C4B_2 encodes complement component 4B, a serum protein involved in the classical complement cascade and an HLA Class III antigen associated with the Chido/Rodgers blood group system. As a component of the complement system, C4B participates in immune activation and clearance of immune complexes. C4B gene copy number (GCN) variation is a critical genetic factor influencing disease susceptibility. Low C4B copy numbers constitute a significant risk factor for systemic lupus erythematosus (SLE), particularly juvenile-onset SLE (JSLE), where low C4B GCN showed an odds ratio of 3.26 for JSLE versus 1.13 for adult-onset SLE 1. Similarly, low C4A copy numbers (≤2 copies) and higher HERV-K insertion frequency within C4A increase SLE risk 2. However, C4 copy number diversity does not correlate with disease phenotypes, disease activity, or serum complement levels in SLE patients 2. In rheumatoid arthritis families, the rare C4B*3 variant and the extended haplotype Bw62,C4A*3,C4B*3,DR4 showed modest association with disease susceptibility 3. Gene expression profiling in familial myeloproliferative neoplasms identified C4B_2 as overexpressed, suggesting involvement in inflammatory-immune regulatory networks 4. C4B_2 represents functionally important genetic variation in complement regulation with significant immunological and disease relevance in autoimmune conditions.