C1GALT1 (core 1 synthase, glycoprotein-N-acetylgalactosamine 3-beta-galactosyltransferase 1) is a Golgi-localized glycosyltransferase that catalyzes synthesis of the core 1 O-glycan structure (Gal-β1-3GalNAc-α1-Ser/Thr), a universal precursor for extended O-glycans on mucin-type glycoproteins 1. The enzyme requires its specific molecular chaperone Cosmc for proper folding and activity 2. C1GALT1 plays essential roles in angiogenesis, platelet production, and kidney development 1. Disruption of C1GALT1 function has dual and context-dependent roles in disease. Loss of C1GALT1 promotes aggressive pancreatic adenocarcinoma development and metastasis through increased Tn antigen expression on MUC16 3, while in Ewing sarcoma, C1GALT1 promotes disease by O-glycosylating Smoothened to stabilize Hedgehog signaling and activate EWSR1::FLI1 expression 4. Conversely, reduced C1GALT1 expression in IgA nephropathy correlates with galactose-deficient IgA1 levels 5. Germline mutations in C1GALT1C1 (encoding Cosmc) cause congenital O-glycosylation disorders presenting with immunodeficiency, thrombocytopenia, and kidney injury 2. Pan-cancer analysis reveals C1GALT1 is differentially expressed across tumor types with variable prognostic significance and immune correlations 6.