NM_000180.4(GUCY2D):c.1343C>A (p.Ser448Ter)

For GUCY2D c.1343C>A (p.Ser448Ter), subretinal gene augmentation is a credible therapeutic strategy because this nonsense allele fits the classic loss-of-function logic that ATSN-101 is designed to bypass. The best current evidence is disease-level rather than variant-level, but the mechanism is well aligned with a null GUCY2D variant and early human data now show sustained retinal-sensitivity improvement in biallelic GUCY2D-associated LCA.

ClinVar classifies p.Ser448Ter as pathogenic, and the stop-gain mechanism is consistent with loss of retinal guanylyl cyclase 1 function. In the phase 1/2 ATSN-101 study published in The Lancet in 2024, 15 patients with biallelic GUCY2D mutations received unilateral subretinal AAV5 therapy; at the high dose, mean dark-adapted full-field stimulus testing improved by 20.3 dB in treated eyes versus 1.1 dB in untreated eyes at month 12, and three of six high-dose participants who completed mobility testing reached the maximum score in the treated eye (PMID:39244273). Natural-history work has also shown that many patients with GUCY2D-LCA retain a meaningful amount of photoreceptor structure despite severe dysfunction, which strengthens the case for gene augmentation if intervention occurs before advanced degeneration (PMID:33670772).

The evidence remains early-phase, open-label, and unilateral, so the magnitude and durability of benefit still need confirmation in larger cohorts and longer follow-up. The trial was not specific to p.Ser448Ter, and treatment success depends on residual photoreceptor integrity and surgical delivery quality rather than genotype alone. This is therefore a strong translational fit for a null GUCY2D allele, but not yet proof that every patient carrying p.Ser448Ter will achieve clinically meaningful functional rescue.