CLCN3 encodes a strongly outwardly rectifying, electrogenic H+/Cl- exchanger that mediates chloride-proton exchange across intracellular and plasma membranes 1. The protein is highly conserved across species from yeast to humans, indicating fundamental evolutionary importance 1. CLCN3 localizes to early endosomes, synaptic vesicles, and secretory granules, where it functions in vesicular trafficking and ion homeostasis 2. The gene is primarily expressed in neuroectodermal tissues, particularly in hippocampus and olfactory regions, with developmental regulation in pulmonary epithelium 13. CLCN3 dysfunction causes severe neurodevelopmental disorders characterized by global developmental delay, intellectual disability, hypotonia, and brain structural abnormalities including hippocampal degradation 4. Both loss-of-function and de novo missense variants (such as p.Gly327Ser and p.Gly327Asp) cause disease, suggesting dominant-negative effects 4. Beyond neurology, CLCN3 is dysregulated in multiple cancer types and influences tumor microenvironment interactions through the HNRNPK/CLCN3 axis 5. In metabolic disease, Clcn3 deficiency ameliorates high-fat diet-induced obesity and attenuates adipose tissue macrophage inflammation via TLR-4/NF-κB signaling 6. These findings establish CLCN3 as a multifunctional ion transporter critical for neurological development, immune regulation, and metabolic homeostasis.