BRAF p.Thr244Pro
c.730A>C · rs397507465 · VCV40346
ClinGen expert panel — RASopathy VCEP
Pathogenic for cardiofaciocutaneous syndrome. Applied ACMG criteria (verbatim):
PM6 PM2 PS2 PM1 PP2 PP3
Curation rationale (ClinGen, verbatim)
The c.730A>C (p.Thr244Pro) variant in BRAF has been reported in the literature as a de novo occurrence in at least 2 patients with clinical features of a RASopathy (PM6 and PS2; PMID 17551924 and 18042262). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). The variant is located in the BRAF gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID 29493581). This variant is in a location which has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of BRAF (PM1; PMID 29493581). Computational prediction tools and conservation analysis suggest that the p.Thr244Pro variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PP2, PP3, PM1, PM2, PM6, PS2.
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.9193 | likely pathogenic ✓ concordant with ClinVar |
|---|---|---|
| REVEL | 0.855 | moderately pathogenic-leaning |
| SaProt | LLR -13.67 | damaging |
| ⇒ AlphaMissense, REVEL and SaProt all call this damaging. | ||
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
| Constraint at this position | ||
| Conservation | phyloP 7.8 | GERP 3.5, phastCons 1 |
| Overall | ||
| CADD | 29.7 | PHRED · no single calibrated threshold — expert panels disagree |
AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.
Population frequency
Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.
Variant & gene context
- Gene
- BRAF
- Protein
- p.Thr244Pro
- Coding
- c.730A>C
- MANE Select
- NM_004333
- dbSNP
- rs397507465
- Type
- single nucleotide variant
- Location
- chr7:140801542 (GRCh38)
- Gene constraint
- LOEUF 0.237 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
- Structure
- AlphaFold pLDDT 67.87 · 135 PDB
- Residue 244
- a UniProt-annotated variant site (in cfc1)
Similar variants
- BRAF p.Thr244Ser Uncertain significance ★ ⚠ same residue
- BRAF p.Thr244= Likely benign ★ same residue
- BRAF p.Ala246Pro Pathogenic ★★★ same condition
- BRAF p.Asn581Asp Pathogenic ★★★ same condition
- BRAF p.Asp594Val Pathogenic ★★★ same condition
- BRAF p.Cys532Tyr Likely pathogenic ★★★ same condition
- BRAF p.Gln257Arg Pathogenic ★★★ same condition
- BRAF p.Gly265Arg Likely pathogenic ★★★ same condition
Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →
Cite Sugi Variant
Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/braf-p-thr244pro (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown