BRAF p.Val600Gly
c.1799T>G · rs113488022 · VCV40389
ClinGen expert panel — RASopathy VCEP
Pathogenic for RASopathy. Applied ACMG criteria (verbatim):
PM6 PM2 PS4_Supporting PS3 PM1 PP2 PP3
Curation rationale (ClinGen, verbatim)
The c.1799T>G (p.Val600Gly) variant in BRAF is absent from gnomAD (PM2). It has been identified in one individual with Cardiofaciocutaneous syndrome (PS4_Supporting; PMID: 20735442). It has also been reported in the literature as an unconfirmed de novo occurrence (PM6; GeneDx internal communication). In vitro functional studies provide some evidence that the p.Val600Gly variant may impact protein function (PS3; PMID: 20735442). Furthermore, the variant is in a location that 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.Val600Gly variant may impact the protein (PP3). Finally, 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): PS3, PM1, PM2, PM6, PS4_Supporting, PP3, PP2.
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.9773 | likely pathogenic ✓ concordant with ClinVar |
|---|---|---|
| REVEL | 0.925 | moderately pathogenic-leaning |
| SaProt | LLR -13.61 | 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 11 | GERP 6.8, phastCons 1 |
| Overall | ||
| CADD | 31.0 | 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.
Cancer therapy — CIViC
| Disease | Therapies | Level | Significance |
|---|---|---|---|
| Melanoma | Refametinib | C | Resistance |
| Erdheim-Chester Disease | Vemurafenib | A | Sensitivity/Response |
| Melanoma | Vemurafenib,Atezolizumab,Cobimetinib | A | Sensitivity/Response |
| Langerhans-cell Histiocytosis | Vemurafenib | B | Sensitivity/Response |
| Childhood Low-grade Glioma | Tovorafenib | A | Sensitivity/Response |
| Histiocytic Sarcoma | Dabrafenib/Trametinib Regimen | C | Sensitivity/Response |
| Anaplastic Thyroid Carcinoma | Dabrafenib/Trametinib Regimen | C | Sensitivity/Response |
| Melanoma | Encorafenib,Binimetinib | B | Sensitivity/Response |
Variant & gene context
- Gene
- BRAF
- Protein
- p.Val600Gly
- Coding
- c.1799T>G
- MANE Select
- NM_004333
- dbSNP
- rs113488022
- Type
- single nucleotide variant
- Location
- chr7:140753336 (GRCh38)
- Gene constraint
- LOEUF 0.237 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
- Structure
- AlphaFold pLDDT 67.87 · 135 PDB
- Residue 600
- an α-helix; the protein kinase domain; a UniProt-annotated variant site (in a melanoma cell line; requires 2 nucleotide substitutions); a UniProt-annotated variant site (in crc; also found in sarcoma, metastatic melanoma, ovarian serous carcinoma, pilocytic astrocytoma; somatic mutation; most common mutation; constitutive and elevated kinase activity; efficiently induces cell transformation; suppression of mutation in melanoma causes growth arrest and promotes apoptosis; loss of regulation by pmrt5)
Similar variants
- BRAF p.Val600Glu Conflicting classifications of pathogenicity ★ ⚠ same residue
- BRAF p.Val600= Likely benign ★ same residue
- BRAF p.Val600Leu Pathogenic/Likely pathogenic ★★ same residue
- BRAF p.Val600Met Likely pathogenic ★ 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-val600gly (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown