This variant is absent from population databases (gnomAD v2.1, v4.1, Canada; AF=0%), meeting PM2 at moderate strength.¹ Multiple in silico predictors support a deleterious effect: REVEL score 0.922 is strongly pathogenic, and BayesDel additive score 0.549 supports deleteriousness, meeting PP3 at supporting strength.² No other pathogenic criteria were met. PVS1 is not applicable (missense variant). PS3 was not met (no functional data identified). PS1, PS4, PS5, PM1, PM5, and PP5 did not yield evidence for this variant.³ No benign criteria were met. BA1 and BS1 are not met (variant absent from population databases). BP1 is not met (missense variants are established in CREBBP disease). BP4 is not met (in silico predictors favor pathogenicity).⁴ Total evidence: 1 moderate pathogenic criterion (PM2) + 1 supporting pathogenic criterion (PP3). This does not meet the threshold for Likely Pathogenic (requires 2 moderate + 2 supporting, or 1 moderate + 4 supporting, or 1 strong + 2 supporting, etc.) per generic ACMG/AMP 2015 combination rules.⁵ The variant is classified as a Variant of Uncertain Significance (VUS). The missense substitution p.Cys1237Ser in the PHD finger domain of CREBBP, complete absence from population databases, and concordant in silico predictions warrant further investigation including functional studies, segregation analysis, and clinical correlation.⁶