ARMS2 (age-related maculopathy susceptibility 2) is a gene located on chromosome 10 that plays a critical role in age-related macular degeneration (AMD) susceptibility. The gene is expressed in mitochondria and photoreceptor inner segments, where it contributes to retina homeostasis through protein binding functions 1. The A69S variant (rs10490924) in ARMS2 represents one of the strongest genetic risk factors for neovascular AMD, with homozygous risk genotypes conferring substantially higher AMD risk (OR=8.57) compared to the well-established CFH Y402H variant (OR=4.89) 2. The A69S variant demonstrates differential effects across disease subtypes, conferring stronger risk for neovascular AMD (allelic OR=3.09) than polypoidal choroidal vasculopathy (OR=2.13) 3. Functionally, ARMS2 risk variants exhibit synergistic interaction with cigarette smoking in AMD pathogenesis, suggesting involvement in common pathways including the complement system 4. Clinically, the A69S polymorphism predicts treatment response to anti-angiogenic therapy, particularly in East Asian populations, with G allele carriers showing better treatment response 5. Multiple ARMS2 variants contribute cumulatively to AMD risk beyond the primary A69S locus 6. However, the precise molecular mechanism by which ARMS2 variants confer AMD risk remains incompletely understood, with debate ongoing regarding causality versus linkage disequilibrium with nearby HTRA1 7.