ALG3 encodes an alpha-1,3-mannosyltransferase that catalyzes a critical step in the biosynthesis of dolichol-linked oligosaccharides, which serve as glycan precursors for protein N-linked glycosylation. Specifically, ALG3 adds the first dolichyl-derived mannose in an alpha-1,3 linkage to a pentamannosyl intermediate, generating the Man(6)GlcNAc(2)-PP-dolichol substrate for the downstream enzyme ALG9. This enzymatic activity occurs in the endoplasmic reticulum lumen and is essential for the assembly of the 14-sugar oligosaccharide that is subsequently transferred to nascent proteins by oligosaccharyltransferases. Pathogenic variants in ALG3 cause ALG3-congenital disorder of glycosylation (ALG3-CDG), a rare autosomal recessive disease characterized by severe neurologic, cardiac, musculoskeletal, and ophthalmic manifestations, with nearly half of patients dying during the neonatal period 1. Visual impairment in ALG3-CDG is most commonly associated with optic nerve hypoplasia 1. Cardiac involvement is documented in congenital disorders of glycosylation 2. Beyond monogenic CDG, ALG3 expression is elevated in multiple cancers and associates with poor prognosis. In triple-negative breast cancer, high ALG3 expression predicts unfavorable clinical features and shorter overall survival, and ALG3-mediated N-glycosylation of PD-L1 reduces anti-PD-1 immunotherapy efficacy 3. Similar roles have been identified in hepatocellular carcinoma 4 and nasopharyngeal carcinoma, where targeting ALG3 combined with gemcitabine may overcome drug resistance 5.