NM_006164.4:c.100C>G (p.Arg34Gly) is a missense variant in exon 2 of NFE2L2. It is absent from gnomAD v2.1 and v4.1 population databases (PM2_Supporting).¹ The variant is located at codon 34 within the Neh2 domain (residues 16–89), the KEAP1-binding degron that is a critical and well-established functional domain. Arg34 is a statistically significant cancer hotspot residue, and other missense alterations at this codon (R34Q, R34P) are recurrently observed in NSCLC and other cancers with no benign variation at this codon (PM1).² The variant has been reported in COSMIC (COSV67960061, n=42) as a somatic mutation. OncoKB classifies it as Likely Oncogenic (somatic context). These somatic observations do not directly inform germline pathogenicity under ACMG/AMP.³ In silico predictions are equivocal: REVEL score 0.543 (borderline), BayesDel score 0.170 (low), and SpliceAI max delta 0.00. These do not meet the threshold for PP3 or BP4.⁴ No functional studies, case-control data, de novo observations, segregation data, or authoritative germline classifications are available for this variant. The majority of criteria cannot be assessed. Applying the generic ACMG/AMP 2015 combination rules: PM1 (moderate) + PM2_Supporting (supporting) = 1 moderate + 1 supporting. This is insufficient for a Likely Pathogenic classification (requires 2 moderate, or 1 strong + 1 moderate, or 1 strong + ≥2 supporting). No benign criteria are met. The variant is classified as a Variant of Uncertain Significance (VUS).⁵