NM_004380.2:c.3215C>G (p.Ser1072Cys) is a missense variant in CREBBP. It is absent from ClinVar and absent from gnomAD v2.1, with a single heterozygous observation in gnomAD v4.1 at extremely low frequency (AF=6.19×10⁻⁷, 1/1,614,258).¹ This low population frequency meets PM2 at supporting strength.² Multiple computational predictors support a benign impact: REVEL score 0.046 (benign-leaning), BayesDel score -0.448 (predicted benign), and SpliceAI predicts no splice alteration (max Δ=0.00). This meets BP4 at supporting benign strength.³ No variant-specific functional data, de novo observations, segregation data, or published case reports are available. No same-codon pathogenic comparators exist for PM5 or PS1. The variant is not in a mutational hotspot or characterized functional domain.⁴ The variant does not qualify for PVS1 (missense, not a null variant). BP1 does not apply because missense variants are an established disease mechanism in CREBBP.⁵ With one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4), the evidence is balanced and insufficient for classification as pathogenic, likely pathogenic, likely benign, or benign. This variant is classified as a Variant of Uncertain Significance (VUS) per ACMG/AMP 2015 guidelines.⁶