CREBBP NM_004380.2:c.5671G>A (p.Gly1891Arg) is a missense variant in exon 31 of CREBBP, a gene associated with autosomal dominant Rubinstein-Taybi syndrome through haploinsufficiency and loss-of-function mechanisms.¹ The variant is absent from gnomAD v2.1 and extremely rare in gnomAD v4.1 (allele frequency 3.11e-6; 5/1,608,878 alleles; no homozygotes), meeting PM2 at supporting strength for a dominant disorder.² Multiple in silico tools do not support a deleterious effect: SpliceAI predicts no splice alteration (max delta = 0.00), REVEL score is 0.388 (below typical pathogenic threshold), and BayesDel score is -0.135549 (benign range), meeting BP4 at supporting benign strength.³ The variant is absent from ClinVar, and no published literature specifically reporting NM_004380.2:c.5671G>A was identified across five screened abstracts addressing CREBBP in germline disease contexts.⁴ No functional studies, de novo observations, co-segregation data, or case-control evidence was identified for this variant. PVS1 is not applicable as the variant is missense, not a null variant.⁵ Under generic ACMG/AMP 2015 combination rules, the applicable criteria are PM2 (supporting) and BP4 (supporting benign). These partially offset, resulting in an overall classification of Variant of Uncertain Significance (VUS).⁶ The observation of five carriers in gnomAD v4.1 (including one in the African/African American subpopulation) without homozygotes is noted; however, in the absence of individual-level phenotype data, this does not independently establish benignity. The gnomAD filtering allele frequency (grpmax FAF = 7.9e-7) confirms extreme rarity.⁷