AP2S1 encodes the sigma 2 subunit of adaptor protein complex 2 (AP-2), which is essential for clathrin-mediated endocytosis and membrane protein trafficking 1. AP2S1 cooperates with viral receptors like HAVCR1 for pathogen internalization through clathrin-mediated endocytosis, as demonstrated in Zika virus infection studies 1. The protein plays a critical role in calcium homeostasis by regulating calcium-sensing receptor (CaSR) trafficking and function 2. Mechanistically, AP2S1 interacts with other AP2 subunits and the CaSR to facilitate proper receptor localization and signaling 2. Heterozygous missense mutations at codon 15 (p.Arg15Cys, p.Arg15His, p.Arg15Leu) cause familial hypocalciuric hypercalcemia type 3 (FHH3), characterized by hypercalcemia, hypermagnesaemia, and hypophosphataemia 32. These mutations impair protein-protein interactions between AP2σ2 and other AP2 subunits, as well as with the CaSR 2. Mouse models demonstrate that AP2S1 mutations cause marked hypercalcemia that can be ameliorated with cinacalcet treatment 2. Additionally, AP2S1 regulates amyloid precursor protein (APP) degradation through late endosome-lysosome fusion, suggesting potential roles in Alzheimer's disease pathophysiology 4. Clinically, AP2S1 mutations represent approximately 6% of CASR-negative FHH cases 5.