NM_006218.3:c.370C>T (p.Pro124Ser) is a missense variant in PIK3CA, a gene in which gain-of-function missense variants cause brain malformations including megalencephaly and focal cortical dysplasia.¹ This variant is absent from gnomAD v4.1 (0/1,608,782 alleles) and gnomAD v2.1, supporting PM2_Supporting under the Brain Malformations VCEP population criterion.² PIK3CA has high missense constraint (gnomAD missense z-score >3.09), meeting PP2_Supporting under the VCEP specification.³ Residue Pro124 lies within the adaptor-binding domain region, outside the VCEP Table 4 approved critical functional domains (AA 322-483 and AA 797-1068 kinase domains); PM1_Supporting is therefore not met.⁴ No functional study has directly tested P124S. PMID:22430209 tested P124L (a different missense at the same residue) in a somatic cancer context and demonstrated gain-of-function activity, but this evidence is not transferable to P124S and does not satisfy VCEP PS3 requirements.⁵ Total Tavtigian points: PM2_Supporting (+1) + PP2_Supporting (+1) = 2 points. Under the VCEP point framework (>10 Pathogenic, 6-9 Likely Pathogenic, 0-5 VUS), a score of 2 falls within the VUS range.⁶ This variant is classified as a Variant of Uncertain Significance (VUS) under the ClinGen Brain Malformations Expert Panel specifications version 1.1.0.⁷