NM_006164.4:c.101G>A (p.Arg34Gln) in NFE2L2 is a missense variant absent from all population databases (gnomAD v2.1, v4.1, gnomAD-Canada).¹ The variant is located at Arg34 in the Neh2 domain, the KEAP1-binding domain critical for NRF2 regulation. Arg34 is the most frequently mutated NRF2 residue across cancer types and lies within a statistically significant mutational hotspot.² Functional studies in HEK293T cells demonstrate that NRF2-R34Q partially escapes KEAP1-mediated repression (luciferase activity retained at ~60% vs <10% for wild-type), has extended protein half-life, and shows reduced ubiquitylation, consistent with a gain-of-function effect.³ Multiple in silico prediction tools do not predict a deleterious effect: REVEL score 0.412, BayesDel score 0.146, and SpliceAI maximum delta score 0.00.⁴ This variant has been reported in ClinVar as Uncertain significance by two clinical laboratories (GeneDx, Labcorp). No de novo observations, cosegregation data, or case-control studies are available.⁵ Applying generic ACMG/AMP 2015 combination rules (PMID:25741868), the evidence profile includes two moderate pathogenic criteria (PM1, PM2), one supporting pathogenic criterion (PS3), and one supporting benign criterion (BP4), resulting in an overall classification of Uncertain significance.⁶