VPS33A is a core Sec1/Munc18 family protein of the CORVET and HOPS multi-subunit tethering complexes 1 that mediates vesicle fusion in endocytic and autophagic pathways 2. VPS33A functions in fusion of endosomes and autophagosomes with lysosomes through its recruitment to HOPS via VPS16 interaction, a mechanism essential for lysosomal trafficking 2. The protein acts as a Rab5 and Rab7 effector in early and late endosomal maturation, facilitating SNARE-mediated membrane fusion during endosome-to-lysosome conversion 3. Mutations in VPS33A cause mucopolysaccharidosis-plus syndrome (MPSPS), an autosomal recessive lysosomal storage disorder characterized by GAG accumulation without lysosomal enzyme deficiency 4. The pathogenic p.R498W mutation destabilizes VPS33A protein, leading to proteasomal degradation and reduced HOPS/CORVET complex abundance 5. This results in lysosomal over-acidification, impaired glycosphingolipid trafficking, and abnormal endosomal/lysosomal morphology 5. MPSPS presents with MPS-like features plus atypical manifestations including cardiac defects, renal dysfunction, and hematopoietic disorders, with most infantile cases fatal by 20 months 6. Proteasome inhibitors and glucosylceramide synthesis inhibitors partially correct trafficking defects in patient cells, suggesting therapeutic approaches 57.