ALG3 encodes an alpha-1,3-mannosyltransferase that catalyzes a critical step in N-linked glycosylation by adding the first luminal mannose to Man(5)GlcNAc(2)-PP-dolichol, generating Man(6)GlcNAc(2)-PP-dolichol as substrate for ALG9 1. This enzyme operates within the endoplasmic reticulum during dolichol-linked oligosaccharide biosynthesis, which serves as the glycan precursor for asparagine-linked protein glycosylation [UniProt annotation]. ALG3 is also involved in broader cellular processes through protein-protein interactions with OSBP, CREB3, and LRP1, suggesting roles beyond glycosylation 2. Pathogenic ALG3 variants cause congenital disorder of glycosylation type 1D (ALG3-CDG), a rare autosomal recessive condition characterized by severe neurologic, cardiac, musculoskeletal, and ophthalmic manifestations, with nearly 50% mortality before the neonatal period 3. Visual impairment commonly results from optic nerve hypoplasia 3. Additionally, ALG3 is markedly upregulated in multiple malignancies including triple-negative breast cancer, nasopharyngeal carcinoma, and hepatocellular carcinoma, where elevated expression correlates with poor prognosis and reduced immunotherapy efficacy 456. In cancer contexts, ALG3-mediated N-glycosylation of PD-L1 and FOXD1 modulates the tumor microenvironment by reducing CD8+ T cell infiltration and enhancing regulatory T cell populations, promoting immune evasion and chemotherapy resistance 45. Thus, ALG3 represents both a disease-causing gene in glycosylation disorders and an emerging oncoimmunological biomarker.