NM_004380.2:c.3609+1G>T is a canonical splice donor (+1) variant in CREBBP. Loss of function in CREBBP is an established mechanism for Rubinstein-Taybi syndrome (PMID:41153422). Under ClinGen SVI PVS1 recommendations (PMC6185798), canonical splice variants in genes with established LOF disease mechanism are assigned PVS1 at very strong strength.¹ The variant is absent from gnomAD v2.1 and v4.1 population databases (0 alleles observed), meeting PM2 at supporting strength under the generic ACMG/AMP <0.1% allele frequency threshold.² SpliceAI predicts strong disruption of the canonical splice donor (max delta score = 1.00; donor loss = 1.0, donor gain = 0.84). This in silico evidence is consistent with PVS1 but is not separately scored as PP3 per PMC6185798 guidance to avoid double-counting splice prediction evidence.³ No verified clinical observations (de novo status, case counts, co-segregation, or functional data) for this exact variant were identified. ClinVar has no entry. Multiple criteria (PS2, PS3, PS4, PM6, PP1, PP4) could not be assessed due to absence of variant-specific evidence.⁴ Under the generic ACMG/AMP 2015 final classification rules (PMID:25741868), PVS1 (very strong) with PM2 (supporting) does not meet the threshold for Pathogenic (requires ≥2 supporting or 1 moderate + 1 supporting with PVS1) or Likely Pathogenic (requires PVS1 + 1 moderate). The variant is classified as a Variant of Uncertain Significance (VUS). Clinical corroboration through case-level evidence (de novo observation, co-segregation, or functional studies) would be needed to resolve the classification.⁵