CLCN6 encodes a voltage-gated chloride-proton (Cl⁻/H⁺) antiporter localized to late endosomal and lysosomal membranes, predominantly expressed in the nervous system 1. The protein mediates bidirectional exchange of chloride ions against protons, contributing to late endosomal acidification and maintaining chloride homeostasis 2. ATP binding to cytosolic CLCN6 domains enhances ion transport activity 1. CLCN6 dysfunction manifests in multiple disease contexts. Loss-of-function mutations cause neuronal ceroid lipofuscinosis (NCL), characterized by autophagy impairment, lysosomal dysfunction, and neurodegeneration 2. Conversely, gain-of-function variants disrupt autophagic flux and activate transcription factors TFEB/TFE3, leading to pathological cellular accumulation 2. Disease-associated mutations cluster around residues Y553, F317, and T520 1. Clinically, CLCN6 variants associate with cardiovascular and hematologic phenotypes. Rare coding variants reduce blood pressure and hypertension risk 3, while common variants in the MTHFR-CLCN6-NPPA-NPPB cluster associate with elevated NT-proBNP levels and preeclampsia susceptibility 45. In cancer, CLCN6 upregulation promotes prostate cancer cell proliferation and predicts biochemical recurrence 6. These findings highlight CLCN6's pleiotropic roles in lysosomal homeostasis, blood pressure regulation, and cancer biology.