AP3S2 encodes the sigma-2 subunit of the adaptor protein complex 3 (AP-3), which facilitates vesicle trafficking from the Golgi to lysosomes and synaptic terminals. While its cellular function is well-established, AP3S2 has emerged as a significant diabetes susceptibility gene through genome-wide association studies. Multiple studies have identified the rs2028299 polymorphism near AP3S2 as strongly associated with type 2 diabetes risk across diverse populations 12. The CA genotype of rs2028299 confers substantially increased diabetes risk (OR=12.60) in North Indian populations 2. This variant also shows association with gestational diabetes in Asian Indians, though not reaching statistical significance 3. Functional studies demonstrate that AP3S2 variants affect first-phase insulin secretion, suggesting the gene influences pancreatic β-cell function 4. The AP3S2 locus contains predicted microRNA target sites that overlap with potentially causal diabetes variants, indicating complex regulatory mechanisms 5. Additionally, AP3S2 polymorphisms have been associated with hepatocellular carcinoma risk in hepatitis B patients 6 and show genetic correlation with peripheral artery disease 7, suggesting broader metabolic and vascular effects beyond diabetes.