NM_000463.3(UGT1A1):c.1305-1G>A

For UGT1A1 c.1305-1G>A, liver-directed gene replacement remains the strongest mechanism-matched therapeutic direction because this canonical splice-acceptor variant is expected to cause severe loss of normal UGT1A1 function, and current UGT1A1 augmentation programs do not depend on rescuing the endogenous splice defect.

ClinVar classifies UGT1A1 c.1305-1G>A as pathogenic. In Crigler-Najjar models, liver-directed AAV-UGT1A1 vectors have shown durable bilirubin correction and survival benefit (PMID:27722180; PMID:29448836). Translational support now extends into patients: the phase 1/2 GNT0003 study reported sustained bilirubin lowering and marked reduction in phototherapy burden after systemic AAV-UGT1A1 treatment in Crigler-Najjar syndrome (PMID:37585628; NCT:NCT03466463). Because c.1305-1G>A is a canonical splice-site loss-of-function allele, supplying an intact hepatic UGT1A1 transgene is more directly supported than variant-specific splice repair approaches at the current stage of development.

The clinical evidence is disease-level rather than specific to c.1305-1G>A, so this is a mechanism-based interpretation rather than proof of variant-specific response. AAV treatment feasibility still depends on liver status, vector immunity, dose-related safety, and access to specialized centers. Durability beyond current follow-up and the practical inability to easily re-dose the same AAV platform remain important unresolved constraints.