MANBA encodes a lysosomal exoglycosidase that cleaves beta-linked mannose residues from N-linked glycoprotein oligosaccharides, functioning in glycoprotein catabolism and lysosomal protein modification 1. The enzyme is highly expressed in kidney tubule cells and plays critical roles in endolysosomal function, including endocytosis and autophagy pathways 1. Disease relevance is broad: homozygous loss-of-function MANBA variants cause beta-mannosidosis, a lysosomal storage disorder presenting with hearing loss and mental retardation, particularly prevalent in Central European Roma populations (c.2158-2A>G variant frequency of 3.77% in Roma carriers) 2. Heterozygous loss-of-function variants increase renal failure incidence and associate with chr4 kidney disease (CKD) susceptibility; MANBA expression is reduced in kidneys carrying CKD risk alleles, and Manba-deficient mice develop severe kidney fibrosis upon toxic injury 1. Additionally, the MS-risk polymorphism rs7665090 reduces MANBA expression and enzymatic activity in lymphocytes, correlating with lysosomal dysfunction and impaired metabolic activation 3. MANBA variants also associate with primary biliary cholangitis susceptibility through transcription factor-regulated gene expression 4 and represent candidate biomarkers in myocardial infarction pathogenesis 5. Recurrent structural alterations at the MANBA locus occur in pediatric acute lymphoblastic leukemia 6.