NM_006218.3:c.2176G>A (p.Glu726Lys) is a missense variant in PIK3CA exon 14 that is absent from gnomAD population databases (PM2_Supporting).¹ The variant was identified as a confirmed de novo event in one MCAP patient and as a postzygotic mosaic mutation in two additional unrelated MCAP patients, consistent with the known gain-of-function disease mechanism (PS2_Moderate).² Four independently reported patients with megalencephaly-capillary malformation syndrome and brain overgrowth phenotypes carry this variant, with strong phenotype specificity for the disorder (PS4_Strong).³ This variant has been classified as Pathogenic by the ClinGen Brain Malformations Variant Curation Expert Panel after expert panel review (ClinVar Variation ID: 376476).⁴ Using the Brain Malformations VCEP Tavtigian point framework (Path Supporting +1, Path Moderate +2, Path Strong +4, Path Very Strong +8), the assigned criteria yield a total of 7 points, which falls within the Likely Pathogenic range (6 to 9 points). The expert panel classification of Pathogenic likely reflects additional criteria such as PM1 or PS3 applied with access to the VCEP functional assay spreadsheet and Table 2A phenotype point values.⁵