C4A_2 encodes the A isotype of complement component 4, a critical protein in the classical complement pathway involved in immune surveillance and clearance of immune complexes. The gene exhibits significant copy number variation (CNV), with individuals carrying 0-4 copies, which directly impacts disease susceptibility 1. Low C4A gene copy number (<2 copies) confers a 3.59-fold increased risk for systemic lupus erythematosus (SLE) development compared to normal/high copy numbers (≥2), with even stronger associations observed in juvenile-onset SLE 12. Mechanistically, reduced C4A gene dosage impairs complement-mediated immune complex clearance, leading to autoimmune manifestations. Clinically, patients with low C4A copy numbers experience greater disease severity, as evidenced by higher permanent organ damage scores (SLICC-DI median 1.5 vs 1.0) and increased risk of pericarditis in juvenile patients 12. Population studies reveal ethnic variation in C4A allele frequencies, with specific allotypes like C4A*3 being predominant in Korean populations 3. The C4A gene can undergo duplication events, creating extended haplotypes with multiple functional copies that influence complement activity and disease risk 4. These findings establish C4A copy number as both a genetic risk factor and potential biomarker for autoimmune disease severity.