NM_002393.4:c.1091G>T (p.Arg364Ile) is a missense variant in exon 11 of MDM4 encoding the RING finger domain. This variant is absent from large population cohorts including gnomAD v2.1, v4.1, and gnomAD-Canada, meeting PM2 at supporting strength.¹ Multiple in silico tools predict a deleterious effect: REVEL score 0.502 and BayesDel score 0.217 both exceed damaging thresholds, meeting PP3 at supporting strength. SpliceAI predicts no splicing impact (max delta 0.07).² No variant-specific functional studies, de novo observations, cosegregation data, case-control data, or ClinVar submissions were identified for this variant.³ The variant lies in the MDM4 RING finger domain (residues 290–490) which is critical for MDM2 heterodimerization and p53 regulation, but no formal mutational hotspot has been established for PM1. PVS1 is not applicable as this is a missense variant that does not fall into null variant categories under generic ClinGen SVI PVS1 framework.⁴ With PM2_Supporting and PP3_Supporting, the variant receives two supporting-level pathogenic criteria. No benign criteria are met. By generic ACMG/AMP 2015 combination rules (PMID:25741868), two supporting criteria are insufficient to reach Likely Pathogenic (which requires at least one strong criterion + two supporting, or two moderate). The variant is classified as a Variant of Uncertain Significance (VUS).⁵