","pmids":["1776135"],"is_preprint":false},{"year":1992,"finding":"A splice site mutation at the exon 3a donor site of SERPINC1 causes exon 3a skipping in lymphocyte mRNA, producing an abnormally sized transcript and resulting in type I antithrombin III deficiency, demonstrating that mRNA splicing defects can cause quantitative antithrombin deficiency.","method":"PCR/direct sequencing; ectopic transcript analysis of lymphocyte mRNA; cDNA sequencing; oligonucleotide discriminant hybridization","journal":"Genomics","confidence":"High","confidence_rationale":"Tier 1 — multiple orthogonal methods (sequencing, ectopic transcript analysis, cDNA sequencing, hybridization) establishing mechanism of splicing defect","pmids":["1505975"],"is_preprint":false},{"year":1995,"finding":"A length polymorphism in the ATIII (SERPINC1) promoter has cell-line-dependent effects on promoter strength (1.6-fold higher for L allele in HepG2; 1.7-fold higher for S allele in Hep3B), but does not significantly affect plasma ATIII activity in vivo.","method":"Transient transfection of AT3 promoter/luciferase reporter gene constructs into two human hepatoma cell lines; in vivo plasma ATIII activity assay in 155 individuals","journal":"Blood coagulation & fibrinolysis","confidence":"Medium","confidence_rationale":"Tier 2 — reporter assay in two cell lines with in vivo validation, single lab","pmids":["8562837"],"is_preprint":false},{"year":2009,"finding":"Large deletions in SERPINC1 (including whole gene deletions and partial exon deletions) are detected by MLPA and explain approximately half of otherwise unexplained type I antithrombin deficiency; Alu repeat elements mediate recurrent deletional rearrangements at this locus.","method":"Multiplex ligation-dependent probe amplification (MLPA); sequencing of deletion breakpoints; identification of Alu-mediated recombination","journal":"Human genetics","confidence":"High","confidence_rationale":"Tier 2 — MLPA with breakpoint sequencing in 22 probands, multiple deletion types characterized, Alu-mediated mechanism established","pmids":["19760264"],"is_preprint":false},{"year":2012,"finding":"A g.2143 C>G transversion in the SERPINC1 promoter region (170 bp upstream of translation initiation codon), affecting a DNase I footprint-protected regulatory region, significantly impairs but does not abolish downstream transcription, causing type I antithrombin deficiency.","method":"Sequencing of 15,375 bp of SERPINC1 including promoter; reporter gene assay in hepatic cell lines; genotype-phenotype analysis in affected family","journal":"Thrombosis and haemostasis","confidence":"High","confidence_rationale":"Tier 1–2 — reporter assay combined with family genotype-phenotype analysis and cell line experiments; first regulatory mutation in SERPINC1","pmids":["22234719"],"is_preprint":false},{"year":2016,"finding":"SERPINC1 contains functional vitamin D receptor elements (VDREs) in its promoter and intron 1; mutations disrupting these VDREs cause moderate antithrombin deficiency, and treatment of HepG2 cells with the vitamin D analog paricalcitol dose-dependently increases SERPINC1 transcripts and secreted antithrombin, demonstrating transcriptional regulation of SERPINC1 by vitamin D.","method":"Sequencing of promoter and intronic regions; in silico VDRE identification; HepG2 cell incubation with paricalcitol; RT-PCR and measurement of secreted antithrombin","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 — cell model with dose-response, VDRE identification, and functional mutations; single lab","pmids":["27003919"],"is_preprint":false},{"year":2016,"finding":"Defective N-glycosylation (hypoglycosylation) of antithrombin, caused by mutations in N-glycosylation pathway genes rather than SERPINC1 itself, causes antithrombin deficiency and thrombophilia; this can be transient (associated with alcohol intake) and affects multiple N-glycoproteins.","method":"Electrophoresis, HPLC, Q-TOF analysis of glycoforms; whole exome sequencing; clinical and biochemical characterization of patients","journal":"Journal of thrombosis and haemostasis","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal glycoprotein analyses and genetic sequencing; single center but orthogonal methods","pmids":["27214821"],"is_preprint":false},{"year":2016,"finding":"A small in-frame deletion of four amino acids (INEL) in exon 4 of SERPINC1 causes type I antithrombin deficiency by promoting endoplasmic reticulum (ER) stress, which leads to intracellular retention and ER-associated degradation of the mutant antithrombin protein; suppression of ER stress enhanced secretion and inhibition of ER-associated degradation suppressed release.","method":"Whole-exome sequencing; cell-based expression studies; ER stress assays; pharmacological inhibition of ER stress and ER-associated degradation","journal":"Oncotarget","confidence":"High","confidence_rationale":"Tier 1–2 — mechanistic dissection with pharmacological modulation of ER stress and degradation pathways; multiple orthogonal approaches","pmids":["27708219"],"is_preprint":false},{"year":2022,"finding":"Two SERPINC1 variants (p.Glu227Lys and p.Asn224His) impair or abolish N-glycosylation at Asn224, causing a form of antithrombin deficiency not detected by routine functional assays (normal anti-FXa/anti-FIIa activity) but detectable by impaired anti-FVIIa activity and heat stability testing; the β glycoform lacking two N-glycans shows reduced secretion, increased heparin affinity, no inhibitory activity, and a potential dominant-negative effect; Lysine residues near the N-glycosylation sequon impair glycosylation efficacy.","method":"Eukaryotic expression model; anti-FXa, anti-FIIa, anti-FVIIa activity assays; heat stability test; thrombin generation assay; site-directed mutagenesis of N-glycosylation sequon flanking residues; glycoform analysis","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1 — multiple orthogonal functional assays, mutagenesis, glycoform characterization, and mechanistic elucidation in single rigorous study","pmids":["35486842"],"is_preprint":false},{"year":2014,"finding":"A novel SERPINC1 mutation g.1267G>A (p.A391T) in exon 7 reduces the heparin binding capacity of antithrombin by 44.25% compared to controls, without affecting AT activity or antigen levels, demonstrating that this residue is involved in heparin binding function.","method":"SERPINC1 gene sequencing; heparin binding assay (heparin-antithrombin binding ratio); coagulation parameter measurement","journal":"Thrombosis research","confidence":"Medium","confidence_rationale":"Tier 2 — direct heparin binding assay with comparison to healthy controls, single lab","pmids":["25312341"],"is_preprint":false},{"year":2020,"finding":"A SERPINC1 missense mutation (Cys462Tyr) disrupts the disulfide bond between Cys279 and Cys462, leading to type I hereditary antithrombin deficiency with reduced antigen and activity levels, demonstrating the structural importance of this disulfide bond.","method":"SERPINC1 exon sequencing; AT activity and antigen measurement; bioinformatics structural analysis of disulfide bond disruption; family segregation","journal":"Clinical biochemistry","confidence":"Medium","confidence_rationale":"Tier 2–3 — sequencing with functional assays and structural prediction; disulfide bond disruption supported by bioinformatics and clinical phenotype","pmids":["32745482"],"is_preprint":false},{"year":2023,"finding":"A SERPINC1 frameshift mutation c.1247dupC (p.Ser417LysfsTer48) results in impaired secretion of mutant antithrombin, causing quantitative (type I) antithrombin deficiency; the mutant protein is retained intracellularly rather than secreted.","method":"Plasmid transfection of GFP- and HA-tagged wild-type and mutant SERPINC1 into HEK293T cells; confocal laser scanning microscopy; Western blot","journal":"Thrombosis journal","confidence":"Medium","confidence_rationale":"Tier 2 — cell-based expression with imaging and Western blot using two distinct tags; single lab","pmids":["38347553"],"is_preprint":false},{"year":2023,"finding":"A SERPINC1 nonsense mutation p.Lys322stop generates a truncated antithrombin protein that is retained intracellularly and not secreted, as demonstrated by absence of mutant protein in culture medium despite its presence in cell lysates; mRNA levels are unaffected, placing the defect at the protein secretion level.","method":"RT-qPCR for mRNA quantification; Western blot and ELISA for protein; immunocytofluorescence for localization; expression in HEK293T cells","journal":"Orphanet journal of rare diseases","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods in cell model; single lab","pmids":["39707449"],"is_preprint":false},{"year":2023,"finding":"A SERPINC1 mutation p.Gly308Cys causes proteasome-dependent degradation of antithrombin in the cytoplasm by altering local residue hydrophobicity, demonstrated by rescue of protein levels with proteasome inhibitor MG132; a co-inherited p.Asn107* mutation causes nonsense-mediated mRNA decay, eliminating the transcript.","method":"RT-qPCR; Western blot; ELISA; immunocytofluorescence; proteasome inhibitor (MG132) treatment; expression in HEK293T cells","journal":"Gene","confidence":"High","confidence_rationale":"Tier 1–2 — pharmacological rescue experiment (MG132) plus mRNA quantification, protein detection, and localization; two distinct degradation mechanisms established in one study","pmids":["38104950"],"is_preprint":false},{"year":2025,"finding":"The SERPINC1 variant p.Leu158Gln causes type I antithrombin deficiency by impairing secretion and causing cytoplasmic retention/aggregation of the mutant protein; the mutation does not disrupt conserved disulfide bonds or N-glycosylation sites but reduces both quantity and functional activity of secreted antithrombin.","method":"Sanger sequencing; expression in HEK293T cells; immunoblotting; immunofluorescence; ELISA; computational structural analysis","journal":"Thrombosis journal","confidence":"Medium","confidence_rationale":"Tier 2 — cell-based expression with multiple orthogonal readouts; single lab","pmids":["41267092"],"is_preprint":false},{"year":2019,"finding":"Recurrent SERPINC1 mutations at residues Arg294 and Val295 (p.Arg294Leu, p.Arg294Cys, p.Arg294His, p.Val295Met) cause increased endogenous thrombin potential without affecting standard antithrombin antigen levels or anticoagulant activity, identifying a functional hotspot where mutations impair anticoagulant capacity undetectable by standard assays.","method":"SERPINC1 sequencing in 1,304 VTE patients and controls; recombinant protein expression model; thrombin generation assay (endogenous thrombin potential); anti-FXa and anti-FIIa activity assays","journal":"Oncotarget","confidence":"High","confidence_rationale":"Tier 1–2 — large cohort sequencing with recombinant protein expression and thrombin generation assay; novel functional mechanism established","pmids":["29137435"],"is_preprint":false},{"year":2009,"finding":"The SERPINC1 rs2227589 SNP (intron 1) is functionally associated with slightly but significantly lower plasma antithrombin activity and antigen levels in carriers of the A allele; the linked promoter polymorphism rs3138521 has no independent functional consequence.","method":"Genotyping of 298 blood donors; plasma anti-FXa activity and antithrombin antigen measurement; linkage disequilibrium analysis","journal":"Haematologica","confidence":"Medium","confidence_rationale":"Tier 2 — large population study with functional assays and genetic dissection; single lab","pmids":["19229049"],"is_preprint":false},{"year":2019,"finding":"In grass carp, KLF2A (Krüppel-like factor 2a) transcription factor positively regulates serpinc1 expression through direct promoter interaction, and both KLF2A and serpinc1 overexpression activate interferon responses and suppress reovirus replication.","method":"Dual-luciferase reporter assay; dose-dependent overexpression; RT-PCR; viral replication assay in CIK cells","journal":"Fish & shellfish immunology","confidence":"Low","confidence_rationale":"Tier 3 — fish ortholog; single lab; mechanistic link established by reporter assay but not in mammalian cells","pmids":["36400369"],"is_preprint":false},{"year":2026,"finding":"The SERPINC1 p.M313T variant introduces aberrant O-linked glycosylation within the breach region of antithrombin, causing conformational instability (reduced thermostability, increased latent/denatured forms, increased RCL flexibility) despite paradoxically enhanced inhibitory activity, explaining a transient antithrombin deficiency phenotype.","method":"Thrombin generation test; thermal stability assay; native-urea PAGE; recombinant protein expression; glycosidase enzymatic treatment; molecular dynamics simulation; AT activity assays","journal":"Thrombosis and haemostasis","confidence":"High","confidence_rationale":"Tier 1 — reconstitution with recombinant protein, glycosidase treatment to confirm O-glycosylation, multiple structural and functional assays, and molecular dynamics simulation in single rigorous study","pmids":["41862219"],"is_preprint":false},{"year":2019,"finding":"SERPINC1 large deletions detected by MLPA in Japanese patients include Alu-mediated and non-Alu-mediated complex genomic rearrangements; non-Alu events can be explained by the fork stalling and template switching (FoSTeS) mechanism.","method":"PCR-mediated direct sequencing; MLPA for copy number; in vitro exon trap assay for splice-site mutations; complex rearrangement breakpoint analysis","journal":"Thrombosis research","confidence":"Medium","confidence_rationale":"Tier 2 — MLPA with mechanistic classification of rearrangement types and exon trap assays; single lab","pmids":["31030036"],"is_preprint":false},{"year":2024,"finding":"A SERPINC1 frameshift mutation c.1377delC (p.Asn460Thrfs*20) leads to reduced AT protein expression in transfected cells and is predicted to disrupt the Cys279–Cys462 disulfide bond; a co-analyzed p.Arg229* nonsense mutation produces a truncated protein detected at 35 kDa without significant change in protein localization.","method":"Next-generation sequencing; Sanger sequencing; lentiviral plasmid transfection into HEK293T cells; Western blot; immunofluorescence localization; bioinformatics structural analysis","journal":"Thrombosis journal","confidence":"Medium","confidence_rationale":"Tier 2 — cell-based expression with Western blot and immunofluorescence; two mutations characterized by different mechanisms; single lab","pmids":["36624481"],"is_preprint":false}],"current_model":"SERPINC1 encodes antithrombin III (ATIII), a serine protease inhibitor that inactivates thrombin and activated coagulation factors (IXa, Xa, XIa, XIIa, VIIa) through its reactive center loop; heparin binding at a distinct site (involving Arg47, Pro41 region) accelerates this inhibition; N-glycosylation at multiple sites (including Asn224) is essential for proper folding, secretion, and inhibitory function; mutations cause antithrombin deficiency via reactive-site disruption, heparin-binding site impairment, aberrant glycosylation (N- or O-linked), ER stress-induced retention, proteasome-dependent degradation, nonsense-mediated mRNA decay, or large genomic deletions mediated by Alu elements; transcription is regulated by promoter elements including vitamin D receptor elements; the rs2227589 intronic polymorphism modestly reduces antithrombin levels through an undefined mechanism."},"narrative":{"teleology":[{"year":1989,"claim":"Establishing that the reactive-center loop and heparin-binding site are genetically separable functional domains: point mutations at the reactive center (Ala384Pro, Arg393His) abolished thrombin inhibition while distinct mutations (Pro41Leu, Arg47Cys) selectively impaired heparin binding, defining two independent functional surfaces on antithrombin.","evidence":"PCR-based exon sequencing with allele-specific oligonucleotide hybridization and functional classification by protease reactivity and heparin binding assays in multiple variant families","pmids":["2794060"],"confidence":"High","gaps":["Crystal structure of mutant–heparin complexes not determined","Kinetic parameters for individual factor inhibition not measured for each variant"]},{"year":1992,"claim":"Demonstrating that splicing defects cause quantitative (type I) antithrombin deficiency: a donor splice-site mutation caused exon 3a skipping and an abnormal transcript, establishing mRNA processing as a disease mechanism distinct from protein-level dysfunction.","evidence":"Ectopic transcript analysis of lymphocyte mRNA with cDNA sequencing and oligonucleotide discriminant hybridization","pmids":["1505975"],"confidence":"High","gaps":["Nonsense-mediated mRNA decay contribution not quantified for this specific splice mutant","No assessment of whether partial exon-skipping transcripts encode truncated proteins"]},{"year":2009,"claim":"Revealing that Alu-mediated large genomic deletions account for a substantial fraction of previously unexplained type I deficiency: MLPA detected whole-gene and partial deletions in ~50% of unresolved cases, with Alu repeats mediating recombination at breakpoints.","evidence":"MLPA with breakpoint sequencing in 22 probands; Alu-mediated recombination mechanism established; later extended to Japanese patients showing non-Alu FoSTeS-mediated rearrangements","pmids":["19760264","31030036"],"confidence":"High","gaps":["Frequency of FoSTeS-mediated versus Alu-mediated events across populations not established","Functional consequence of partial deletions on mRNA stability not directly tested"]},{"year":2009,"claim":"Identifying a common intronic polymorphism (rs2227589) that modestly reduces circulating antithrombin: the A allele significantly lowered anti-FXa activity and antigen levels, while the linked promoter polymorphism rs3138521 had no independent effect.","evidence":"Genotyping in 298 blood donors with plasma anti-FXa activity and antigen measurement","pmids":["19229049"],"confidence":"Medium","gaps":["Molecular mechanism by which intronic SNP reduces expression is unknown","Effect size may be too small for independent clinical significance"]},{"year":2012,"claim":"Establishing that promoter mutations can cause antithrombin deficiency: a transversion 170 bp upstream of the translation start impaired transcription in reporter assays and cosegregated with type I deficiency in a family, identifying the first regulatory mutation in SERPINC1.","evidence":"Reporter gene assay in hepatic cell lines combined with family genotype-phenotype analysis","pmids":["22234719"],"confidence":"High","gaps":["Transcription factor binding at this site not identified","Chromatin context effects not assessed"]},{"year":2016,"claim":"Discovering vitamin D-responsive transcriptional regulation: functional VDREs in the SERPINC1 promoter and intron 1 drive dose-dependent upregulation of antithrombin by vitamin D analogs, and VDRE-disrupting mutations cause moderate antithrombin deficiency.","evidence":"VDRE identification in silico; HepG2 treatment with paricalcitol showing dose-dependent SERPINC1 mRNA and secreted protein increase","pmids":["27003919"],"confidence":"Medium","gaps":["In vivo validation of vitamin D-mediated antithrombin regulation in human subjects not performed","VDR ChIP confirmation at SERPINC1 locus not reported"]},{"year":2016,"claim":"Defining ER stress and ER-associated degradation as a pathogenic mechanism: an in-frame deletion in exon 4 triggered ER stress leading to intracellular retention; pharmacological suppression of ER stress enhanced secretion while inhibition of ER-associated degradation blocked clearance, dissecting the proteostatic fate of misfolded antithrombin.","evidence":"Cell-based expression with ER stress assays and pharmacological modulation (ER stress inhibitor and proteasome/ERAD inhibitor)","pmids":["27708219"],"confidence":"High","gaps":["Identity of the ER chaperones recognizing misfolded antithrombin not determined","Whether ER stress contributes to liver pathology in patients is unknown"]},{"year":2019,"claim":"Identifying a functional hotspot (Arg294/Val295) where mutations escape standard diagnostic assays: these mutations caused elevated endogenous thrombin potential without reducing anti-FXa or anti-FIIa activity, revealing a class of antithrombin deficiency invisible to conventional testing.","evidence":"Sequencing of 1,304 VTE patients; recombinant expression with thrombin generation assay","pmids":["29137435"],"confidence":"High","gaps":["Structural basis for why these mutations selectively impair thrombin generation is unresolved","Clinical penetrance data for this hotspot limited"]},{"year":2022,"claim":"Establishing the critical role of Asn224 N-glycosylation for antithrombin function: variants abolishing glycosylation at this site generated β-glycoforms with reduced secretion, no inhibitory activity, and dominant-negative effects, while only anti-FVIIa activity and heat stability (not standard assays) detected the deficiency.","evidence":"Site-directed mutagenesis of glycosylation sequon flanking residues; anti-FXa/FIIa/FVIIa activity assays; glycoform analysis in eukaryotic expression model","pmids":["35486842"],"confidence":"High","gaps":["Structural basis for dominant-negative effect of β-glycoform not determined at atomic resolution","Whether other N-glycosylation sites show similar functional sensitivity is incompletely explored"]},{"year":2023,"claim":"Distinguishing proteasome-dependent degradation from nonsense-mediated mRNA decay as parallel pathogenic mechanisms: p.Gly308Cys was rescued by proteasome inhibitor MG132 (cytoplasmic degradation), while p.Asn107* eliminated mRNA via NMD, demonstrating that different mutations in the same gene engage fundamentally different quality-control pathways.","evidence":"RT-qPCR, Western blot, ELISA, immunocytofluorescence, and MG132 treatment in HEK293T cells","pmids":["38104950"],"confidence":"High","gaps":["Ubiquitin ligase responsible for targeting misfolded antithrombin to proteasome not identified","Relative contribution of proteasomal vs. ER-associated degradation for missense variants unclear"]},{"year":2026,"claim":"Revealing aberrant O-glycosylation as a novel pathogenic mechanism: the p.Met313Thr variant introduced an O-glycan in the breach region that destabilized antithrombin by increasing latent/denatured forms and RCL flexibility, while paradoxically enhancing inhibitory activity—explaining a transient deficiency phenotype.","evidence":"Recombinant protein expression with glycosidase treatment confirming O-glycosylation; thermal stability assay; native-urea PAGE; molecular dynamics simulation","pmids":["41862219"],"confidence":"High","gaps":["Identity of the O-glycosyltransferase responsible not determined","Whether other breach-region mutations introduce similar aberrant glycosylation is untested","In vivo turnover kinetics of O-glycosylated antithrombin not measured"]},{"year":null,"claim":"The molecular mechanism by which the rs2227589 intronic polymorphism reduces antithrombin levels, and whether vitamin D-mediated transcriptional regulation is physiologically significant in vivo, remain unresolved; additionally, no structural model exists for how β-glycoform antithrombin exerts its dominant-negative effect.","evidence":"","pmids":[],"confidence":"Low","gaps":["Mechanism of rs2227589 effect on expression unknown","In vivo relevance of VDRE-mediated regulation unconfirmed","Atomic-resolution structure of pathogenic glycoform variants lacking"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1,9,16,19]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[8,12,13,15]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[9,12,13]}],"pathway":[{"term_id":"R-HSA-109582","term_label":"Hemostasis","supporting_discovery_ids":[0,1,9,16,19]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[2,4,8,14]}],"complexes":[],"partners":["THROMBIN","HEPARIN","FXA","FVIIA"],"other_free_text":[]},"mechanistic_narrative":"SERPINC1 encodes antithrombin (antithrombin III), the principal serpin-family inhibitor of thrombin and activated coagulation factors (FXa, FIXa, FXIa, FVIIa), whose anticoagulant activity is dramatically accelerated by heparin binding at a distinct exosite involving residues such as Arg47 and Pro41 [PMID:2794060]. Proper N-glycosylation at sites including Asn224 is essential for folding, secretion, and full inhibitory function; loss of glycosylation generates a β-glycoform with reduced secretion and no inhibitory activity, and aberrant O-glycosylation (e.g., at Met313Thr) destabilizes the serpin fold by increasing reactive-center-loop flexibility [PMID:35486842, PMID:41862219]. Mutations in SERPINC1 cause hereditary antithrombin deficiency and thrombophilia through diverse mechanisms including reactive-site disruption, heparin-binding impairment, ER stress with intracellular retention and ER-associated degradation, proteasome-dependent cytoplasmic degradation, nonsense-mediated mRNA decay, and Alu-element-mediated large genomic deletions [PMID:2794060, PMID:27708219, PMID:38104950, PMID:19760264]. Transcription is regulated by promoter elements including functional vitamin D receptor elements in the promoter and intron 1, and the intronic polymorphism rs2227589 modestly reduces plasma antithrombin levels [PMID:27003919, PMID:19229049]."},"prefetch_data":{"uniprot":{"accession":"P01008","full_name":"Antithrombin-III","aliases":["Serpin C1"],"length_aa":464,"mass_kda":52.6,"function":"Most important serine protease inhibitor in plasma that regulates the blood coagulation cascade (PubMed:15140129, PubMed:15853774). AT-III inhibits thrombin, matriptase-3/TMPRSS7, as well as factors IXa, Xa and XIa (PubMed:15140129). Its inhibitory activity is greatly enhanced in the presence of heparin","subcellular_location":"Secreted, extracellular space","url":"https://www.uniprot.org/uniprotkb/P01008/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SERPINC1","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SERPINC1","total_profiled":1310},"omim":[{"mim_id":"619525","title":"CONGENITAL DISORDER OF GLYCOSYLATION, TYPE IIw; CDG2W","url":"https://www.omim.org/entry/619525"},{"mim_id":"614921","title":"CONGENITAL DISORDER OF GLYCOSYLATION, TYPE It; CDG1T","url":"https://www.omim.org/entry/614921"},{"mim_id":"614507","title":"CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Ir; CDG1R","url":"https://www.omim.org/entry/614507"},{"mim_id":"613118","title":"ANTITHROMBIN III DEFICIENCY; AT3D","url":"https://www.omim.org/entry/613118"},{"mim_id":"612379","title":"CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Iq; CDG1Q","url":"https://www.omim.org/entry/612379"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"liver","ntpm":4726.5}],"url":"https://www.proteinatlas.org/search/SERPINC1"},"hgnc":{"alias_symbol":["ATIII","MGC22579"],"prev_symbol":["AT3"]},"alphafold":{"accession":"P01008","domains":[{"cath_id":"3.30.497.10","chopping":"77-254_356-405","consensus_level":"medium","plddt":91.5327,"start":77,"end":405},{"cath_id":"2.30.39.10","chopping":"262-352_427-457","consensus_level":"medium","plddt":93.618,"start":262,"end":457}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P01008","model_url":"https://alphafold.ebi.ac.uk/files/AF-P01008-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P01008-F1-predicted_aligned_error_v6.png","plddt_mean":84.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SERPINC1","jax_strain_url":"https://www.jax.org/strain/search?query=SERPINC1"},"sequence":{"accession":"P01008","fasta_url":"https://rest.uniprot.org/uniprotkb/P01008.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P01008/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P01008"}},"corpus_meta":[{"pmid":"2794060","id":"PMC_2794060","title":"Molecular characterization of antithrombin III (ATIII) variants using polymerase chain reaction. Identification of the ATIII Charleville as an Ala 384 Pro mutation.","date":"1989","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/2794060","citation_count":60,"is_preprint":false},{"pmid":"28424376","id":"PMC_28424376","title":"SerpinC1/Antithrombin III in kidney-related diseases.","date":"2017","source":"Clinical science (London, England : 1979)","url":"https://pubmed.ncbi.nlm.nih.gov/28424376","citation_count":55,"is_preprint":false},{"pmid":"24196373","id":"PMC_24196373","title":"Impact of the type of SERPINC1 mutation and subtype of antithrombin deficiency on the thrombotic phenotype in hereditary antithrombin deficiency.","date":"2013","source":"Thrombosis and haemostasis","url":"https://pubmed.ncbi.nlm.nih.gov/24196373","citation_count":54,"is_preprint":false},{"pmid":"28300866","id":"PMC_28300866","title":"Thrombotic risk according to SERPINC1 genotype in a large cohort of subjects with antithrombin inherited 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of structural models of different AT3 copies in the genus Capsicum.","date":"2024","source":"Journal of biomolecular structure & dynamics","url":"https://pubmed.ncbi.nlm.nih.gov/38354741","citation_count":0,"is_preprint":false},{"pmid":"38448020","id":"PMC_38448020","title":"[Phenotypic and genetic analysis of a Chinese pedigree affected with Hereditary antithrombin deficiency due to a novel variant of SERPINC1 gene].","date":"2024","source":"Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/38448020","citation_count":0,"is_preprint":false},{"pmid":"39093784","id":"PMC_39093784","title":"Atypical pulmonary thromboembolism caused by the mutation site SERPINC1 of the antithrombin III gene: A case report.","date":"2024","source":"Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/39093784","citation_count":0,"is_preprint":false},{"pmid":"37829283","id":"PMC_37829283","title":"Case report: A case of new mutation in SERPINC1 leading to thrombotic microangiopathy.","date":"2023","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/37829283","citation_count":0,"is_preprint":false},{"pmid":"30431449","id":"PMC_30431449","title":"Safe childbirth for a type 1 antithrombin-deficient woman with novel mutation in the SERPINC1 gene undergoing antithrombin concentrate therapy.","date":"2019","source":"Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis","url":"https://pubmed.ncbi.nlm.nih.gov/30431449","citation_count":0,"is_preprint":false},{"pmid":"37385134","id":"PMC_37385134","title":"Human induced pluripotent stem cells derived from a patient with a mutation of SERPINC1 c.236G>A (p.R79H).","date":"2023","source":"Stem cell research","url":"https://pubmed.ncbi.nlm.nih.gov/37385134","citation_count":0,"is_preprint":false},{"pmid":"40050974","id":"PMC_40050974","title":"The novel SERPINC1 missense mutation c.1148 T > A (p.L383H) causes hereditary antithrombin deficiency and thromboembolism in a Chinese family: a case report.","date":"2025","source":"Journal of medical case reports","url":"https://pubmed.ncbi.nlm.nih.gov/40050974","citation_count":0,"is_preprint":false},{"pmid":"38801563","id":"PMC_38801563","title":"Long-range and real-time PCR identification of a large SERPINC1 deletion in a patient with antithrombin deficiency.","date":"2024","source":"International journal of hematology","url":"https://pubmed.ncbi.nlm.nih.gov/38801563","citation_count":0,"is_preprint":false},{"pmid":"41366676","id":"PMC_41366676","title":"Genetic and clinical characterization of two families with severe venous thromboembolism due to nonsense mutations in the SERPINC1 gene.","date":"2025","source":"Thrombosis journal","url":"https://pubmed.ncbi.nlm.nih.gov/41366676","citation_count":0,"is_preprint":false},{"pmid":"39526669","id":"PMC_39526669","title":"A novel SERPINC1 c.119G>A (p.Cys40Tyr) mutation with variable clinical expression in an Indian family.","date":"2024","source":"Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis","url":"https://pubmed.ncbi.nlm.nih.gov/39526669","citation_count":0,"is_preprint":false},{"pmid":"41862219","id":"PMC_41862219","title":"SERPINC1 p.M313T Variant Induces Aberrant O-Glycosylation and Leads to Conformational Instability-Related Transient Antithrombin Deficiency.","date":"2026","source":"Thrombosis and haemostasis","url":"https://pubmed.ncbi.nlm.nih.gov/41862219","citation_count":0,"is_preprint":false},{"pmid":"36120956","id":"PMC_36120956","title":"First Report of an α Chain Variant [Hb Coombe Park (HBA2: c.382A>G)] from India, Coinherited with a Novel SERPINC1 Gene Mutation: A Double Whammy?","date":"2022","source":"Hemoglobin","url":"https://pubmed.ncbi.nlm.nih.gov/36120956","citation_count":0,"is_preprint":false},{"pmid":"38224959","id":"PMC_38224959","title":"Digenic Inheritance of PROC and SERPINC1 Mutations Contributes to Multiple Sites Venous Thrombosis.","date":"2024","source":"Hamostaseologie","url":"https://pubmed.ncbi.nlm.nih.gov/38224959","citation_count":0,"is_preprint":false},{"pmid":"41861498","id":"PMC_41861498","title":"Identification of new molecular mechanisms of antithrombin deficiency: six new SERPINC1 variants in a Polish cohort.","date":"2026","source":"Thrombosis research","url":"https://pubmed.ncbi.nlm.nih.gov/41861498","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":47910,"output_tokens":5346,"usd":0.11196},"stage2":{"model":"claude-opus-4-6","input_tokens":8890,"output_tokens":3027,"usd":0.180188},"total_usd":0.292148,"stage1_batch_id":"msgbatch_011rkcQdVV1RaFq9XhcG6df6","stage2_batch_id":"msgbatch_01RzgrJafdF4EWHhj5mNi6dh","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1989,\n      \"finding\": \"Point mutations in the reactive center of antithrombin III (ATIII) impair serine protease reactivity: ATIII Charleville (Ala384Pro) and ATIII Avranches (Arg393His) were identified as reactive-site mutations that abolish thrombin inhibition, while Pro41Leu and Arg47Cys mutations impair heparin binding.\",\n      \"method\": \"PCR amplification of gene exons followed by allele-specific oligonucleotide dot blot and direct sequencing; functional classification by protease reactivity and heparin binding assays\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct sequencing with functional classification; multiple mutations and phenotypes characterized in one study, replicated across multiple variant families\",\n      \"pmids\": [\"2794060\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"Arg406 in the conserved C-terminal core region near the reactive site of antithrombin III is critical for biological function; mutation Arg406Met (AT-III Kyoto) results in reduced antigen, progressive activity, and heparin cofactor activity, demonstrating the functional importance of this conserved region.\",\n      \"method\": \"PCR followed by direct DNA sequencing; functional assays for antigen level, progressive activity, and heparin cofactor activity\",\n      \"journal\": \"Thrombosis research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — sequencing with multiple functional assays in a single patient, single lab\",\n      \"pmids\": [\"1776135\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"A splice site mutation at the exon 3a donor site of SERPINC1 causes exon 3a skipping in lymphocyte mRNA, producing an abnormally sized transcript and resulting in type I antithrombin III deficiency, demonstrating that mRNA splicing defects can cause quantitative antithrombin deficiency.\",\n      \"method\": \"PCR/direct sequencing; ectopic transcript analysis of lymphocyte mRNA; cDNA sequencing; oligonucleotide discriminant hybridization\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — multiple orthogonal methods (sequencing, ectopic transcript analysis, cDNA sequencing, hybridization) establishing mechanism of splicing defect\",\n      \"pmids\": [\"1505975\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"A length polymorphism in the ATIII (SERPINC1) promoter has cell-line-dependent effects on promoter strength (1.6-fold higher for L allele in HepG2; 1.7-fold higher for S allele in Hep3B), but does not significantly affect plasma ATIII activity in vivo.\",\n      \"method\": \"Transient transfection of AT3 promoter/luciferase reporter gene constructs into two human hepatoma cell lines; in vivo plasma ATIII activity assay in 155 individuals\",\n      \"journal\": \"Blood coagulation & fibrinolysis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reporter assay in two cell lines with in vivo validation, single lab\",\n      \"pmids\": [\"8562837\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Large deletions in SERPINC1 (including whole gene deletions and partial exon deletions) are detected by MLPA and explain approximately half of otherwise unexplained type I antithrombin deficiency; Alu repeat elements mediate recurrent deletional rearrangements at this locus.\",\n      \"method\": \"Multiplex ligation-dependent probe amplification (MLPA); sequencing of deletion breakpoints; identification of Alu-mediated recombination\",\n      \"journal\": \"Human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — MLPA with breakpoint sequencing in 22 probands, multiple deletion types characterized, Alu-mediated mechanism established\",\n      \"pmids\": [\"19760264\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"A g.2143 C>G transversion in the SERPINC1 promoter region (170 bp upstream of translation initiation codon), affecting a DNase I footprint-protected regulatory region, significantly impairs but does not abolish downstream transcription, causing type I antithrombin deficiency.\",\n      \"method\": \"Sequencing of 15,375 bp of SERPINC1 including promoter; reporter gene assay in hepatic cell lines; genotype-phenotype analysis in affected family\",\n      \"journal\": \"Thrombosis and haemostasis\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — reporter assay combined with family genotype-phenotype analysis and cell line experiments; first regulatory mutation in SERPINC1\",\n      \"pmids\": [\"22234719\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"SERPINC1 contains functional vitamin D receptor elements (VDREs) in its promoter and intron 1; mutations disrupting these VDREs cause moderate antithrombin deficiency, and treatment of HepG2 cells with the vitamin D analog paricalcitol dose-dependently increases SERPINC1 transcripts and secreted antithrombin, demonstrating transcriptional regulation of SERPINC1 by vitamin D.\",\n      \"method\": \"Sequencing of promoter and intronic regions; in silico VDRE identification; HepG2 cell incubation with paricalcitol; RT-PCR and measurement of secreted antithrombin\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — cell model with dose-response, VDRE identification, and functional mutations; single lab\",\n      \"pmids\": [\"27003919\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Defective N-glycosylation (hypoglycosylation) of antithrombin, caused by mutations in N-glycosylation pathway genes rather than SERPINC1 itself, causes antithrombin deficiency and thrombophilia; this can be transient (associated with alcohol intake) and affects multiple N-glycoproteins.\",\n      \"method\": \"Electrophoresis, HPLC, Q-TOF analysis of glycoforms; whole exome sequencing; clinical and biochemical characterization of patients\",\n      \"journal\": \"Journal of thrombosis and haemostasis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal glycoprotein analyses and genetic sequencing; single center but orthogonal methods\",\n      \"pmids\": [\"27214821\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"A small in-frame deletion of four amino acids (INEL) in exon 4 of SERPINC1 causes type I antithrombin deficiency by promoting endoplasmic reticulum (ER) stress, which leads to intracellular retention and ER-associated degradation of the mutant antithrombin protein; suppression of ER stress enhanced secretion and inhibition of ER-associated degradation suppressed release.\",\n      \"method\": \"Whole-exome sequencing; cell-based expression studies; ER stress assays; pharmacological inhibition of ER stress and ER-associated degradation\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — mechanistic dissection with pharmacological modulation of ER stress and degradation pathways; multiple orthogonal approaches\",\n      \"pmids\": [\"27708219\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Two SERPINC1 variants (p.Glu227Lys and p.Asn224His) impair or abolish N-glycosylation at Asn224, causing a form of antithrombin deficiency not detected by routine functional assays (normal anti-FXa/anti-FIIa activity) but detectable by impaired anti-FVIIa activity and heat stability testing; the β glycoform lacking two N-glycans shows reduced secretion, increased heparin affinity, no inhibitory activity, and a potential dominant-negative effect; Lysine residues near the N-glycosylation sequon impair glycosylation efficacy.\",\n      \"method\": \"Eukaryotic expression model; anti-FXa, anti-FIIa, anti-FVIIa activity assays; heat stability test; thrombin generation assay; site-directed mutagenesis of N-glycosylation sequon flanking residues; glycoform analysis\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — multiple orthogonal functional assays, mutagenesis, glycoform characterization, and mechanistic elucidation in single rigorous study\",\n      \"pmids\": [\"35486842\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"A novel SERPINC1 mutation g.1267G>A (p.A391T) in exon 7 reduces the heparin binding capacity of antithrombin by 44.25% compared to controls, without affecting AT activity or antigen levels, demonstrating that this residue is involved in heparin binding function.\",\n      \"method\": \"SERPINC1 gene sequencing; heparin binding assay (heparin-antithrombin binding ratio); coagulation parameter measurement\",\n      \"journal\": \"Thrombosis research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct heparin binding assay with comparison to healthy controls, single lab\",\n      \"pmids\": [\"25312341\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"A SERPINC1 missense mutation (Cys462Tyr) disrupts the disulfide bond between Cys279 and Cys462, leading to type I hereditary antithrombin deficiency with reduced antigen and activity levels, demonstrating the structural importance of this disulfide bond.\",\n      \"method\": \"SERPINC1 exon sequencing; AT activity and antigen measurement; bioinformatics structural analysis of disulfide bond disruption; family segregation\",\n      \"journal\": \"Clinical biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — sequencing with functional assays and structural prediction; disulfide bond disruption supported by bioinformatics and clinical phenotype\",\n      \"pmids\": [\"32745482\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"A SERPINC1 frameshift mutation c.1247dupC (p.Ser417LysfsTer48) results in impaired secretion of mutant antithrombin, causing quantitative (type I) antithrombin deficiency; the mutant protein is retained intracellularly rather than secreted.\",\n      \"method\": \"Plasmid transfection of GFP- and HA-tagged wild-type and mutant SERPINC1 into HEK293T cells; confocal laser scanning microscopy; Western blot\",\n      \"journal\": \"Thrombosis journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — cell-based expression with imaging and Western blot using two distinct tags; single lab\",\n      \"pmids\": [\"38347553\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"A SERPINC1 nonsense mutation p.Lys322stop generates a truncated antithrombin protein that is retained intracellularly and not secreted, as demonstrated by absence of mutant protein in culture medium despite its presence in cell lysates; mRNA levels are unaffected, placing the defect at the protein secretion level.\",\n      \"method\": \"RT-qPCR for mRNA quantification; Western blot and ELISA for protein; immunocytofluorescence for localization; expression in HEK293T cells\",\n      \"journal\": \"Orphanet journal of rare diseases\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods in cell model; single lab\",\n      \"pmids\": [\"39707449\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"A SERPINC1 mutation p.Gly308Cys causes proteasome-dependent degradation of antithrombin in the cytoplasm by altering local residue hydrophobicity, demonstrated by rescue of protein levels with proteasome inhibitor MG132; a co-inherited p.Asn107* mutation causes nonsense-mediated mRNA decay, eliminating the transcript.\",\n      \"method\": \"RT-qPCR; Western blot; ELISA; immunocytofluorescence; proteasome inhibitor (MG132) treatment; expression in HEK293T cells\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — pharmacological rescue experiment (MG132) plus mRNA quantification, protein detection, and localization; two distinct degradation mechanisms established in one study\",\n      \"pmids\": [\"38104950\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"The SERPINC1 variant p.Leu158Gln causes type I antithrombin deficiency by impairing secretion and causing cytoplasmic retention/aggregation of the mutant protein; the mutation does not disrupt conserved disulfide bonds or N-glycosylation sites but reduces both quantity and functional activity of secreted antithrombin.\",\n      \"method\": \"Sanger sequencing; expression in HEK293T cells; immunoblotting; immunofluorescence; ELISA; computational structural analysis\",\n      \"journal\": \"Thrombosis journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — cell-based expression with multiple orthogonal readouts; single lab\",\n      \"pmids\": [\"41267092\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Recurrent SERPINC1 mutations at residues Arg294 and Val295 (p.Arg294Leu, p.Arg294Cys, p.Arg294His, p.Val295Met) cause increased endogenous thrombin potential without affecting standard antithrombin antigen levels or anticoagulant activity, identifying a functional hotspot where mutations impair anticoagulant capacity undetectable by standard assays.\",\n      \"method\": \"SERPINC1 sequencing in 1,304 VTE patients and controls; recombinant protein expression model; thrombin generation assay (endogenous thrombin potential); anti-FXa and anti-FIIa activity assays\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — large cohort sequencing with recombinant protein expression and thrombin generation assay; novel functional mechanism established\",\n      \"pmids\": [\"29137435\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"The SERPINC1 rs2227589 SNP (intron 1) is functionally associated with slightly but significantly lower plasma antithrombin activity and antigen levels in carriers of the A allele; the linked promoter polymorphism rs3138521 has no independent functional consequence.\",\n      \"method\": \"Genotyping of 298 blood donors; plasma anti-FXa activity and antithrombin antigen measurement; linkage disequilibrium analysis\",\n      \"journal\": \"Haematologica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — large population study with functional assays and genetic dissection; single lab\",\n      \"pmids\": [\"19229049\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In grass carp, KLF2A (Krüppel-like factor 2a) transcription factor positively regulates serpinc1 expression through direct promoter interaction, and both KLF2A and serpinc1 overexpression activate interferon responses and suppress reovirus replication.\",\n      \"method\": \"Dual-luciferase reporter assay; dose-dependent overexpression; RT-PCR; viral replication assay in CIK cells\",\n      \"journal\": \"Fish & shellfish immunology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — fish ortholog; single lab; mechanistic link established by reporter assay but not in mammalian cells\",\n      \"pmids\": [\"36400369\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"The SERPINC1 p.M313T variant introduces aberrant O-linked glycosylation within the breach region of antithrombin, causing conformational instability (reduced thermostability, increased latent/denatured forms, increased RCL flexibility) despite paradoxically enhanced inhibitory activity, explaining a transient antithrombin deficiency phenotype.\",\n      \"method\": \"Thrombin generation test; thermal stability assay; native-urea PAGE; recombinant protein expression; glycosidase enzymatic treatment; molecular dynamics simulation; AT activity assays\",\n      \"journal\": \"Thrombosis and haemostasis\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstitution with recombinant protein, glycosidase treatment to confirm O-glycosylation, multiple structural and functional assays, and molecular dynamics simulation in single rigorous study\",\n      \"pmids\": [\"41862219\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SERPINC1 large deletions detected by MLPA in Japanese patients include Alu-mediated and non-Alu-mediated complex genomic rearrangements; non-Alu events can be explained by the fork stalling and template switching (FoSTeS) mechanism.\",\n      \"method\": \"PCR-mediated direct sequencing; MLPA for copy number; in vitro exon trap assay for splice-site mutations; complex rearrangement breakpoint analysis\",\n      \"journal\": \"Thrombosis research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — MLPA with mechanistic classification of rearrangement types and exon trap assays; single lab\",\n      \"pmids\": [\"31030036\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"A SERPINC1 frameshift mutation c.1377delC (p.Asn460Thrfs*20) leads to reduced AT protein expression in transfected cells and is predicted to disrupt the Cys279–Cys462 disulfide bond; a co-analyzed p.Arg229* nonsense mutation produces a truncated protein detected at 35 kDa without significant change in protein localization.\",\n      \"method\": \"Next-generation sequencing; Sanger sequencing; lentiviral plasmid transfection into HEK293T cells; Western blot; immunofluorescence localization; bioinformatics structural analysis\",\n      \"journal\": \"Thrombosis journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — cell-based expression with Western blot and immunofluorescence; two mutations characterized by different mechanisms; single lab\",\n      \"pmids\": [\"36624481\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SERPINC1 encodes antithrombin III (ATIII), a serine protease inhibitor that inactivates thrombin and activated coagulation factors (IXa, Xa, XIa, XIIa, VIIa) through its reactive center loop; heparin binding at a distinct site (involving Arg47, Pro41 region) accelerates this inhibition; N-glycosylation at multiple sites (including Asn224) is essential for proper folding, secretion, and inhibitory function; mutations cause antithrombin deficiency via reactive-site disruption, heparin-binding site impairment, aberrant glycosylation (N- or O-linked), ER stress-induced retention, proteasome-dependent degradation, nonsense-mediated mRNA decay, or large genomic deletions mediated by Alu elements; transcription is regulated by promoter elements including vitamin D receptor elements; the rs2227589 intronic polymorphism modestly reduces antithrombin levels through an undefined mechanism.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"SERPINC1 encodes antithrombin (antithrombin III), the principal serpin-family inhibitor of thrombin and activated coagulation factors (FXa, FIXa, FXIa, FVIIa), whose anticoagulant activity is dramatically accelerated by heparin binding at a distinct exosite involving residues such as Arg47 and Pro41 [PMID:2794060]. Proper N-glycosylation at sites including Asn224 is essential for folding, secretion, and full inhibitory function; loss of glycosylation generates a β-glycoform with reduced secretion and no inhibitory activity, and aberrant O-glycosylation (e.g., at Met313Thr) destabilizes the serpin fold by increasing reactive-center-loop flexibility [PMID:35486842, PMID:41862219]. Mutations in SERPINC1 cause hereditary antithrombin deficiency and thrombophilia through diverse mechanisms including reactive-site disruption, heparin-binding impairment, ER stress with intracellular retention and ER-associated degradation, proteasome-dependent cytoplasmic degradation, nonsense-mediated mRNA decay, and Alu-element-mediated large genomic deletions [PMID:2794060, PMID:27708219, PMID:38104950, PMID:19760264]. Transcription is regulated by promoter elements including functional vitamin D receptor elements in the promoter and intron 1, and the intronic polymorphism rs2227589 modestly reduces plasma antithrombin levels [PMID:27003919, PMID:19229049].\",\n  \"teleology\": [\n    {\n      \"year\": 1989,\n      \"claim\": \"Establishing that the reactive-center loop and heparin-binding site are genetically separable functional domains: point mutations at the reactive center (Ala384Pro, Arg393His) abolished thrombin inhibition while distinct mutations (Pro41Leu, Arg47Cys) selectively impaired heparin binding, defining two independent functional surfaces on antithrombin.\",\n      \"evidence\": \"PCR-based exon sequencing with allele-specific oligonucleotide hybridization and functional classification by protease reactivity and heparin binding assays in multiple variant families\",\n      \"pmids\": [\"2794060\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Crystal structure of mutant–heparin complexes not determined\", \"Kinetic parameters for individual factor inhibition not measured for each variant\"]\n    },\n    {\n      \"year\": 1992,\n      \"claim\": \"Demonstrating that splicing defects cause quantitative (type I) antithrombin deficiency: a donor splice-site mutation caused exon 3a skipping and an abnormal transcript, establishing mRNA processing as a disease mechanism distinct from protein-level dysfunction.\",\n      \"evidence\": \"Ectopic transcript analysis of lymphocyte mRNA with cDNA sequencing and oligonucleotide discriminant hybridization\",\n      \"pmids\": [\"1505975\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Nonsense-mediated mRNA decay contribution not quantified for this specific splice mutant\", \"No assessment of whether partial exon-skipping transcripts encode truncated proteins\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Revealing that Alu-mediated large genomic deletions account for a substantial fraction of previously unexplained type I deficiency: MLPA detected whole-gene and partial deletions in ~50% of unresolved cases, with Alu repeats mediating recombination at breakpoints.\",\n      \"evidence\": \"MLPA with breakpoint sequencing in 22 probands; Alu-mediated recombination mechanism established; later extended to Japanese patients showing non-Alu FoSTeS-mediated rearrangements\",\n      \"pmids\": [\"19760264\", \"31030036\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Frequency of FoSTeS-mediated versus Alu-mediated events across populations not established\", \"Functional consequence of partial deletions on mRNA stability not directly tested\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Identifying a common intronic polymorphism (rs2227589) that modestly reduces circulating antithrombin: the A allele significantly lowered anti-FXa activity and antigen levels, while the linked promoter polymorphism rs3138521 had no independent effect.\",\n      \"evidence\": \"Genotyping in 298 blood donors with plasma anti-FXa activity and antigen measurement\",\n      \"pmids\": [\"19229049\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism by which intronic SNP reduces expression is unknown\", \"Effect size may be too small for independent clinical significance\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Establishing that promoter mutations can cause antithrombin deficiency: a transversion 170 bp upstream of the translation start impaired transcription in reporter assays and cosegregated with type I deficiency in a family, identifying the first regulatory mutation in SERPINC1.\",\n      \"evidence\": \"Reporter gene assay in hepatic cell lines combined with family genotype-phenotype analysis\",\n      \"pmids\": [\"22234719\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Transcription factor binding at this site not identified\", \"Chromatin context effects not assessed\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Discovering vitamin D-responsive transcriptional regulation: functional VDREs in the SERPINC1 promoter and intron 1 drive dose-dependent upregulation of antithrombin by vitamin D analogs, and VDRE-disrupting mutations cause moderate antithrombin deficiency.\",\n      \"evidence\": \"VDRE identification in silico; HepG2 treatment with paricalcitol showing dose-dependent SERPINC1 mRNA and secreted protein increase\",\n      \"pmids\": [\"27003919\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo validation of vitamin D-mediated antithrombin regulation in human subjects not performed\", \"VDR ChIP confirmation at SERPINC1 locus not reported\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defining ER stress and ER-associated degradation as a pathogenic mechanism: an in-frame deletion in exon 4 triggered ER stress leading to intracellular retention; pharmacological suppression of ER stress enhanced secretion while inhibition of ER-associated degradation blocked clearance, dissecting the proteostatic fate of misfolded antithrombin.\",\n      \"evidence\": \"Cell-based expression with ER stress assays and pharmacological modulation (ER stress inhibitor and proteasome/ERAD inhibitor)\",\n      \"pmids\": [\"27708219\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the ER chaperones recognizing misfolded antithrombin not determined\", \"Whether ER stress contributes to liver pathology in patients is unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identifying a functional hotspot (Arg294/Val295) where mutations escape standard diagnostic assays: these mutations caused elevated endogenous thrombin potential without reducing anti-FXa or anti-FIIa activity, revealing a class of antithrombin deficiency invisible to conventional testing.\",\n      \"evidence\": \"Sequencing of 1,304 VTE patients; recombinant expression with thrombin generation assay\",\n      \"pmids\": [\"29137435\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for why these mutations selectively impair thrombin generation is unresolved\", \"Clinical penetrance data for this hotspot limited\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Establishing the critical role of Asn224 N-glycosylation for antithrombin function: variants abolishing glycosylation at this site generated β-glycoforms with reduced secretion, no inhibitory activity, and dominant-negative effects, while only anti-FVIIa activity and heat stability (not standard assays) detected the deficiency.\",\n      \"evidence\": \"Site-directed mutagenesis of glycosylation sequon flanking residues; anti-FXa/FIIa/FVIIa activity assays; glycoform analysis in eukaryotic expression model\",\n      \"pmids\": [\"35486842\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for dominant-negative effect of β-glycoform not determined at atomic resolution\", \"Whether other N-glycosylation sites show similar functional sensitivity is incompletely explored\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Distinguishing proteasome-dependent degradation from nonsense-mediated mRNA decay as parallel pathogenic mechanisms: p.Gly308Cys was rescued by proteasome inhibitor MG132 (cytoplasmic degradation), while p.Asn107* eliminated mRNA via NMD, demonstrating that different mutations in the same gene engage fundamentally different quality-control pathways.\",\n      \"evidence\": \"RT-qPCR, Western blot, ELISA, immunocytofluorescence, and MG132 treatment in HEK293T cells\",\n      \"pmids\": [\"38104950\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Ubiquitin ligase responsible for targeting misfolded antithrombin to proteasome not identified\", \"Relative contribution of proteasomal vs. ER-associated degradation for missense variants unclear\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Revealing aberrant O-glycosylation as a novel pathogenic mechanism: the p.Met313Thr variant introduced an O-glycan in the breach region that destabilized antithrombin by increasing latent/denatured forms and RCL flexibility, while paradoxically enhancing inhibitory activity—explaining a transient deficiency phenotype.\",\n      \"evidence\": \"Recombinant protein expression with glycosidase treatment confirming O-glycosylation; thermal stability assay; native-urea PAGE; molecular dynamics simulation\",\n      \"pmids\": [\"41862219\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the O-glycosyltransferase responsible not determined\", \"Whether other breach-region mutations introduce similar aberrant glycosylation is untested\", \"In vivo turnover kinetics of O-glycosylated antithrombin not measured\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The molecular mechanism by which the rs2227589 intronic polymorphism reduces antithrombin levels, and whether vitamin D-mediated transcriptional regulation is physiologically significant in vivo, remain unresolved; additionally, no structural model exists for how β-glycoform antithrombin exerts its dominant-negative effect.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Mechanism of rs2227589 effect on expression unknown\", \"In vivo relevance of VDRE-mediated regulation unconfirmed\", \"Atomic-resolution structure of pathogenic glycoform variants lacking\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1, 9, 16, 19]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [8, 12, 13, 15]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [9, 12, 13]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-109582\", \"supporting_discovery_ids\": [0, 1, 9, 16, 19]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [2, 4, 8, 14]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"thrombin\",\n      \"heparin\",\n      \"FXa\",\n      \"FVIIa\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}