GALNT12 (polypeptide N-acetylgalactosaminyltransferase 12) catalyzes the initial step of O-linked oligosaccharide biosynthesis by transferring N-acetyl-D-galactosamine to serine or threonine residues on protein substrates, particularly mucin-type proteins in digestive organs. This enzymatic activity occurs in the Golgi apparatus and is essential for proper protein glycosylation. Mechanistically, GALNT12 functions through O-glycosylation of specific receptor proteins. For example, GALNT12 augments O-glycosylation of BMPR1A to activate bone morphogenetic protein (BMP) signaling 1, and influences epidermal growth factor (EGF) signaling through effects on Akt/PI3K/mTOR pathway activation 2. GALNT12 expression inversely correlates with galactose-deficient IgA1 levels, with genetic interactions observed with C1GALT1 3. Clinically, GALNT12 dysfunction associates with multiple malignancies and inflammatory conditions. Reduced GALNT12 expression suppresses prostate cancer bone metastasis by activating BMP signaling 1 and glioblastoma progression via Akt signaling 2. Conversely, deleterious germline variants exhibit higher burden in colorectal cancer cases versus controls, with multiple missense variants reducing enzymatic activity >2-fold 4, supporting GALNT12 as a moderate penetrance colorectal cancer susceptibility gene 4. Additionally, GALNT12 downregulation in endometriosis correlates with protective immune phenotypes 5. Pathogenic variants have also been identified in pancreatic cancer patients 6, highlighting GALNT12's broader role in cancer predisposition.