ALG8 encodes a dolichyl pyrophosphate glucosyltransferase essential for the early steps of N-linked protein glycosylation. The enzyme catalyzes addition of the second glucose residue to dolichol-linked oligosaccharide intermediates in the endoplasmic reticulum lumen, generating substrates for downstream glycosylation enzymes. This pathway is required for proper maturation and trafficking of polycystin-1 and other glycoproteins critical for cellular function. At the population level, gnomAD v4.1 classifies ALG8 as LoF-tolerant (LOEUF=0.91); this is distinct from clinical pathogenicity, as 63 ClinVar variants are classified as pathogenic or likely pathogenic. Biallelic or compound heterozygous ALG8 mutations cause congenital disorder of glycosylation type 1H (ALG8-CDG), manifesting with hypotonia, protein-losing enteropathy, hepatic dysfunction, and multisystem involvement including cardiac, ocular, and musculoskeletal abnormalities 1. Monoallelic loss-of-function variants increase risk of autosomal dominant polycystic kidney and liver disease, with ALG8 mutations identified in approximately 1.3% of multiplex polycystic kidney/liver families 2. Affected individuals typically develop mild-to-moderate kidney cysts with preserved renal function, though severe polycystic liver disease can occur 32. Recent evidence suggests ALG8 overexpression in hepatocellular carcinoma correlates with poor prognosis and may promote tumor progression via Wnt/β-catenin signaling 4, though therapeutic development remains early.