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.

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.

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.

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.

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.