The NM_004456.5:c.1937A>T (p.Tyr646Phe) variant in EZH2 is absent from large population databases including gnomAD v2.1 and v4.1, consistent with a rare pathogenic variant (PM2_Supporting).¹ The variant affects Tyr646 in the SET domain of EZH2, the critical catalytic domain responsible for histone H3K27 methyltransferase activity. This residue is a well-established mutational hotspot recurrently altered in B-cell lymphomas, and benign variation at this position is not observed (PM1).² Multiple independent functional studies from four publications demonstrate that the p.Tyr646Phe (also known as Y641F) alteration produces a gain-of-function effect: altered substrate specificity leading to increased H3K27 trimethylation in vitro and in vivo (Morin et al. 2010, Sneeringer et al. 2010, Yap et al. 2011), and resistance to Jak2/β-TrCP-mediated degradation resulting in enhanced protein stability (Sahraeian et al. 2014). These well-established functional assays consistently support a damaging effect on the EZH2 protein (PS3_Strong).³ In silico predictions are discordant: REVEL predicts a pathogenic effect (0.853) while BayesDel predicts a benign effect (0.139). SpliceAI predicts no splicing impact (max delta 0.01). These mixed computational predictions do not meet the threshold for either PP3 or BP4.⁴ Overall classification: Likely Pathogenic. Using generic ACMG/AMP 2015 combination rules (PMID:25741868), the evidence profile of 1 Strong (PS3) + 1 Moderate (PM1) + 1 Supporting (PM2) satisfies the Likely Pathogenic threshold (1 Strong AND 1-2 Moderate).⁵