ATP6V1B2 encodes the V1B2 non-catalytic subunit of the vacuolar H+-ATPase (V-ATPase), a multisubunit proton pump complex 1. As part of the peripheral V1 complex, ATP6V1B2 coordinates with other subunits to hydrolyze ATP, enabling the membrane-integral V0 complex to translocate protons and acidify intracellular compartments including lysosomes, melanosomes, and synaptic vesicles 2. In renal intercalated cells, ATP6V1B2 can partially compensate for ATP6V1B1 deficiency under baseline conditions to mediate urinary proton secretion. Regulation occurs through phosphorylation: ABL1 kinase phosphorylates ATP6V1B2 at Y68 to facilitate V-ATPase assembly and maintain lysosomal acidification during autophagy and mitophagy 3, while SIRT1 deacetylates the protein to modulate V-ATPase function 4. Pathogenic variants cause multisystem lysosomal disorders through gain-of-function mechanisms increasing V-ATPase activity and lysosomal over-acidification 1. Dominant mutations associate with dominant deafness-onychodystrophy (DDOD) syndrome, Zimmermann-Laband syndrome (ZLS), and DOORS syndrome (deafness, onychodystrophy, osteodystrophy, developmental delay, seizures), characterized by hair cell loss, abnormal lysosomal morphology, and neurological features 56. Gene therapy restores function: AAV-mediated ATP6V1B2 delivery prevented hair cell degeneration and rescued auditory/vestibular function for ≥24 weeks 5, offering clinical potential for ATP6V1B2-associated hearing loss.