NM_001238.4:c.254G>A (p.Arg85Gln) is a missense variant in CCNE1. This variant is present at extremely low frequency in population databases: gnomAD v2.1 AF=0.0064% (16/251,482 alleles), gnomAD v4.1 AF=0.0040% (65/1,614,002 alleles), with no homozygotes observed. The maximum subpopulation frequency is 0.051% in the South Asian population. These frequencies meet the PM2 threshold (<0.1%).¹ Multiple in silico prediction tools concordantly support a benign interpretation: REVEL score 0.031 (benign range), BayesDel score -0.586 (predicts benign), and SpliceAI max delta 0.00 (no predicted splicing impact). These findings meet the BP4 threshold (multiple lines of computational evidence suggest no impact).² This variant has been reported in ClinVar as Uncertain significance by a single clinical laboratory (Ambry Genetics; criteria provided, single submitter). No expert panel review or pathogenic assertion is available.³ No variant-specific functional studies, de novo observations, segregation data, or case-control evidence are available. Applying the generic ACMG/AMP 2015 combination rules (PMID:25741868): PM2 (supporting) is balanced by BP4 (supporting). Neither a pathogenic combination (requiring ≥2 supporting or ≥1 moderate + ≥1 supporting) nor a benign/likely benign combination (requiring ≥2 supporting benign or ≥1 strong benign + ≥1 supporting benign) is satisfied.⁴ Overall classification: Uncertain significance.