CLCN5 encodes ClC-5, an electrogenic Cl⁻/H⁺ antiporter that functions as a proton-coupled chloride transporter, exchanging chloride ions against protons 1. ClC-5 localizes to endosomal and lysosomal membranes and is strongly expressed in renal proximal tubules, where it plays a critical role in endocytic protein uptake and prevention of proteinuria 2. The protein functions as part of an endosomal macromolecular complex responsible for albumin and low-molecular-weight protein reabsorption 3. Recent structural studies confirm ClC-5 interacts with TMEM9 and TMEM9B as subunits of chloride-proton antiporter complexes in early endosomes 4. CLCN5 mutations cause Dent disease 1 (also termed low molecular weight proteinuria with hypercalciuria and nephrocalcinosis), an X-linked renal tubular disorder characterized by proximal tubule dysfunction 5. The disease manifests primarily in males with low-molecular-weight proteinuria, hypercalciuria, nephrolithiasis, nephrocalcinosis, and progressive renal failure 6. Approximately 60% of Dent disease patients carry CLCN5 mutations 7. Progression to end-stage renal failure occurs in 30-80% of affected males between the 3rd and 5th decades 5. Management focuses on supportive care, treatment of hypercalciuria, and prevention of nephrolithiasis, with prognosis generally favorable in most patients.