NM_000455.5:c.580G>C (p.Asp194His) is located in exon 4 of STK11, within the protein kinase domain catalytic loop (DLKPEN motif), a critical functional domain. The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, representing coverage of over 800,000 alleles (PM2_moderate).¹ Asp194 is a statistically significant hotspot residue in the kinase active site, and no benign missense variants are observed at this codon in population databases (PM1_moderate).² Multiple in silico algorithms predict a deleterious effect: REVEL score 0.943, BayesDel score 0.524 (PP3_supporting).³ SpliceAI predicts no significant splice impact (max delta = 0.02), consistent with a missense mechanism rather than splicing disruption.⁴ The variant has been observed in somatic cancers (COSMIC COSV99045288, n=3), which is consistent with a potential oncogenic role but does not directly inform germline pathogenicity. ClinVar contains two submissions: Uncertain Significance (Invitae, SCV001518979) and Likely Pathogenic (CeGaT, SCV002498394). Neither is from an expert panel.⁵ No de novo observations, cosegregation data, or functional studies specific to p.Asp194His were identified in the literature. The absence of variant-specific functional data, segregation evidence, and case-control studies limits the certainty of classification.