{"gene":"CFB","run_date":"2026-04-28T17:28:52","timeline":{"discoveries":[{"year":2023,"finding":"A non-synonymous variant (G252S) in CFB impairs its binding to C3b, reduces CFB cleavage by factor D, and diminishes complement-driven macrophage phagocytosis and cytokine secretion. The serine at position 252 generates a de novo glycosylation site that accounts for the loss-of-function phenotype.","method":"Cell-free recombinant protein binding/cleavage assay with site-directed mutagenesis; macrophage phagocytosis by flow cytometry; serum from homozygous risk patients","journal":"Gut","confidence":"High","confidence_rationale":"Tier 1-2 — in vitro reconstitution with mutagenesis, multiple orthogonal functional assays, confirmed in patient serum","pmids":["37080587"],"is_preprint":false},{"year":2022,"finding":"CFB deficiency in diabetic kidney disease attenuates tubulointerstitial injury by inhibiting complement alternative pathway activation, suppressing NF-κB p65-mediated transcription of ceramide synthase genes (CERS3), and thereby reducing ceramide biosynthesis. C3 knockdown abolished CFB-mediated NF-κB signaling and ceramide production, placing CFB upstream of C3 activation in this pathway.","method":"Cfb-knockout diabetic mouse model; siRNA knockdown of CFB in HK-2 cells under high-glucose conditions; exogenous ceramide rescue and CERS inhibitor experiments; C3 siRNA epistasis","journal":"JCI insight","confidence":"High","confidence_rationale":"Tier 2 — clean KO + KD with defined cellular phenotype, multiple epistasis experiments, and pharmacological rescue, single lab but orthogonal methods","pmids":["36546481"],"is_preprint":false},{"year":1998,"finding":"Rainbow trout factor B (Bf-1 and Bf-2) forms the alternative pathway C3 convertase and is cleaved into Ba- and Bb-like fragments in the presence of C3, factor D, and Mg2+-EGTA, mirroring the catalytic mechanism of mammalian CFB. Trout Bf-2 also restores hemolytic activity through both the alternative and classical pathways.","method":"In vitro C3 convertase reconstitution with purified components; hemolytic activity restoration assay with Bf-depleted trout serum","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstitution of enzymatic cleavage and convertase activity with purified components","pmids":["9780182"],"is_preprint":false},{"year":2007,"finding":"Nurse shark Bf/C2 molecules contain a leader peptide, three CCP domains, one VWF-A domain, and a serine protease domain with a putative factor D/C1s/MASP cleavage site, establishing the conserved domain architecture required for CFB catalytic function. Structural analysis indicated their molecular organization is more similar to C2 than factor B.","method":"cDNA cloning, structural/sequence analysis, Southern blot, tissue expression profiling","journal":"Developmental and comparative immunology","confidence":"Medium","confidence_rationale":"Tier 3 — structural/sequence characterization without direct enzymatic functional assay","pmids":["17482263"],"is_preprint":false},{"year":1991,"finding":"The BF F allotype has lower hemolytic activity but higher protein concentration than the BF S allotype; this difference in hemolytic activity is allele-intrinsic and associated with specific MHC haplotypes, suggesting haplotype-specific regulatory or structural determinants of CFB function.","method":"Allele-specific hemolytic activity assay by agarose overlay and densitometry; crossed immunoelectrophoresis for protein quantitation; family haplotype analysis","journal":"Immunogenetics","confidence":"Medium","confidence_rationale":"Tier 2 — direct quantitative hemolytic and protein assay in human samples, single lab, moderate confidence","pmids":["1916952"],"is_preprint":false}],"current_model":"CFB (complement factor B) encodes the catalytic subunit of the alternative pathway C3 convertase (C3bBb): it binds C3b, is cleaved by factor D into Ba and Bb fragments, and the Bb fragment provides serine protease activity that cleaves C3 and C5; a pCD-associated loss-of-function variant (G252S) impairs C3b binding and cleavage, reducing complement activation and macrophage phagocytosis, while CFB deficiency protects against diabetic kidney injury by blocking NF-κB-driven ceramide synthase transcription downstream of alternative pathway activation."},"narrative":{"teleology":[{"year":1991,"claim":"Establishing that naturally occurring CFB allotypes (BF F vs. BF S) differ in intrinsic hemolytic activity showed that structural polymorphisms within CFB itself modulate complement functional output, independent of protein concentration.","evidence":"Allele-specific hemolytic activity and crossed immunoelectrophoresis in human samples with MHC haplotype analysis","pmids":["1916952"],"confidence":"Medium","gaps":["The specific amino acid differences responsible for allotype-dependent activity differences were not identified","No structural or binding data explaining the reduced hemolytic efficiency of the F allotype"]},{"year":1998,"claim":"Reconstitution of the alternative pathway C3 convertase from purified trout factor B, C3, and factor D demonstrated that CFB cleavage into Ba- and Bb-like fragments and subsequent convertase assembly is an evolutionarily conserved catalytic mechanism.","evidence":"In vitro C3 convertase reconstitution with purified components and hemolytic restoration assay in Bf-depleted trout serum","pmids":["9780182"],"confidence":"High","gaps":["The precise structural determinants of C3b–Bb interaction were not resolved","Kinetic parameters of trout vs. mammalian convertase were not compared"]},{"year":2007,"claim":"Cloning of nurse shark Bf/C2 established the deep conservation of CFB domain architecture (CCP–VWF-A–serine protease with a factor D cleavage site), anchoring the structural requirements for convertase catalytic function across jawed vertebrates.","evidence":"cDNA cloning, domain architecture analysis, and tissue expression profiling in nurse shark","pmids":["17482263"],"confidence":"Medium","gaps":["No enzymatic activity or convertase assembly was directly demonstrated for the shark protein","Functional divergence between Bf and C2 paralogs at the activity level was not tested"]},{"year":2022,"claim":"Demonstrating that CFB deficiency protects against diabetic kidney injury by blocking C3 activation, NF-κB p65-driven ceramide synthase transcription, and ceramide accumulation revealed a downstream effector pathway linking alternative complement activation to lipotoxic tissue damage.","evidence":"Cfb-knockout diabetic mice; siRNA knockdown in HK-2 cells under high glucose; C3 siRNA epistasis; exogenous ceramide rescue and CERS inhibitor experiments","pmids":["36546481"],"confidence":"High","gaps":["Whether this ceramide-mediated pathway operates in non-renal tissues is unknown","The complement activation product (C3a, C5a, or MAC) responsible for triggering NF-κB was not identified"]},{"year":2023,"claim":"Identifying that the G252S variant creates a de novo N-glycosylation site that impairs C3b binding and factor D cleavage provided a precise molecular explanation for loss-of-function complement deficiency and reduced macrophage effector activity in patients.","evidence":"Recombinant protein binding/cleavage assays with site-directed mutagenesis; flow cytometry–based macrophage phagocytosis; patient serum functional validation","pmids":["37080587"],"confidence":"High","gaps":["Structural visualization (e.g., cryo-EM) of the glycosylated variant bound to C3b is lacking","The full clinical spectrum of G252S homozygosity beyond the reported pCD cohort is not defined"]},{"year":null,"claim":"A high-resolution structural basis for how specific CFB polymorphisms modulate convertase assembly kinetics and substrate specificity (C3 vs. C5) remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No atomic-resolution structure of allotype-specific or glycosylation-mutant CFB in complex with C3b has been reported in this literature","The identity of the downstream complement effector (C3a/C5a/MAC) driving NF-κB activation in kidney tubular cells is unknown","Whether CFB proteolytic activity has substrates beyond C3 and C5 has not been explored"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,2]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[2]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,2,4]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,1,2]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[1]}],"complexes":["C3bBb (alternative pathway C3 convertase)"],"partners":["C3","CFD","C3B"],"other_free_text":[]},"mechanistic_narrative":"CFB (complement factor B) encodes the catalytic subunit of the alternative pathway C3 convertase (C3bBb), a serine protease that is cleaved by factor D into Ba and Bb fragments upon binding C3b, with the Bb fragment providing the proteolytic activity that cleaves C3 and C5 to propagate complement activation [PMID:9780182]. This domain architecture—comprising complement control protein (CCP) domains, a von Willebrand factor type A domain mediating C3b interaction, and a C-terminal serine protease domain—is deeply conserved across vertebrates [PMID:17482263]. A loss-of-function variant (G252S) that introduces a de novo glycosylation site impairs C3b binding and factor D-mediated cleavage, reducing complement-driven macrophage phagocytosis and cytokine secretion [PMID:37080587]. In diabetic kidney disease, CFB deficiency attenuates tubulointerstitial injury by blocking C3 activation and downstream NF-κB p65-mediated transcription of ceramide synthase genes, linking alternative pathway signaling to lipid-mediated tissue damage [PMID:36546481]."},"prefetch_data":{"uniprot":{"accession":"P00751","full_name":"Complement factor B","aliases":["C3/C5 convertase","Glycine-rich beta glycoprotein","GBG","PBF2","Properdin factor B"],"length_aa":764,"mass_kda":85.5,"function":"Precursor of the catalytic component of the C3 and C5 convertase complexes of the alternative pathway of the complement system, a cascade of proteins that leads to phagocytosis and breakdown of pathogens and signaling that strengthens the adaptive immune system (PubMed:3638964, PubMed:624565, PubMed:6554279, PubMed:6919543, PubMed:9748277). The alternative complement pathway acts as an amplification loop that enhances other complement pathways (classical, lectin and GZMK) by promoting formation of additional C3 and C5 convertases (PubMed:3638964, PubMed:624565, PubMed:6554279, PubMed:6919543, PubMed:9748277). CFB is cleaved and activated by CFD to generate Ba and Bb chains; Bb chain constituting the catalytic component of the C3 and C5 convertases (PubMed:6769474, PubMed:9748277) Serine protease component of the complement C3 and C5 convertase complexes of the alternative complement pathway (PubMed:30643019, PubMed:3638964, PubMed:624565, PubMed:6554279, PubMed:6919543). Following cleavage and activation by factor D (CFD), forms the C3 convertase together with complement C3b (PubMed:3638964, PubMed:624565, PubMed:6554279, PubMed:6919543, PubMed:9748277). As part of the C3 convertase, cleaves and activates C3 into C3a anaphylatoxin and C3b opsonin, the next components of the complement pathways (PubMed:3638964, PubMed:624565, PubMed:6554279, PubMed:6919543, PubMed:9748277). When an additional complement C3b molecule binds to the C3 convertase, forms the C5 convertase, which cleaves and activates C5 into C5a anaphylatoxin and C5b component of the membrane attack complex (PubMed:30643019, PubMed:624565, PubMed:6554279) Involved in proliferation and differentiation of preactivated B-lymphocytes, rapid spreading of peripheral blood monocytes, stimulation of lymphocyte blastogenesis and lysis of erythrocytes","subcellular_location":"Cell surface","url":"https://www.uniprot.org/uniprotkb/P00751/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CFB","classification":"Not Classified","n_dependent_lines":15,"n_total_lines":1208,"dependency_fraction":0.012417218543046357},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CFB","total_profiled":1310},"omim":[{"mim_id":"615561","title":"COMPLEMENT FACTOR B DEFICIENCY; CFBD","url":"https://www.omim.org/entry/615561"},{"mim_id":"615489","title":"MACULAR DEGENERATION, AGE-RELATED, 14; ARMD14","url":"https://www.omim.org/entry/615489"},{"mim_id":"613927","title":"COMPLEMENT COMPONENT 2; C2","url":"https://www.omim.org/entry/613927"},{"mim_id":"612924","title":"HEMOLYTIC UREMIC SYNDROME, ATYPICAL, SUSCEPTIBILITY TO, 4; AHUS4","url":"https://www.omim.org/entry/612924"},{"mim_id":"612923","title":"HEMOLYTIC UREMIC SYNDROME, ATYPICAL, SUSCEPTIBILITY TO, 3; AHUS3","url":"https://www.omim.org/entry/612923"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Endoplasmic reticulum","reliability":"Approved"},{"location":"Vesicles","reliability":"Approved"},{"location":"Cell Junctions","reliability":"Additional"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"liver","ntpm":2370.8}],"url":"https://www.proteinatlas.org/search/CFB"},"hgnc":{"alias_symbol":["H2-Bf"],"prev_symbol":["BFD","BF"]},"alphafold":{"accession":"P00751","domains":[{"cath_id":"2.10.70.10","chopping":"43-99","consensus_level":"high","plddt":86.7296,"start":43,"end":99},{"cath_id":"2.10.70.10","chopping":"104-218","consensus_level":"high","plddt":94.413,"start":104,"end":218},{"cath_id":"3.40.50.410","chopping":"232-247_267-468","consensus_level":"high","plddt":87.9477,"start":232,"end":468},{"cath_id":"2.40.10.120","chopping":"489-755","consensus_level":"medium","plddt":90.8607,"start":489,"end":755}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P00751","model_url":"https://alphafold.ebi.ac.uk/files/AF-P00751-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P00751-F1-predicted_aligned_error_v6.png","plddt_mean":86.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CFB","jax_strain_url":"https://www.jax.org/strain/search?query=CFB"},"sequence":{"accession":"P00751","fasta_url":"https://rest.uniprot.org/uniprotkb/P00751.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P00751/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P00751"}},"corpus_meta":[{"pmid":"16518403","id":"PMC_16518403","title":"Variation in factor B (BF) and complement component 2 (C2) genes is associated with age-related macular degeneration.","date":"2006","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/16518403","citation_count":870,"is_preprint":false},{"pmid":"7605629","id":"PMC_7605629","title":"Winged helix transcription factor BF-1 is essential for the development of the cerebral hemispheres.","date":"1995","source":"Neuron","url":"https://pubmed.ncbi.nlm.nih.gov/7605629","citation_count":488,"is_preprint":false},{"pmid":"1350202","id":"PMC_1350202","title":"Telencephalon-restricted expression of BF-1, a new member of the HNF-3/fork head gene family, in the developing rat brain.","date":"1992","source":"Neuron","url":"https://pubmed.ncbi.nlm.nih.gov/1350202","citation_count":381,"is_preprint":false},{"pmid":"36476380","id":"PMC_36476380","title":"Enhanced neutralization resistance of SARS-CoV-2 Omicron subvariants BQ.1, BQ.1.1, BA.4.6, BF.7, and BA.2.75.2.","date":"2022","source":"Cell host & microbe","url":"https://pubmed.ncbi.nlm.nih.gov/36476380","citation_count":225,"is_preprint":false},{"pmid":"83027","id":"PMC_83027","title":"A haplotype study of HLA complex with special reference to the HLA-DR series and to Bf. 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complement-driven macrophage phagocytosis and cytokine secretion. The serine at position 252 generates a de novo glycosylation site that accounts for the loss-of-function phenotype.\",\n      \"method\": \"Cell-free recombinant protein binding/cleavage assay with site-directed mutagenesis; macrophage phagocytosis by flow cytometry; serum from homozygous risk patients\",\n      \"journal\": \"Gut\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro reconstitution with mutagenesis, multiple orthogonal functional assays, confirmed in patient serum\",\n      \"pmids\": [\"37080587\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CFB deficiency in diabetic kidney disease attenuates tubulointerstitial injury by inhibiting complement alternative pathway activation, suppressing NF-κB p65-mediated transcription of ceramide synthase genes (CERS3), and thereby reducing ceramide biosynthesis. C3 knockdown abolished CFB-mediated NF-κB signaling and ceramide production, placing CFB upstream of C3 activation in this pathway.\",\n      \"method\": \"Cfb-knockout diabetic mouse model; siRNA knockdown of CFB in HK-2 cells under high-glucose conditions; exogenous ceramide rescue and CERS inhibitor experiments; C3 siRNA epistasis\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO + KD with defined cellular phenotype, multiple epistasis experiments, and pharmacological rescue, single lab but orthogonal methods\",\n      \"pmids\": [\"36546481\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Rainbow trout factor B (Bf-1 and Bf-2) forms the alternative pathway C3 convertase and is cleaved into Ba- and Bb-like fragments in the presence of C3, factor D, and Mg2+-EGTA, mirroring the catalytic mechanism of mammalian CFB. Trout Bf-2 also restores hemolytic activity through both the alternative and classical pathways.\",\n      \"method\": \"In vitro C3 convertase reconstitution with purified components; hemolytic activity restoration assay with Bf-depleted trout serum\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution of enzymatic cleavage and convertase activity with purified components\",\n      \"pmids\": [\"9780182\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Nurse shark Bf/C2 molecules contain a leader peptide, three CCP domains, one VWF-A domain, and a serine protease domain with a putative factor D/C1s/MASP cleavage site, establishing the conserved domain architecture required for CFB catalytic function. Structural analysis indicated their molecular organization is more similar to C2 than factor B.\",\n      \"method\": \"cDNA cloning, structural/sequence analysis, Southern blot, tissue expression profiling\",\n      \"journal\": \"Developmental and comparative immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — structural/sequence characterization without direct enzymatic functional assay\",\n      \"pmids\": [\"17482263\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"The BF F allotype has lower hemolytic activity but higher protein concentration than the BF S allotype; this difference in hemolytic activity is allele-intrinsic and associated with specific MHC haplotypes, suggesting haplotype-specific regulatory or structural determinants of CFB function.\",\n      \"method\": \"Allele-specific hemolytic activity assay by agarose overlay and densitometry; crossed immunoelectrophoresis for protein quantitation; family haplotype analysis\",\n      \"journal\": \"Immunogenetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct quantitative hemolytic and protein assay in human samples, single lab, moderate confidence\",\n      \"pmids\": [\"1916952\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CFB (complement factor B) encodes the catalytic subunit of the alternative pathway C3 convertase (C3bBb): it binds C3b, is cleaved by factor D into Ba and Bb fragments, and the Bb fragment provides serine protease activity that cleaves C3 and C5; a pCD-associated loss-of-function variant (G252S) impairs C3b binding and cleavage, reducing complement activation and macrophage phagocytosis, while CFB deficiency protects against diabetic kidney injury by blocking NF-κB-driven ceramide synthase transcription downstream of alternative pathway activation.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"CFB (complement factor B) encodes the catalytic subunit of the alternative pathway C3 convertase (C3bBb), a serine protease that is cleaved by factor D into Ba and Bb fragments upon binding C3b, with the Bb fragment providing the proteolytic activity that cleaves C3 and C5 to propagate complement activation [PMID:9780182]. This domain architecture—comprising complement control protein (CCP) domains, a von Willebrand factor type A domain mediating C3b interaction, and a C-terminal serine protease domain—is deeply conserved across vertebrates [PMID:17482263]. A loss-of-function variant (G252S) that introduces a de novo glycosylation site impairs C3b binding and factor D-mediated cleavage, reducing complement-driven macrophage phagocytosis and cytokine secretion [PMID:37080587]. In diabetic kidney disease, CFB deficiency attenuates tubulointerstitial injury by blocking C3 activation and downstream NF-κB p65-mediated transcription of ceramide synthase genes, linking alternative pathway signaling to lipid-mediated tissue damage [PMID:36546481].\",\n  \"teleology\": [\n    {\n      \"year\": 1991,\n      \"claim\": \"Establishing that naturally occurring CFB allotypes (BF F vs. BF S) differ in intrinsic hemolytic activity showed that structural polymorphisms within CFB itself modulate complement functional output, independent of protein concentration.\",\n      \"evidence\": \"Allele-specific hemolytic activity and crossed immunoelectrophoresis in human samples with MHC haplotype analysis\",\n      \"pmids\": [\"1916952\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"The specific amino acid differences responsible for allotype-dependent activity differences were not identified\",\n        \"No structural or binding data explaining the reduced hemolytic efficiency of the F allotype\"\n      ]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Reconstitution of the alternative pathway C3 convertase from purified trout factor B, C3, and factor D demonstrated that CFB cleavage into Ba- and Bb-like fragments and subsequent convertase assembly is an evolutionarily conserved catalytic mechanism.\",\n      \"evidence\": \"In vitro C3 convertase reconstitution with purified components and hemolytic restoration assay in Bf-depleted trout serum\",\n      \"pmids\": [\"9780182\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"The precise structural determinants of C3b–Bb interaction were not resolved\",\n        \"Kinetic parameters of trout vs. mammalian convertase were not compared\"\n      ]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Cloning of nurse shark Bf/C2 established the deep conservation of CFB domain architecture (CCP–VWF-A–serine protease with a factor D cleavage site), anchoring the structural requirements for convertase catalytic function across jawed vertebrates.\",\n      \"evidence\": \"cDNA cloning, domain architecture analysis, and tissue expression profiling in nurse shark\",\n      \"pmids\": [\"17482263\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No enzymatic activity or convertase assembly was directly demonstrated for the shark protein\",\n        \"Functional divergence between Bf and C2 paralogs at the activity level was not tested\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstrating that CFB deficiency protects against diabetic kidney injury by blocking C3 activation, NF-κB p65-driven ceramide synthase transcription, and ceramide accumulation revealed a downstream effector pathway linking alternative complement activation to lipotoxic tissue damage.\",\n      \"evidence\": \"Cfb-knockout diabetic mice; siRNA knockdown in HK-2 cells under high glucose; C3 siRNA epistasis; exogenous ceramide rescue and CERS inhibitor experiments\",\n      \"pmids\": [\"36546481\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether this ceramide-mediated pathway operates in non-renal tissues is unknown\",\n        \"The complement activation product (C3a, C5a, or MAC) responsible for triggering NF-κB was not identified\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identifying that the G252S variant creates a de novo N-glycosylation site that impairs C3b binding and factor D cleavage provided a precise molecular explanation for loss-of-function complement deficiency and reduced macrophage effector activity in patients.\",\n      \"evidence\": \"Recombinant protein binding/cleavage assays with site-directed mutagenesis; flow cytometry–based macrophage phagocytosis; patient serum functional validation\",\n      \"pmids\": [\"37080587\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural visualization (e.g., cryo-EM) of the glycosylated variant bound to C3b is lacking\",\n        \"The full clinical spectrum of G252S homozygosity beyond the reported pCD cohort is not defined\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"A high-resolution structural basis for how specific CFB polymorphisms modulate convertase assembly kinetics and substrate specificity (C3 vs. C5) remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No atomic-resolution structure of allotype-specific or glycosylation-mutant CFB in complex with C3b has been reported in this literature\",\n        \"The identity of the downstream complement effector (C3a/C5a/MAC) driving NF-κB activation in kidney tubular cells is unknown\",\n        \"Whether CFB proteolytic activity has substrates beyond C3 and C5 has not been explored\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 2, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"complexes\": [\n      \"C3bBb (alternative pathway C3 convertase)\"\n    ],\n    \"partners\": [\n      \"C3\",\n      \"CFD\",\n      \"C3b\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}