The BRAF c.736G>C (p.Ala246Pro) missense variant is absent from gnomAD population databases (PM2_Supporting).

The variant lies within exon 6, a critical functional domain defined by the ClinGen RASopathy VCEP v2.3.0 (PM1_Moderate).

The variant has been observed in multiple unrelated probands with cardio-facio-cutaneous syndrome, including the original CFC discovery cohort (Niihori et al. 2006), and is classified as Pathogenic by the ClinGen RASopathy VCEP in ClinVar with submissions from 9 clinical laboratories (PS4_Supporting).

A de novo occurrence was reported in a CFC proband with both parents negative, though without molecular confirmation of parentage (PM6_Supporting).

In silico predictions support a deleterious effect: REVEL score is 0.928, exceeding the VCEP threshold of 0.7 (PP3).

BRAF exhibits a high gnomAD missense z-score (>3.09), indicating constraint against missense variation, and missense variants are a common disease mechanism for RASopathies (PP2).

Functional studies by Wen et al. 2013 demonstrated that A246P increases Ras binding affinity relative to wild-type, consistent with a gain-of-function mechanism, though the assay is not in the VCEP-approved functional studies list (PS3 not assessed).

Under the ClinGen RASopathy VCEP v2.3.0 combination rules (Rule15: 1 moderate + ≥4 supporting → Likely Pathogenic), the variant meets PM1 (moderate) plus PM2_Supporting, PM6_Supporting, PS4_Supporting, PP2, and PP3 (5 supporting criteria), resulting in a classification of Likely Pathogenic.