NM_001126131.1:c.3436C>T (p.Arg1146Cys) is a missense variant in exon 21 of POLG, encoding the catalytic subunit of mitochondrial DNA polymerase gamma. This variant is present in gnomAD v2.1 at an overall allele frequency of 0.01874% (53/282,776 alleles, 0 homozygotes), with the highest subpopulation frequency of 0.03508% in the East Asian population, exceeding the VCEP BS1 threshold of >0.0092%.¹ The variant is absent from gnomAD v4.1 and gnomAD-Canada.² The REVEL in silico prediction score of 0.915 exceeds the VCEP threshold of >0.75 for PP3 at Supporting strength, indicating computational evidence of a deleterious effect.³ SpliceAI predicts no splicing impact (max delta score = 0.00).⁴ This variant has been reported in ClinVar (VariationID: 21313) as a Variant of Uncertain Significance by 8 clinical laboratories and as Benign by 1 clinical laboratory (review status: criteria provided, single submitter).⁵ The variant has been observed once in the COSMIC somatic cancer database (COSV51525791). Amino acid position 1146 is not located within any of the POLG functional domains specified by the VCEP (TPP binding site, heterodimer interface, heterotetramer interface, or phosphorylation loop).⁶ No de novo observations, segregation data, same-residue pathogenic comparators, or functional studies were identified for this specific variant in the available evidence. Applying the VCEP framework: BS1 (Strong benign) is met based on population frequency exceeding the gene-specific threshold; PP3 (Supporting pathogenic) is met based on REVEL score >0.75. No other criteria are met. The strong benign criterion outweighs the single supporting pathogenic criterion.⁷