NM_001015877.1:c.823G>A (p.Gly275Arg) in PHF6 is absent from gnomAD v2.1 and v4.1 population databases, supporting PM2.¹ Gly275 resides within the extended PHD finger domain 2 (ePHD2, residues 249-295), a functionally critical domain for PHF6 nucleolar localization and transcriptional regulation, supporting PM1 at supporting weight. The variant has been reported in ClinVar as Uncertain significance (1 clinical laboratory, SCV001142206) with maternal origin; no de novo occurrence, pathogenic assertion, or functional evidence was identified.² No pathogenic missense comparator at codon 275, no case-control data, no cosegregation data, and no functional studies were identified, leaving PS1, PS4, PS5, PP1, PS3, and PM5 unmet. In silico predictions are inconclusive: BayesDel score is borderline (0.4267), SpliceAI predicts no splice impact (max delta 0.01), and REVEL is unavailable, insufficient for PP3 or BP4.³ Applying generic ACMG/AMP 2015 final combination rules (PMID:25741868), two supporting pathogenic criteria (PM1_Supporting + PM2_Supporting) are insufficient to reach Likely Pathogenic; no benign criteria are met. The variant is classified as a Variant of Uncertain Significance (VUS).⁴