ATP6V0A4 encodes the a4 subunit of vacuolar H+-ATPase (V-ATPase), a multisubunit proton pump that acidifies intracellular compartments and, when targeted to the plasma membrane in specialized cells, acidifies the extracellular environment. In the kidney, V-ATPase is essential for vectorial acid transport into urine, particularly through α-intercalated cells of the collecting duct 1. Most pathogenic variants cause loss of function, impairing urinary acidification and leading to distal renal tubular acidosis (dRTA), characterized by failure to acidify urine below pH 5.5 2. Patients with ATP6V0A4 mutations present with metabolic acidosis, hypokalemia, and hypercalciuria, often diagnosed in infancy with heightened susceptibility to kidney damage 3. Untreated dRTA can progress to nephrolithiasis, nephrocalcinosis, bone demineralization, and chr7 kidney disease. A recent 2025 study identified an atypical gain-of-function mutation (p.V512L) causing hyperacidification and metabolic alkalosis instead 4, broadening the phenotypic spectrum. Clinical management focuses on alkali supplementation, with the extended-release formulation ADV7103 recently approved by the European Medicine Agency 5. At the population level, gnomAD v4.1 classifies ATP6V0A4 as LoF-tolerant (LOEUF=0.92); this is distinct from clinical pathogenicity in disease contexts, where 85 ClinVar pathogenic variants are documented.