ALG2 (alpha-1,3/1,6-mannosyltransferase) is a mannosyltransferase that catalyzes a critical step in N-linked glycosylation by adding the second and third mannose residues to dolichol-linked oligosaccharide precursors on the cytoplasmic face of the endoplasmic reticulum 1. Specifically, ALG2 transfers alpha-1,3-mannose followed preferentially by alpha-1,6-mannose onto ManGlcNAc2-pyrophosphate-dolichol to generate the branched Man3GlcNAc2-pyrophosphate-dolichol core oligosaccharide, which serves as substrate for subsequent glycosylation enzymes 1. This sequential biosynthesis is essential for generating the 14-sugar oligosaccharide that nascent proteins receive through N-glycosylation. Beyond its canonical role in glycosylation, ALG2 functions as a calcium-sensing protein involved in cellular stress responses. Upon lysosomal calcium release triggered by osmotic or nutrient stress, ALG2 recruits ESCRT proteins to damaged lysosomes, enhancing membrane resilience and preventing rupture 2. Additionally, calcium signaling through the ALG2-ALIX complex promotes stress granule formation for cell survival during lysosomal damage 3. Pathogenic ALG2 variants cause congenital disorder of glycosylation 1I and congenital myasthenic syndrome 14 4, reflecting the critical importance of proper N-glycosylation for neuromuscular junction function and overall protein quality.