The variant NM_006218.4:c.1324G>C (p.Ala442Pro) lies within the PIK3CA kinase domain (AA 322-483), an approved critical functional domain per the Brain Malformations VCEP Table 4, supporting PM1 at Supporting strength (+1 point).¹ The variant is rare in population databases: gnomAD v2.1 reports 1 allele in 233,204 (AF 4.29e-06) and v4.1 reports 8 alleles in 1,597,406 (AF 5.01e-06). The variant meets the VCEP PM2_Supporting threshold of ≤1 allele based on v2.1 data (+1 point). gnomAD v4.1 showing 8 alleles is noted for reviewer consideration.² PIK3CA has a high missense constraint z-score in gnomAD (well above the 3.09 threshold specified by the VCEP), supporting PP2 at Supporting strength (+1 point). Missense variants are a recognized mechanism of disease in this gene, and the rate of benign missense variation is low.³ No variant-specific functional studies were identified: OncoKB reports Unknown Oncogenic Effect, COSMIC has no entry, and none of the six reviewed publications contained variant-specific functional data. PS3 is not met.⁴ No affected individuals with this variant have been reported in ClinVar (single submitter, Uncertain significance, no case-level detail) or the literature. PS4 cannot be assessed without phenotype data.⁵ Under the Brain Malformations VCEP Tavtigian point framework (page 12), the total evidence score is +3 points (PM1_Supporting +1, PM2_Supporting +1, PP2_Supporting +1), which falls in the VUS range (0 to 5 points). The variant is classified as Uncertain Significance.⁶