CLCN7 encodes a slowly voltage-gated chloride/proton (Cl-/H+) antiporter that mediates 2Cl-/H+ exchange across lysosomal and late endosomal membranes 1. Operating as a counter-ion transporter paired with v-ATPase complexes, ClC-7 maintains intravesicular ion homeostasis and contributes to lysosomal acidification 1. The protein functions as a dimer, with conserved gating glutamate residues characteristic of antiporters 1. Loss-of-function CLCN7 mutations cause osteopetrosis through defective osteoclast bone resorption. Biallelic mutations result in autosomal recessive osteopetrosis (ARO) with variable neurodegeneration and lysosomal storage 1, while heterozygous mutations cause autosomal dominant osteopetrosis type 2 (ADO2), characterized by generalized osteosclerosis and "bone-in-bone" radiographic features, though disease penetrance is ~66% 23. Missense mutations typically reduce chloride currents through dominant-negative mechanisms 1. Paradoxically, gain-of-function CLCN7 variants cause hypopigmentation, organomegaly, and delayed myelination (HOD syndrome) without osteopetrosis 4. These mutations shift voltage-dependent gating to less positive potentials, increasing Cl- uptake and inducing pathologically enlarged lysosomes across multiple tissues 4. Currently, no disease-specific treatments exist; management focuses on monitoring complications 3.