BRAF p.Thr599Arg
c.1796C>G · rs121913375 · VCV280033
ClinGen expert panel — RASopathy VCEP
Pathogenic for RASopathy. Applied ACMG criteria (verbatim):
PM2 PS2_VeryStrong PS3 PS4_Moderate PM1 PP2
Curation rationale (ClinGen, verbatim)
The c.1796C>G (p.Thr599Arg) variant in BRAF was absent from large population studies (PM2; gnomad.broadinstitute.org). It was observed in 3 probands diagnosed with cardiofaciocutaneous syndrome (PS4_Moderate; PMIDs: 19206169, 28650561; Otto-von-Guericke-Universität Magdeburg internal communication). In two of these patients, as well as one proband with phenotypic features suggestive of a RASopathy but no clinical diagnosis, the variant occurred de novo; parentage was confirmed in 2 of these cases (PS2_VS; PMIDs: 19206169, 28650561; GeneDx internal data, SCV000329761.7). The variant occurs in the CR3 activation domain of BRAF, which has been defined by the ClinGen RASopathy Expert Panel as a region important for protein function (PM1; PMID 29493581). In vitro functional studies provide some evidence that the p.Thr599Arg variant may impact protein function (PS3; PMID: 19206169). Additionally, the variant is located in BRAF, 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). 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): PS2_VeryStrong, PS3, PS4_Moderate, PM1, PM2, PP2.
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.9963 | likely pathogenic ✓ concordant with ClinVar |
|---|---|---|
| REVEL | 0.693 | pathogenic-leaning |
| SaProt | LLR -13.64 | 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 12 | GERP 6.8, phastCons 1 |
| Overall | ||
| CADD | 27.8 | 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.Thr599Arg
- Coding
- c.1796C>G
- MANE Select
- NM_004333
- dbSNP
- rs121913375
- Type
- single nucleotide variant
- Location
- chr7:140753339 (GRCh38)
- Gene constraint
- LOEUF 0.237 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
- Structure
- AlphaFold pLDDT 67.87 · 135 PDB
- Residue 599
- an α-helix; the protein kinase domain; a UniProt-annotated variant site (in cfc1)
Similar variants
- BRAF p.Thr599Ile Pathogenic ★★★ same residue
- BRAF p.Thr599= Conflicting classifications of pathogenicity ★ same residue
- BRAF p.Thr599Lys Likely pathogenic ★ same residue
- BRAF p.Thr599Ala Uncertain significance ★ ⚠ 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
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-thr599arg (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown