NM_006231.4:c.1871A>C (p.His624Pro) is a missense variant in exon 19 of POLE, located in the C-terminal polymerase domain outside the exonuclease domain (residues ~268–471) where established pathogenic hotspot variants cluster.¹ This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, comprising over 300,000 population alleles without observation (PM2_Supporting).² The variant has been reported in ClinVar as Uncertain significance by a single clinical laboratory (Labcorp Genetics, SCV001206773), and no additional submissions from expert panels are available.³ The León-Castillo et al. 2020 custom POLE framework does not assign PM1, PS4, PP3, or BP4 to this variant, as p.His624Pro is absent from all supplementary tables (S1, S2, S3) and is not among the established exonuclease-domain hotspot or recurrent variants.⁴ Computational analyses are equivocal: REVEL score 0.712 is borderline; BayesDel score 0.151 is modest; SpliceAI predicts no splicing impact (max delta 0.01). These do not meet thresholds for PP3 or BP4 under either the custom or generic frameworks.⁵ No variant-specific functional studies, segregation data, de novo observations, case-control enrichment, or phenotype specificity data were identified in the literature or public databases.⁶ With only PM2_Supporting met, this variant does not reach the threshold for Likely Pathogenic (requires ≥2 Supporting with at least PVS1, or 1 Moderate + 4 Supporting, etc.) or Likely Benign (requires ≥2 Supporting benign). The variant remains classified as a Variant of Uncertain Significance (VUS) under ACMG/AMP 2015 combination rules.⁷