NM_000463.3(UGT1A1):c.840C>A (p.Cys280Ter)

For UGT1A1 c.840C>A (p.Cys280Ter), liver-directed gene augmentation remains the strongest mechanism-matched therapeutic direction because this nonsense allele is expected to cause severe loss of UGT1A1 function, and current augmentation programs bypass the premature stop by delivering an intact hepatic transgene.

ClinVar classifies UGT1A1 c.840C>A (p.Cys280Ter) as pathogenic. In Crigler-Najjar models, liver-directed AAV-UGT1A1 vectors produced durable bilirubin correction and survival benefit (PMID:27722180; PMID:29448836). Human translation has been demonstrated in the phase 1/2 GNT0003 study, where systemic AAV-UGT1A1 delivery reduced bilirubin and substantially lowered phototherapy burden in Crigler-Najjar syndrome (PMID:37585628; NCT:NCT03466463). Because p.Cys280Ter is a true stop-gain allele in a classic loss-of-function disease, transgene supplementation is more directly supported than codon-specific rescue at the current stage of development.

The clinical evidence is disease-level rather than specific to p.Cys280Ter, so this should be read as a mechanism-based interpretation rather than proof of allele-specific response. Treatment feasibility still depends on liver status, vector immunity, dose-related safety, and access. Re-dosing limitations and longer-term durability remain unresolved for the AAV platform.