NM_004380.2:c.3780-2A>G is a canonical splice acceptor variant (position -2 of intron 20) in CREBBP, a gene in which loss of function is an established mechanism for autosomal-dominant Rubinstein-Taybi syndrome.¹ Under the ClinGen SVI PVS1 decision tree (PMC6185798), this canonical ±1,2 splice variant meets PVS1 at very strong strength given the established CREBBP loss-of-function disease mechanism and absence of downgrade factors.² The variant is absent from gnomAD v4.1 (0/1,591,234 alleles) and gnomAD v2.1, meeting PM2 at moderate strength.³ SpliceAI strongly predicts an effect on splicing (max delta 1.0, acceptor gain 1.0, acceptor loss 0.99), and BayesDel predicts a deleterious score of 0.66, consistent with a pathogenic splice-altering variant. These in silico predictions are not separately credited under PP3 per PVS1 stacking guidance.⁴ The variant is absent from ClinVar, and no published case reports, functional studies, or de novo reports were identified for NM_004380.2:c.3780-2A>G in the available literature.⁵ Overall, the variant meets 1 very strong criterion (PVS1) and 1 moderate criterion (PM2). No benign criteria are met. Per the ACMG/AMP 2015 scoring rubric (1 very strong + 1 moderate), this variant is classified as PATHOGENIC.⁶