ATP6AP1 is an accessory subunit of the vacuolar H+-ATPase (V-ATPase) that functions as a structural hub for V-ATPase assembly and lysosomal acidification 1. Beyond its canonical role in acidifying intracellular compartments including secretory vesicles and lysosomes 1, ATP6AP1 serves as an unconventional guanine nucleotide exchange factor (GEF) for the mTORC1 activator Rheb, promoting GTP loading through its C-terminal tri-aspartate motif 2. ATP6AP1 also regulates intracellular iron homeostasis and HIF1A signaling under aerobic conditions [UniProt]. Clinically, ATP6AP1 is relevant to multiple disease pathways: metformin's therapeutic effects depend on ATP6AP1-mediated V-ATPase inhibition and AMPK activation 3, while ATP6AP1 overexpression in luminal breast cancer promotes proliferation and tamoxifen resistance by enhancing autophagy through coordinated regulation of lysosomal acidification and autophagosome-lysosome fusion 4. ATP6AP1 mutations cause congenital disorders of glycosylation (CDG) with intellectual disability, hepatopathy, and immunodeficiency 56, with intronic variants affecting mRNA processing identified in affected patients 6.