NM_000455.5:c.1226G>A (p.Arg409Gln) is a missense variant in STK11, a gene associated with autosomal dominant Peutz-Jeghers syndrome.¹ This variant is present at extremely low frequency in population databases: gnomAD v2.1 allele frequency 0.0036% (7/193,536 alleles) and gnomAD v4.1 allele frequency 0.0033% (52/1,587,284 alleles), with no homozygotes observed. PM2 (supporting) is met.² Multiple computational prediction tools suggest a benign effect: REVEL score 0.122, BayesDel score -0.514, and SpliceAI max delta 0.00. BP4 (supporting) is met.³ A same-residue variant, p.Arg409Trp (R409W), was evaluated in a functional study (PMID:34849607) and was found to retain WT-like kinase activity and p53-mediated transcriptional activation, suggesting that amino acid substitution at this position may not disrupt STK11 function.⁴ The variant has been reported in ClinVar predominantly as a variant of uncertain significance (11 clinical laboratories), with 2 laboratories classifying as likely benign and 1 as benign. No expert panel review is available.⁵ This variant is observed in COSMIC in somatic cancers at low frequency (n=1), which does not provide evidence for germline pathogenicity. No variant-specific publications were identified in the reviewed literature. PMID:34849607 evaluated R409W at the same residue but did not directly study R409Q.⁶ Applying generic ACMG/AMP 2015 classification rules: one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4) are met. These offset each other, resulting in an overall classification of Uncertain Significance.⁷