The KRAS NM_001369786.1:c.65A>G (p.Gln22Arg, p.Q22R) variant has been observed in somatic cancers in COSMIC (3 occurrences) and has been reported in ClinVar as pathogenic, including expert-panel review by the ClinGen RASopathy Variant Curation Expert Panel.¹ Different missense changes at the same KRAS codon 22, including p.Gln22Glu, p.Gln22Lys, and p.Gln22Leu, have also been reported in ClinVar as pathogenic or likely pathogenic, supporting PM5 at moderate strength.² This variant is absent from gnomAD v2.1 and gnomAD v4.1, which supports PM2 at supporting strength and is below the KRAS benign frequency thresholds for BS1 and BA1.³ Published KRAS functional studies included p.Gln22Arg among germline KRAS variants with abnormal biochemical or signaling properties, but the currently reviewed RASopathy VCEP functional-study matrix did not clearly establish a qualifying approved-assay count for PS3 assignment.⁴ Computational evidence supports a damaging missense effect, with REVEL 0.749 meeting the KRAS PP3 threshold of at least 0.7, while SpliceAI predicts no meaningful splice effect with a maximum delta score of 0.01; the BayesDel score is 0.273188.⁵