NM_006231.4:c.3386A>G (p.Asp1129Gly) in POLE is a rare missense variant with an allele frequency of 0.00025% in gnomAD v4.1 (4/1,613,948 alleles, 0 homozygotes), meeting PM2 at supporting strength.¹ This variant is absent from gnomAD v2.1 and has a grpmax filtering allele frequency of 7.9e-07, consistent with a rare variant.² The variant has been reported as Uncertain significance in ClinVar (VariationID 934060) by a single clinical laboratory (Labcorp Genetics, SCV001373503).³ This variant has previously been reported in somatic cancers (COSMIC COSV57675934, n=1). SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02).⁴ The variant is absent from the León-Castillo et al. 2020 supplementary tables of recurrent POLE endometrial carcinoma variants and does not map to any of the five established exonuclease-domain hotspot positions (P286R, V411L, S297F, A456P, S459F).⁵ In silico predictions are conflicting: REVEL score of 0.797 is in the deleterious range but BayesDel score of 0.157532 is in the benign range, and HCI prior is not available, precluding application of PP3 or BP4.⁶ OncoKB did not identify variant-specific reviewed functional evidence for p.Asp1129Gly.⁷ Overall, only one supporting-level pathogenic criterion (PM2) is met. No benign criteria are met. The evidence is insufficient for a classification beyond Variant of Uncertain Significance under the custom POLE framework (León-Castillo et al. 2020).⁸