VPS51 is a shared subunit of the GARP (Golgi-associated retrograde protein) and EARP (endosome-associated recycling protein) complexes, heterotetrameric tethering complexes that function at the trans-Golgi network and recycling endosomes respectively 1. VPS51 mediates retrograde transport from endosomes to the trans-Golgi network and promotes SNARE-dependent fusion of endosome-derived carriers, essential for acid hydrolase receptor trafficking and lysosomal biogenesis 1. The EARP complex associates with Rab4-positive endosomes to support recycling of transferrin receptor to the plasma membrane 1. VPS51 dysfunction disrupts multiple cellular processes: patient fibroblasts with VPS51 mutations exhibit altered cation-independent mannose 6-phosphate receptor distribution, lysosomal swelling, and impaired vesicular trafficking 1. A novel homozygous VPS51 variant (c.1511C>T; p.Thr504Met) causes severe neurodevelopmental disease with developmental delay, microcephaly, epilepsy, and intellectual disability, accompanied by decreased autophagy-related gene expression, disrupted mitochondrial metabolism, and increased mitochondria-lysosome contact sites 2. VPS51 mutations are associated with pontocerebellar hypoplasia 13 1. Additionally, GARP complex components including VPS51 are required for extracellular monkeypox virus formation, demonstrating roles in viral egress pathways 3.