NM_203407.3:c.551A>G (p.Tyr184Cys) is a missense variant in EZHIP, a gene encoding a PRC2 inhibitory protein with a described role in posterior fossa group A ependymomas.¹ This variant is present at extremely low frequency in population databases: gnomAD v2.1 AF = 6.60×10⁻⁶ (1/151,595 alleles) and gnomAD v4.1 AF = 5.40×10⁻⁶ (3/555,183 alleles), with no homozygotes observed (PM2_Supporting).² In a functional study of EZHIP/CXorf67 in PFA ependymomas (PMID 29909548), lentiviral expression of the p.Tyr184Cys mutant in neural stem cells and HEK293 cells produced reduction in H3K27me3 levels comparable to wildtype, demonstrating that the variant retains PRC2 inhibitory activity. This constitutes PS3_Supporting in a somatic cancer context; relevance to germline disease is uncertain.³ Multiple lines of computational evidence predict a benign effect: BayesDel score of −0.923011 strongly predicts benign, and SpliceAI predicts no splicing impact (max delta = 0.01) (BP4_Supporting).⁴ The variant is absent from ClinVar and has not been classified by any clinical laboratory or expert panel.⁵ The p.Tyr184Cys substitution lies outside the characterized mutational hotspot region of EZHIP (codons 71–122) and is not located at a statistically significant cancer hotspot residue.⁶ Overall, the variant has one pathogenic supporting criterion (PS3_Supporting), one benign supporting criterion (BP4_Supporting), and one population-based supporting criterion (PM2_Supporting). The evidence is insufficient to classify the variant as pathogenic, likely pathogenic, benign, or likely benign; it remains a variant of uncertain significance.⁷