(A) Predicted topology of OCA2 with albinism-associated mutations: K614E (dark blue) in a conserved cytoplasmic loop, V443I (purple) in a highly conserved luminal loop, and 5mut (light blue) consisting of 5 point mutations (V443I, M446V, I473S, N476D, N489D) in the same luminal loop. (B) mCherry-tagged WT, K614E, and V443I OCA2 localized to LAMP1-GFP-positive isolated endolysosomes (merged in yellow), while 5mut did not (scale bar = 5 μm). (C) Representative I–V relationships measured in response to voltage ramps from endolysosomes expressing WT, K614E, V443I, or from endolysosomes isolated from cells expressing 5mut OCA2. (D) Average IOCA2 current densities (pA/pF) measured at 100 mV (±s.e.m., n = 4–8 endolysosomes for each condition). (E) Melan-ink4a melanocytes expressing mCherry-tagged (red) WT, V443I, or K614E and stained with anti-tyrosinase-related protein one (TYRP1) antibodies (green). Insets, 3× magnification of boxed regions. Merged images (right) show that WT, V443I, and K614E OCA2 variants localize primarily to TYRP1-positive compartments (scale bar = 10 μm).