ALG1 encodes a β1,4-mannosyltransferase that catalyzes the initial step of mannose addition in N-linked protein glycosylation 1. Specifically, ALG1 adds the first mannose residue to chitobiosyldiphosphodolichol on the cytoplasmic face of the endoplasmic reticulum membrane, producing Man1GlcNAc(2)-PP-dolichol, a substrate for subsequent ALG2-mediated glycosylation 2. This enzyme is essential for assembling the dolichol-linked oligosaccharide (DLO) precursor containing 14 sugars that is transferred to nascent proteins by oligosaccharyltransferases 3. The N-terminal transmembrane domain is critical for catalytic activity 3. Pathogenic variants in ALG1 cause ALG1-CDG, a rare autosomal recessive congenital disorder of glycosylation 4. ALG1-CDG presents with multi-organ involvement including seizures, developmental delay, hypotonia, and cardiac/liver involvement, with severity correlating to specific mutation locations 4. Patient fibroblasts show dysregulated proteomes, reduced high-mannose and complex/hybrid glycopeptides, and accumulated short oligosaccharides as biomarkers 5. Additionally, ALG1 deficiency promotes hepatocellular carcinoma cell migration through altered N-cadherin glycosylation, suggesting roles beyond glycosylation disorders 6. A tetrasaccharide biomarker (NeuAc-Gal-GlcNAc2) detectable in all ALG1-CDG patients provides diagnostic utility 1.