C4A is a complement component released upon activation of the classical complement pathway through cleavage by proteases including C1s and MASP2. Unlike the structurally similar anaphylatoxins C3a and C5a, C4A has no identified receptor and cannot signal through C3a or C5a receptors; its inflammatory effects observed in early studies were likely due to contamination with C3a or C5a rather than C4A itself. C4A functions primarily in immune complex processing, binding preferentially to immune complexes with approximately fivefold higher efficiency at this task compared to its paralog C4B 1. The gene exhibits remarkable structural and copy-number diversity across human populations, with individuals carrying between one and four C4 genes organized in different configurations 2. In systemic lupus erythematosus (SLE), C4A deficiency—typically caused by gene deletion—represents one of the strongest monogenic risk factors 3. Low C4A copy number is associated with 3.59-fold increased SLE risk and greater disease severity, including higher permanent damage scores 4. C4A variants also influence schizophrenia risk; increased brain C4A expression correlates with schizophrenia susceptibility and excessive synaptic pruning in preclinical models 5. C4A copy number variations also contribute to systemic sclerosis susceptibility, with distinct effects across autoantibody-defined subgroups 6.