The PIK3CA c.2171A>G (p.Lys724Arg; p.K724R) variant has not been observed in somatic cancers in COSMIC and has not been reported in ClinVar.¹ This variant is absent from gnomAD v2.1 and gnomAD v4.1, which supports PM2 at Supporting strength under the Brain Malformations VCEP rarity rule.² Under the Brain Malformations VCEP specification, Lys724 is outside the approved PIK3CA PM1 domains at amino acids 322-483 and 797-1068, so PM1 is not met.³ Computational results were reviewed, but PP3 is not applicable for PIK3CA gain-of-function missense variants in this VCEP; SpliceAI predicts no significant splice effect with a max delta score of 0.02, REVEL is 0.399, and BayesDel is -0.142828.⁴