B-Cell Immunity & Antibody-Mediated Disease

BANK1 scaffold protein missense variant that shifts B-cell receptor signaling toward hyperactivation, increasing risk for systemic lupus erythematosus and other B-cell-driven autoimmune diseases

Frameshift deletion in SERPING1 eliminating C1-inhibitor function — causes hereditary angioedema Type I with recurrent life-threatening swelling attacks

Frameshift deletion in SERPING1 (p.Lys390fs) abolishing C1-inhibitor production — causes hereditary angioedema Type I with recurrent life-threatening swelling attacks via uncontrolled bradykinin release

Intronic upstream variant in FCGR2A that modulates surface expression of the FcγRIIa immune receptor on myeloid cells, altering IgG immune complex clearance efficiency and autoimmune susceptibility

Upstream regulatory variant in FCRL3 with a strong eQTL effect on FCRL3 expression in B cells, contributing to susceptibility to IgA nephropathy and potentially other autoimmune conditions through altered B cell receptor signalling thresholds

Intronic variant in Complement Factor B associated with strongly elevated systemic lupus erythematosus risk through alternative complement pathway dysregulation

Regulatory variant upstream of BLK that reduces B-lymphoid tyrosine kinase expression, impairing B-cell tolerance and raising risk for SLE, Sjögren's syndrome, systemic sclerosis, and rheumatoid arthritis

Intronic branch-point variant in BANK1 that shifts isoform balance toward full-length protein with intact TIR domain, amplifying TLR-driven B-cell activation and raising risk for SLE and systemic sclerosis

Missense variant in Fc gamma receptor IIa that substitutes histidine (H131, high-affinity) for arginine (R131, low-affinity) at the IgG2-binding site, altering immune complex clearance efficiency and modulating risk for lupus nephritis, Kawasaki disease, and biologic therapy response

Kozak sequence variant at position −1 of the CD40 start codon — the C allele boosts translational efficiency, producing ~30% more CD40 protein and increasing susceptibility to Graves' disease; the T allele reduces CD40 expression and independently elevates risk for multiple sclerosis and Crohn's disease

Pathogenic missense variant in SERPING1 encoding C1-inhibitor; the Arg400Cys substitution disrupts protein folding and causes hereditary angioedema type 1 through C1-INH deficiency — heterozygous carriers develop recurrent angioedema attacks, while the rare homozygous state produces severe HAE with additional complement depletion

Intronic BLK variant in the FAM167A-BLK regulatory locus that reduces B-lymphoid kinase expression and independently raises risk for systemic lupus erythematosus and related autoimmune diseases

Missense variant in allograft inflammatory factor 1 (Iba1), a macrophage-expressed calcium-binding protein in the MHC class III region, associated with rheumatoid arthritis susceptibility and systemic sclerosis

FAM167A-BLK region regulatory variant that reduces B-lymphoid tyrosine kinase expression and confers risk for the broadest autoimmune disease spectrum of any BLK locus SNP, including SLE, RA, SSc, primary Sjögren's syndrome, APS, myositis, and Kawasaki disease

SERPINA1 intronic variant strongly associated with elevated mortality in ANCA-associated vasculitis patients; in tight linkage disequilibrium with the regulatory risk variant rs7151526

Missense variant in the TACI receptor's cysteine-rich ligand-binding domain that dominantly disrupts BAFF/APRIL signaling; the strongest non-HLA association with infection susceptibility and a known cause of common variable immunodeficiency and IgA deficiency

BANK1 ankyrin-domain missense variant that amplifies B-cell receptor signaling through altered protein-protein interactions; the G allele (Ala383) confers risk for lupus, rheumatoid arthritis, and systemic sclerosis, with RA risk requiring epistatic co-presence of BLK rs13277113

Intronic ITGAV variant associated with rheumatoid arthritis susceptibility in a family-based European study, though larger meta-analyses have not replicated the association; may tag a regulatory haplotype affecting integrin-mediated immune cell trafficking and synovial angiogenesis

Promoter variant in the ITPR3 calcium channel gene affecting NKX2.5 binding and immune cell calcium signaling, associated with lupus, Graves' disease, and rheumatoid arthritis risk

Rare missense variant in Fc gamma receptor IIIa (CD16a) causing an Arg36Ser substitution, associated with systemic lupus erythematosus susceptibility in Chinese family-based studies

Missense variant in the signal peptide of complement factor B forming the H10 protective haplotype that reduces age-related macular degeneration risk by ~50% and dampens alternative complement pathway activation

Intronic variant in CD40 regulating B-cell surface expression; the G allele drives higher CD40 levels and is shared risk across rheumatoid arthritis, SLE, Crohn's disease, and multiple sclerosis

Regulatory variant 2kb upstream of BLK that tags reduced B-lymphoid tyrosine kinase expression, raising risk for systemic lupus erythematosus and autoimmune thyroid disease, particularly in Asian populations

Intronic FCGR2A variant in linkage disequilibrium with the H131R functional polymorphism (rs1801274), tagging the high-IgG2-affinity receptor allele associated with Kawasaki disease susceptibility, autoimmune risk, and differential response to IgG2-dependent vaccines and infections

Intronic C2 variant forming the H7 protective haplotype with CFB R32Q, reducing classical complement activation and cutting AMD risk by roughly half

Missense variant in ATP8B4 converting phenylalanine to leucine at position 436, associated with systemic sclerosis risk and linked to Alzheimer's disease susceptibility through disrupted phospholipid flipping in immune and neural cell membranes

Protective missense variant in complement factor B that reduces alternative pathway C3 convertase formation, lowering AMD risk by roughly half and dampening complement-driven tissue damage

Intronic PXK variant; the G allele is a replicated GWAS risk allele for systemic lupus erythematosus in Europeans, acting through impaired receptor endocytosis and disrupted B-cell immune signalling

Regulatory variant downstream of SERPINA1 associated with increased susceptibility to ANCA-associated vasculitis (GPA/MPA) and higher mortality in AAV patients

Transmembrane domain missense variant in TACI that abolishes NF-κB signaling, impairing B-cell class switching and antibody production; associated with common variable immunodeficiency and selective IgA deficiency

Promoter variant in FCRL3 that alters NF-κB binding and elevates FCRL3 expression on B cells and regulatory T cells, increasing susceptibility to rheumatoid arthritis, Graves' disease, systemic lupus erythematosus, and Hashimoto's thyroiditis

Synonymous C3 variant associated with reduced serum complement C3 levels and increased risk for systemic lupus erythematosus through impaired complement-mediated immune complex clearance

Frameshift deletion in C2 exon 6 causing complete complement C2 deficiency, increasing risk of encapsulated bacterial infections and SLE; most common inherited complement deficiency in Europeans

Missense variant in complement component C2 forming a protective haplotype with CFB that reduces age-related macular degeneration risk by ~45-50%