C4A Gene: Complement C4A – Function, Mutations, and Disease Associations

The C4A gene encodes complement component 4A, a key protein of the classical and lectin complement activation pathways. C4A is part of the central complement component C4, which is cleaved into C4a and C4b fragments. C4b covalently binds to pathogen surfaces and immune complexes, facilitating opsonization and activation of the downstream complement cascade. The gene is located in the MHC class III region on chromosome 6 and exhibits copy number variation (CNV) that influences susceptibility to autoimmune diseases such as systemic lupus erythematosus (SLE) and infections. C4A also carries the Rodgers (Rg) blood group antigens.

Tissue Expression

Cell Line Expression

Hotspot Mutations

Mutation functional classification

• Complement cascade (classical pathway) – Reactome R-HSA-166663

• Complement and coagulation cascades – KEGG hsa04610

• Immune system – Reactome R-HSA-168256

Complement C4A is a 1744-amino-acid glycoprotein synthesized primarily in the liver and secreted into plasma. It is cleaved by C1s into C4a (anaphylatoxin) and C4b, which covalently attaches to target surfaces via its thioester bond. C4b then binds C2 to form the C3 convertase (C4b2a), propagating the complement cascade. C4A preferentially binds to immune complexes and protein antigens, while its isotype C4B binds to carbohydrate-rich surfaces. The protein carries the Rodgers blood group antigens. Deficiency or low copy number of C4A is a strong genetic risk factor for SLE.