NM_003620.3:c.1525G>C (p.Asp509His) is a missense variant in exon 6 of PPM1D that is absent from gnomAD v2.1 and present at very low frequency in gnomAD v4.1 (AF = 0.0086%, 139/1,613,978 alleles, 0 homozygotes; grpmax FAF = 0.0096%), meeting PM2 at supporting level.¹ Multiple lines of in silico evidence suggest a benign effect: REVEL score 0.325 (benign range), BayesDel score 0.081 (tolerated), and SpliceAI max delta 0.00 (no predicted splice impact), meeting BP4 at supporting benign level.² This variant has been reported in ClinVar as Likely benign by a single clinical laboratory (Labcorp/Invitae, 1-star, criteria provided, single submitter). This does not reach the 3-star expert panel threshold for PP5 or BP6 application.³ No variant-specific functional studies, segregation data, de novo observations, or case-control data were identified for this variant. OncoKB reports Unknown Oncogenic Effect with no variant-specific functional evidence.⁴ The variant has not been reported in COSMIC and does not lie in a statistically significant mutational hotspot per cancerhotspots.org. Using generic ACMG/AMP 2015 combination rules (PMID:25741868): PM2 (supporting) and BP4 (supporting benign) are opposing and cancel. No criteria combination threshold for pathogenic, likely pathogenic, benign, or likely benign is reached. This variant is classified as a Variant of Uncertain Significance (VUS).⁵