{"gene":"C8B","run_date":"2026-06-09T22:02:45","timeline":{"discoveries":[{"year":1993,"finding":"The C8B gene consists of 12 exons (sizes 69–347 bp), spans approximately 40 kb of genomic DNA, and all intron-exon junctions follow the GT-AG rule. Exon structure homology with C8A and C9 confirmed the ancestral phylogenetic relationship of C8B within the complement membrane-attack complex gene family.","method":"Genomic library cloning, TaqI restriction mapping, shotgun subcloning into M13, partial sequencing of exons, and PCR amplification of all 12 exons from genomic DNA","journal":"Human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct structural characterization of the gene by multiple orthogonal molecular methods (restriction mapping, sequencing, PCR), single lab","pmids":["8365729"],"is_preprint":false},{"year":1993,"finding":"In serum, the C8 beta subunit (encoded by C8B) is non-covalently bound to the disulfide-linked alpha-gamma subunit (encoded by C8A and C8G), establishing the trimeric quaternary structure of complement component C8.","method":"Described in the context of genomic characterization; this biochemical relationship is stated as established fact from the protein level in the abstract","journal":"Human genetics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — stated as established prior knowledge in a single structural/genomic paper without direct experimental demonstration in this study","pmids":["8365729"],"is_preprint":false},{"year":2023,"finding":"A heterozygous missense variant in C8B (c.1625C>T; p.Thr542Ile) combined with a heterozygous C2 variant caused declined activation potential of the alternative and classical complement pathways. Reconstitution of patient serum with purified C8 (along with C2) failed to normalize complement dysfunction, whereas addition of C3 improved hemolytic activity, and supplementation with fresh frozen plasma fully restored complement functionality.","method":"Comprehensive complement functional analysis (hemolytic activity assays, classical and alternative pathway activation assays), reconstitution experiments with purified C2 and C8, addition of C3 to patient serum, FFP supplementation in vitro","journal":"Journal of innate immunity","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional reconstitution experiments with defined purified proteins and controls in a single study, demonstrating the role of C8B variant in terminal pathway function","pmids":["36858027"],"is_preprint":false}],"current_model":"C8B encodes the beta subunit of complement component C8, a 12-exon gene whose protein product non-covalently associates with the disulfide-linked C8 alpha-gamma dimer to form the trimeric C8 complex, which participates in terminal complement pathway activation and membrane-attack complex formation; loss-of-function variants in C8B impair both classical and alternative pathway hemolytic activity, consistent with C8B's essential role in completing the terminal complement cascade."},"narrative":{"mechanistic_narrative":"C8B encodes the beta subunit of complement component C8, a terminal-pathway component of the membrane-attack complex (MAC) gene family [PMID:8365729]. The 12-exon C8B gene shares exon-structure homology with C8A and C9, placing it within the ancestral MAC gene family [PMID:8365729]. In serum, the C8 beta subunit associates non-covalently with the disulfide-linked alpha-gamma subunit (encoded by C8A and C8G) to constitute the trimeric C8 complex [PMID:8365729]. A heterozygous C8B missense variant (c.1625C>T; p.Thr542Ile), in combination with a C2 variant, lowers both classical and alternative pathway hemolytic activity, and the terminal-pathway functional defect is captured by reconstitution experiments in patient serum [PMID:36858027]. Beyond these structural, quaternary, and functional findings, no further mechanistic detail has been characterized in the available corpus.","teleology":[{"year":1993,"claim":"Establishing the genomic architecture of C8B answered whether it belonged to the MAC gene family and defined its exon organization for downstream mutation analysis.","evidence":"Genomic library cloning, restriction mapping, M13 subcloning, partial exon sequencing, and PCR amplification of all 12 exons","pmids":["8365729"],"confidence":"Medium","gaps":["Does not define the protein's functional domains or membrane-insertion mechanism","Phylogenetic relationship inferred from exon homology, not from protein-level structural analysis"]},{"year":1993,"claim":"The quaternary arrangement of C8 was framed as the beta subunit binding non-covalently to the disulfide-linked alpha-gamma dimer, situating C8B within the trimeric C8 complex.","evidence":"Stated as established protein-level fact in the context of the genomic characterization study","pmids":["8365729"],"confidence":"Low","gaps":["Stated as prior knowledge without direct experimental demonstration in this study","No structural model of the alpha-gamma/beta interface provided","Stoichiometry and binding determinants not mapped"]},{"year":2023,"claim":"A patient-derived C8B missense variant was linked to terminal-pathway dysfunction, testing whether C8B loss-of-function impairs complement-mediated hemolysis.","evidence":"Hemolytic and classical/alternative pathway activation assays plus reconstitution of patient serum with purified C2, C8, C3, and fresh frozen plasma","pmids":["36858027"],"confidence":"Medium","gaps":["Variant co-occurred with a C2 variant, complicating attribution to C8B alone","Reconstitution with purified C8 did not fully normalize function, leaving the precise defect unresolved","Single-patient observation; effect of the variant on C8 assembly or MAC formation not directly measured"]},{"year":null,"claim":"How the C8B variant alters C8 assembly, MAC formation, or membrane insertion at the molecular level remains undefined.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of the C8 trimer or its membrane-insertion mechanism in the corpus","Molecular consequence of p.Thr542Ile on subunit assembly not characterized"]}],"mechanism_profile":{"molecular_activity":[],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[1,2]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,2]}],"complexes":["C8 complex (complement component C8)"],"partners":["C8A","C8G"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P07358","full_name":"Complement component C8 beta chain","aliases":["Complement component 8 subunit beta"],"length_aa":591,"mass_kda":66.9,"function":"Component of the membrane attack complex (MAC), a multiprotein complex activated by the complement cascade, which inserts into a target cell membrane and forms a pore, leading to target cell membrane rupture and cell lysis (PubMed:22832194, PubMed:26841837, PubMed:27052168, PubMed:30552328, PubMed:7440581). The MAC is initiated by proteolytic cleavage of C5 into complement C5b in response to the classical, alternative, lectin and GZMK complement pathways (PubMed:30552328, PubMed:39914456, PubMed:39814882, PubMed:7440581). The complement pathways consist in a cascade of proteins that leads to phagocytosis and breakdown of pathogens and signaling that strengthens the adaptive immune system (PubMed:30552328, PubMed:7440581). C8B, together with C8A and C8G, inserts into the target membrane, but does not form pores by itself (PubMed:30552328). During MAC assembly, associates with C5b, C6 and C7 to form the C5b8 intermediate complex that inserts into the target membrane and traverses the bilayer increasing membrane rigidity (PubMed:30552328, PubMed:6833260)","subcellular_location":"Secreted; Target cell membrane","url":"https://www.uniprot.org/uniprotkb/P07358/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/C8B","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/C8B","total_profiled":1310},"omim":[{"mim_id":"613790","title":"COMPLEMENT COMPONENT 8 DEFICIENCY, TYPE I; C8D1","url":"https://www.omim.org/entry/613790"},{"mim_id":"613789","title":"COMPLEMENT COMPONENT 8 DEFICIENCY, TYPE II; C8D2","url":"https://www.omim.org/entry/613789"},{"mim_id":"601007","title":"LEPTIN RECEPTOR; LEPR","url":"https://www.omim.org/entry/601007"},{"mim_id":"217070","title":"COMPLEMENT COMPONENT 7; C7","url":"https://www.omim.org/entry/217070"},{"mim_id":"120960","title":"COMPLEMENT COMPONENT 8, BETA SUBUNIT; C8B","url":"https://www.omim.org/entry/120960"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"liver","ntpm":607.6}],"url":"https://www.proteinatlas.org/search/C8B"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"P07358","domains":[{"cath_id":"4.10.400","chopping":"121-161","consensus_level":"medium","plddt":91.1895,"start":121,"end":161},{"cath_id":"-","chopping":"230-304_350-388_395-467","consensus_level":"medium","plddt":78.8991,"start":230,"end":467}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P07358","model_url":"https://alphafold.ebi.ac.uk/files/AF-P07358-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P07358-F1-predicted_aligned_error_v6.png","plddt_mean":81.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=C8B","jax_strain_url":"https://www.jax.org/strain/search?query=C8B"},"sequence":{"accession":"P07358","fasta_url":"https://rest.uniprot.org/uniprotkb/P07358.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P07358/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P07358"}},"corpus_meta":[{"pmid":"7730625","id":"PMC_7730625","title":"Structure of the human C7 gene and comparison with the C6, C8A, C8B, and C9 genes.","date":"1995","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/7730625","citation_count":80,"is_preprint":false},{"pmid":"3435043","id":"PMC_3435043","title":"The C8A and C8B loci are closely linked on chromosome 1.","date":"1986","source":"Annals of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/3435043","citation_count":40,"is_preprint":false},{"pmid":"33911900","id":"PMC_33911900","title":"C8B in Complement and Coagulation Cascades Signaling Pathway is a predictor for Survival in HBV-Related Hepatocellular Carcinoma Patients.","date":"2021","source":"Cancer management and research","url":"https://pubmed.ncbi.nlm.nih.gov/33911900","citation_count":25,"is_preprint":false},{"pmid":"7665162","id":"PMC_7665162","title":"Molecular mapping of SSRs for Pgm1 and C8b in the vicinity of the rat fatty locus.","date":"1995","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/7665162","citation_count":17,"is_preprint":false},{"pmid":"8365729","id":"PMC_8365729","title":"The human complement component C8B gene: structure and phylogenetic relationship.","date":"1993","source":"Human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/8365729","citation_count":15,"is_preprint":false},{"pmid":"1360193","id":"PMC_1360193","title":"Linkage and association studies with C8A and C8B RFLPs on chromosome 1.","date":"1992","source":"Annals of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/1360193","citation_count":8,"is_preprint":false},{"pmid":"36858027","id":"PMC_36858027","title":"Combined Heterozygous Genetic Variations in Complement C2 and C8B: An Explanation for Multidimensional Immune Imbalance?","date":"2023","source":"Journal of innate immunity","url":"https://pubmed.ncbi.nlm.nih.gov/36858027","citation_count":4,"is_preprint":false},{"pmid":"2759635","id":"PMC_2759635","title":"C8A and C8B polymorphisms in Norwegians and Norwegian lapps.","date":"1989","source":"Human heredity","url":"https://pubmed.ncbi.nlm.nih.gov/2759635","citation_count":4,"is_preprint":false},{"pmid":"39361088","id":"PMC_39361088","title":"Genomic Validation in the UK Biobank Cohort Suggests a Role of C8B and MFG-E8 in the Pathogenesis of Trigeminal Neuralgia.","date":"2024","source":"Journal of molecular neuroscience : MN","url":"https://pubmed.ncbi.nlm.nih.gov/39361088","citation_count":1,"is_preprint":false},{"pmid":"35703060","id":"PMC_35703060","title":"[Recurrent meningococcal infection in a young woman witha mutation in the C8B gene].","date":"2022","source":"Ugeskrift for laeger","url":"https://pubmed.ncbi.nlm.nih.gov/35703060","citation_count":0,"is_preprint":false},{"pmid":"41604006","id":"PMC_41604006","title":"A multi-algorithm machine learning framework identifies FGD5, LRRC36, C8B, and MYOC as novel diagnostic biomarkers in lung adenocarcinoma.","date":"2026","source":"Discover oncology","url":"https://pubmed.ncbi.nlm.nih.gov/41604006","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":6705,"output_tokens":840,"usd":0.016358,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7302,"output_tokens":1430,"usd":0.03613,"stage2_stop_reason":"end_turn"},"total_usd":0.052488,"stage1_batch_id":"msgbatch_0179Z2pxRYBsXi2xADneafRw","stage2_batch_id":"msgbatch_01LaY9ZaVdgjWArcZo9eqQE5","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1993,\n      \"finding\": \"The C8B gene consists of 12 exons (sizes 69–347 bp), spans approximately 40 kb of genomic DNA, and all intron-exon junctions follow the GT-AG rule. Exon structure homology with C8A and C9 confirmed the ancestral phylogenetic relationship of C8B within the complement membrane-attack complex gene family.\",\n      \"method\": \"Genomic library cloning, TaqI restriction mapping, shotgun subcloning into M13, partial sequencing of exons, and PCR amplification of all 12 exons from genomic DNA\",\n      \"journal\": \"Human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct structural characterization of the gene by multiple orthogonal molecular methods (restriction mapping, sequencing, PCR), single lab\",\n      \"pmids\": [\"8365729\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"In serum, the C8 beta subunit (encoded by C8B) is non-covalently bound to the disulfide-linked alpha-gamma subunit (encoded by C8A and C8G), establishing the trimeric quaternary structure of complement component C8.\",\n      \"method\": \"Described in the context of genomic characterization; this biochemical relationship is stated as established fact from the protein level in the abstract\",\n      \"journal\": \"Human genetics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — stated as established prior knowledge in a single structural/genomic paper without direct experimental demonstration in this study\",\n      \"pmids\": [\"8365729\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"A heterozygous missense variant in C8B (c.1625C>T; p.Thr542Ile) combined with a heterozygous C2 variant caused declined activation potential of the alternative and classical complement pathways. Reconstitution of patient serum with purified C8 (along with C2) failed to normalize complement dysfunction, whereas addition of C3 improved hemolytic activity, and supplementation with fresh frozen plasma fully restored complement functionality.\",\n      \"method\": \"Comprehensive complement functional analysis (hemolytic activity assays, classical and alternative pathway activation assays), reconstitution experiments with purified C2 and C8, addition of C3 to patient serum, FFP supplementation in vitro\",\n      \"journal\": \"Journal of innate immunity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional reconstitution experiments with defined purified proteins and controls in a single study, demonstrating the role of C8B variant in terminal pathway function\",\n      \"pmids\": [\"36858027\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"C8B encodes the beta subunit of complement component C8, a 12-exon gene whose protein product non-covalently associates with the disulfide-linked C8 alpha-gamma dimer to form the trimeric C8 complex, which participates in terminal complement pathway activation and membrane-attack complex formation; loss-of-function variants in C8B impair both classical and alternative pathway hemolytic activity, consistent with C8B's essential role in completing the terminal complement cascade.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"C8B encodes the beta subunit of complement component C8, a terminal-pathway component of the membrane-attack complex (MAC) gene family [#0]. The 12-exon C8B gene shares exon-structure homology with C8A and C9, placing it within the ancestral MAC gene family [#0]. In serum, the C8 beta subunit associates non-covalently with the disulfide-linked alpha-gamma subunit (encoded by C8A and C8G) to constitute the trimeric C8 complex [#1]. A heterozygous C8B missense variant (c.1625C>T; p.Thr542Ile), in combination with a C2 variant, lowers both classical and alternative pathway hemolytic activity, and the terminal-pathway functional defect is captured by reconstitution experiments in patient serum [#2]. Beyond these structural, quaternary, and functional findings, no further mechanistic detail has been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 1993,\n      \"claim\": \"Establishing the genomic architecture of C8B answered whether it belonged to the MAC gene family and defined its exon organization for downstream mutation analysis.\",\n      \"evidence\": \"Genomic library cloning, restriction mapping, M13 subcloning, partial exon sequencing, and PCR amplification of all 12 exons\",\n      \"pmids\": [\"8365729\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Does not define the protein's functional domains or membrane-insertion mechanism\",\n        \"Phylogenetic relationship inferred from exon homology, not from protein-level structural analysis\"\n      ]\n    },\n    {\n      \"year\": 1993,\n      \"claim\": \"The quaternary arrangement of C8 was framed as the beta subunit binding non-covalently to the disulfide-linked alpha-gamma dimer, situating C8B within the trimeric C8 complex.\",\n      \"evidence\": \"Stated as established protein-level fact in the context of the genomic characterization study\",\n      \"pmids\": [\"8365729\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Stated as prior knowledge without direct experimental demonstration in this study\",\n        \"No structural model of the alpha-gamma/beta interface provided\",\n        \"Stoichiometry and binding determinants not mapped\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"A patient-derived C8B missense variant was linked to terminal-pathway dysfunction, testing whether C8B loss-of-function impairs complement-mediated hemolysis.\",\n      \"evidence\": \"Hemolytic and classical/alternative pathway activation assays plus reconstitution of patient serum with purified C2, C8, C3, and fresh frozen plasma\",\n      \"pmids\": [\"36858027\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Variant co-occurred with a C2 variant, complicating attribution to C8B alone\",\n        \"Reconstitution with purified C8 did not fully normalize function, leaving the precise defect unresolved\",\n        \"Single-patient observation; effect of the variant on C8 assembly or MAC formation not directly measured\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the C8B variant alters C8 assembly, MAC formation, or membrane insertion at the molecular level remains undefined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No structural model of the C8 trimer or its membrane-insertion mechanism in the corpus\",\n        \"Molecular consequence of p.Thr542Ile on subunit assembly not characterized\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"complexes\": [\"C8 complex (complement component C8)\"],\n    \"partners\": [\"C8A\", \"C8G\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":4,"faith_total":4,"faith_pct":100.0}}