ATP6V0A4 encodes the a4 subunit of vacuolar H+-ATPase (V-ATPase), a proton pump essential for cellular acidification 1. As a V0 domain component, ATP6V0A4 mediates ATP-dependent proton translocation across membranes, maintaining intracellular compartment pH and, when targeted to the apical plasma membrane of kidney collecting duct cells, enabling urinary acidification 1. In renal type A intercalated cells, ATP6V0A4 drives active acid secretion critical for distal urinary acidification and systemic acid-base homeostasis 2. Loss-of-function mutations in ATP6V0A4 impair proton transport efficacy, causing distal renal tubular acidosis (dRTA) characterized by inability to acidify urine below pH 5.5, often accompanied by sensorineural hearing loss 23. Conversely, a gain-of-function p.V512L mutation was recently identified that enhances V-ATPase activity, producing metabolic alkalosis with acidic urine—expanding ATP6V0A4's phenotypic spectrum 4. Beyond renal function, ATP6V0A4 participates in phagosome maturation, endosomal trafficking, and lysosomal acidification in immune cells 5. Emerging evidence suggests ATP6V0A4 dysregulation may influence cancer progression and immunotherapy responsiveness 6. Untreated dRTA from ATP6V0A4 deficiency causes rickets, nephrolithiasis, and chr7 kidney disease progression 2.