HLA-DOA encodes the alpha subunit of HLA-DO, a heterodimeric non-classical MHC class II molecule that serves as a critical modulator of antigen presentation in B cells 1. The HLA-DO heterodimer functions by interacting with HLA-DM to regulate peptide loading onto MHC class II molecules, with HLA-DO acting as an MHC class II substrate mimic that prevents HLA-DM from binding to classical MHC class II molecules, thereby altering the peptide repertoire and increasing MHC class II-CLIP complexes 2. Despite being considered relatively non-polymorphic, natural variants in HLA-DOA significantly impact protein function, with approximately 98% of individuals expressing the canonical DOA*0101 allele and others expressing variants like DOA*0102, which demonstrates gain-of-function properties 2. The gene shows remarkable evolutionary conservation across mammalian species, suggesting strong selective pressure to maintain functional structure 1. Clinically, HLA-DOA variants have been associated with disease susceptibility, including independent risk contribution to rheumatoid arthritis through a synonymous mutation affecting gene expression 3, increased transplantation-related mortality 4, and differential outcomes in hepatitis B viral infections, where gain-of-function variants are linked to viral persistence while null variants associate with viral clearance 2.