{"gene":"C8B","run_date":"2026-04-28T17:12:38","timeline":{"discoveries":[{"year":1993,"finding":"The C8B gene encodes the beta subunit of complement component C8, which in serum is non-covalently bound to the disulfide-linked alpha-gamma subunit (encoded by C8A and C8G). The C8B gene spans approximately 40 kb and is organized into 12 exons, with all intron-exon junctions following the GT-AG rule. Exon structure confirms phylogenetic relationship with C8A and C9.","method":"Genomic cloning, TaqI restriction mapping, shotgun subcloning, DNA sequencing, PCR amplification of exons","journal":"Human genetics","confidence":"Medium","confidence_rationale":"Tier 2 — gene structure determined by direct molecular cloning and sequencing; subunit assembly described from prior biochemical knowledge cited in the abstract","pmids":["8365729"],"is_preprint":false},{"year":1995,"finding":"The C8B gene is structurally homologous to C6, C7, C8A, and C9 genes, consistent with the terminal complement component family. Comparative exon structure analysis confirmed ancestral relationships among these membrane attack complex components.","method":"Comparative gene structure analysis, intron/exon boundary comparison across C6, C7, C8A, C8B, and C9 genes","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 — direct structural comparison across multiple genes with defined exon boundaries","pmids":["7730625"],"is_preprint":false},{"year":2023,"finding":"A heterozygous C8B variant (c.1625C>T; p.Thr542Ile) combined with a C2 variant results in declined activation potential for the alternative and classical complement pathways and impaired terminal pathway function. Reconstitution with purified C8 (and C2) into patient serum failed to fully normalize complement dysfunction, but addition of C3 improved hemolytic activity, and FFP fully restored complement functionality in vitro.","method":"Patient serum complement functional assays, reconstitution experiments with purified proteins, hemolytic activity assays, genetic analysis","journal":"Journal of innate immunity","confidence":"Medium","confidence_rationale":"Tier 2 — functional reconstitution in patient serum with purified components; single patient/single lab but multiple orthogonal functional assays","pmids":["36858027"],"is_preprint":false}],"current_model":"C8B encodes the beta subunit of complement component C8, a member of the terminal complement complex (MAC) family; the C8 beta chain non-covalently associates with the disulfide-linked C8 alpha-gamma subunit in serum, and loss-of-function variants in C8B impair terminal complement pathway hemolytic activity, as demonstrated by reconstitution experiments showing that C3 supplementation (but not purified C8 alone) can partially restore function in C8B-deficient patient serum."},"narrative":{"teleology":[{"year":1993,"claim":"Determining the genomic organization of C8B established that the beta subunit is encoded by a 12-exon gene whose structure reflects shared ancestry with other MAC components (C8A, C9), providing a molecular framework for understanding C8 trimer assembly.","evidence":"Genomic cloning, restriction mapping, and DNA sequencing of the full C8B locus in human genomic DNA","pmids":["8365729"],"confidence":"Medium","gaps":["No functional assay of C8B protein activity was performed in this study","Promoter and regulatory elements of C8B were not characterized","Assembly mechanism of C8 beta with the alpha-gamma disulfide-linked dimer was not directly tested"]},{"year":1995,"claim":"Comparative exon structure analysis across C6, C7, C8A, C8B, and C9 confirmed that all terminal complement component genes share a common ancestral origin, placing C8B firmly within the MAC gene family.","evidence":"Systematic comparison of intron-exon boundaries across five MAC-family genes","pmids":["7730625"],"confidence":"Medium","gaps":["Functional consequences of structural divergence among paralogs were not tested","No direct biochemical demonstration of how C8B-specific domains contribute to MAC insertion"]},{"year":2023,"claim":"Functional reconstitution experiments in a patient carrying a heterozygous C8B missense variant (p.Thr542Ile) demonstrated that C8B deficiency impairs terminal complement pathway hemolytic activity, and that restoration requires more than purified C8 alone, revealing complex interdependencies in terminal pathway function.","evidence":"Patient serum complement functional assays with reconstitution of purified C8, C2, C3, and fresh frozen plasma; hemolytic activity measurement","pmids":["36858027"],"confidence":"Medium","gaps":["Based on a single patient with a compound C8B/C2 genotype, making it difficult to isolate the C8B-specific contribution","The mechanism by which the p.Thr542Ile substitution disrupts C8 beta function was not structurally characterized","No independent replication in additional C8B-deficient individuals"]},{"year":null,"claim":"The structural basis of C8 beta association with the alpha-gamma heterodimer, the mechanism by which C8 beta contributes to MAC pore formation, and the full phenotypic spectrum of C8B deficiency in humans remain unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No high-resolution structural model of the C8 trimer with beta subunit contacts defined","No systematic genotype-phenotype study of C8B variants in complement deficiency cohorts","Mechanism of C8 beta contribution to membrane insertion of the MAC is unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,1]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,2]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,1,2]}],"complexes":["C8 (complement component 8 trimer)","Membrane attack complex (MAC)"],"partners":["C8A","C8G"],"other_free_text":[]},"mechanistic_narrative":"C8B encodes the beta subunit of complement component C8, which non-covalently associates with the disulfide-linked C8 alpha-gamma heterodimer to form the functional C8 trimer required for membrane attack complex (MAC) assembly in the terminal complement pathway [PMID:8365729]. The gene spans approximately 40 kb organized into 12 exons and is structurally homologous to C6, C7, C8A, and C9, consistent with derivation from a common ancestor of MAC components [PMID:8365729, PMID:7730625]. A heterozygous loss-of-function C8B variant impairs terminal complement pathway hemolytic activity, and reconstitution experiments demonstrate that purified C8 alone is insufficient to restore full function in C8B-deficient patient serum, whereas fresh frozen plasma fully normalizes complement activity in vitro [PMID:36858027]."},"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":24,"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":"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":"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":3,"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":5986,"output_tokens":806,"usd":0.015024},"stage2":{"model":"claude-opus-4-6","input_tokens":3986,"output_tokens":1195,"usd":0.074707},"total_usd":0.089731,"stage1_batch_id":"msgbatch_01TqNM6p6FsoMBT2jzQTwKBr","stage2_batch_id":"msgbatch_01Ya473eco8sTHbvRymQaU8o","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1993,\n      \"finding\": \"The C8B gene encodes the beta subunit of complement component C8, which in serum is non-covalently bound to the disulfide-linked alpha-gamma subunit (encoded by C8A and C8G). The C8B gene spans approximately 40 kb and is organized into 12 exons, with all intron-exon junctions following the GT-AG rule. Exon structure confirms phylogenetic relationship with C8A and C9.\",\n      \"method\": \"Genomic cloning, TaqI restriction mapping, shotgun subcloning, DNA sequencing, PCR amplification of exons\",\n      \"journal\": \"Human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — gene structure determined by direct molecular cloning and sequencing; subunit assembly described from prior biochemical knowledge cited in the abstract\",\n      \"pmids\": [\"8365729\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"The C8B gene is structurally homologous to C6, C7, C8A, and C9 genes, consistent with the terminal complement component family. Comparative exon structure analysis confirmed ancestral relationships among these membrane attack complex components.\",\n      \"method\": \"Comparative gene structure analysis, intron/exon boundary comparison across C6, C7, C8A, C8B, and C9 genes\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct structural comparison across multiple genes with defined exon boundaries\",\n      \"pmids\": [\"7730625\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"A heterozygous C8B variant (c.1625C>T; p.Thr542Ile) combined with a C2 variant results in declined activation potential for the alternative and classical complement pathways and impaired terminal pathway function. Reconstitution with purified C8 (and C2) into patient serum failed to fully normalize complement dysfunction, but addition of C3 improved hemolytic activity, and FFP fully restored complement functionality in vitro.\",\n      \"method\": \"Patient serum complement functional assays, reconstitution experiments with purified proteins, hemolytic activity assays, genetic analysis\",\n      \"journal\": \"Journal of innate immunity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional reconstitution in patient serum with purified components; single patient/single lab but multiple orthogonal functional assays\",\n      \"pmids\": [\"36858027\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"C8B encodes the beta subunit of complement component C8, a member of the terminal complement complex (MAC) family; the C8 beta chain non-covalently associates with the disulfide-linked C8 alpha-gamma subunit in serum, and loss-of-function variants in C8B impair terminal complement pathway hemolytic activity, as demonstrated by reconstitution experiments showing that C3 supplementation (but not purified C8 alone) can partially restore function in C8B-deficient patient serum.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"C8B encodes the beta subunit of complement component C8, which non-covalently associates with the disulfide-linked C8 alpha-gamma heterodimer to form the functional C8 trimer required for membrane attack complex (MAC) assembly in the terminal complement pathway [PMID:8365729]. The gene spans approximately 40 kb organized into 12 exons and is structurally homologous to C6, C7, C8A, and C9, consistent with derivation from a common ancestor of MAC components [PMID:8365729, PMID:7730625]. A heterozygous loss-of-function C8B variant impairs terminal complement pathway hemolytic activity, and reconstitution experiments demonstrate that purified C8 alone is insufficient to restore full function in C8B-deficient patient serum, whereas fresh frozen plasma fully normalizes complement activity in vitro [PMID:36858027].\",\n  \"teleology\": [\n    {\n      \"year\": 1993,\n      \"claim\": \"Determining the genomic organization of C8B established that the beta subunit is encoded by a 12-exon gene whose structure reflects shared ancestry with other MAC components (C8A, C9), providing a molecular framework for understanding C8 trimer assembly.\",\n      \"evidence\": \"Genomic cloning, restriction mapping, and DNA sequencing of the full C8B locus in human genomic DNA\",\n      \"pmids\": [\"8365729\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No functional assay of C8B protein activity was performed in this study\",\n        \"Promoter and regulatory elements of C8B were not characterized\",\n        \"Assembly mechanism of C8 beta with the alpha-gamma disulfide-linked dimer was not directly tested\"\n      ]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Comparative exon structure analysis across C6, C7, C8A, C8B, and C9 confirmed that all terminal complement component genes share a common ancestral origin, placing C8B firmly within the MAC gene family.\",\n      \"evidence\": \"Systematic comparison of intron-exon boundaries across five MAC-family genes\",\n      \"pmids\": [\"7730625\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Functional consequences of structural divergence among paralogs were not tested\",\n        \"No direct biochemical demonstration of how C8B-specific domains contribute to MAC insertion\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Functional reconstitution experiments in a patient carrying a heterozygous C8B missense variant (p.Thr542Ile) demonstrated that C8B deficiency impairs terminal complement pathway hemolytic activity, and that restoration requires more than purified C8 alone, revealing complex interdependencies in terminal pathway function.\",\n      \"evidence\": \"Patient serum complement functional assays with reconstitution of purified C8, C2, C3, and fresh frozen plasma; hemolytic activity measurement\",\n      \"pmids\": [\"36858027\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Based on a single patient with a compound C8B/C2 genotype, making it difficult to isolate the C8B-specific contribution\",\n        \"The mechanism by which the p.Thr542Ile substitution disrupts C8 beta function was not structurally characterized\",\n        \"No independent replication in additional C8B-deficient individuals\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The structural basis of C8 beta association with the alpha-gamma heterodimer, the mechanism by which C8 beta contributes to MAC pore formation, and the full phenotypic spectrum of C8B deficiency in humans remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No high-resolution structural model of the C8 trimer with beta subunit contacts defined\",\n        \"No systematic genotype-phenotype study of C8B variants in complement deficiency cohorts\",\n        \"Mechanism of C8 beta contribution to membrane insertion of the MAC is unknown\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 1, 2]}\n    ],\n    \"complexes\": [\"C8 (complement component 8 trimer)\", \"Membrane attack complex (MAC)\"],\n    \"partners\": [\"C8A\", \"C8G\"],\n    \"other_free_text\": []\n  }\n}\n```"}