ATP6V1B1 encodes the non-catalytic B1 subunit of the V1 domain of vacuolar H+-ATPase (V-ATPase), a multisubunit proton pump essential for cellular acidification 1. As a structural component of V-ATPase, ATP6V1B1 is critical for proper assembly and activity of the complex 1. In renal intercalated cells, ATP6V1B1 mediates proton secretion into urine, enabling proper urinary acidification 1. V-ATPase also acidifies intracellular compartments and, when targeted to the plasma membrane, acidifies the extracellular environment 2. Biallelic mutations in ATP6V1B1 cause autosomal recessive distal renal tubular acidosis (dRTA), characterized by impaired acid excretion and failure to acidify urine below pH 5.5 3. Mutations result in truncated, non-functional protein unable to bind substrate, preventing H+ transport 4. ATP6V1B1 mutations are classically associated with early sensorineural hearing loss; approximately 61.5% of patients with ATP6V1B1 variants experience this complication 5. Untreated dRTA causes rickets, failure to thrive in children, osteomalacia in adults, nephrolithiasis, nephrocalcinosis, and increased chr2 kidney disease risk 3. ATP6V1B1 also restricts HIV-1 entry in dendritic cells through endocytosis regulation 6, and elevated expression associates with poor prognosis and chemotherapy resistance in ovarian cancer 7.