BRAF p.Asp594Val
c.1781A>T · rs121913338 · VCV375946
ClinGen expert panel — RASopathy VCEP
Pathogenic for RASopathy. Applied ACMG criteria (verbatim):
PM2 PS2 PS4_Moderate PM1 PP2 PP3
Curation rationale (ClinGen, verbatim)
The c.1781A>T (p.Asp594Val) variant in BRAF was absent from large population studies (PM2; gnomAD, http://gnomad.broadinstitute.org). The variant has been reported in 3 probands with clinical features of a RASopathy (PS4_Moderate; SCV000935844.1, SCV000965957.1, GeneDx internal data). In one proband, the variant was reported as de novo with confirmed parentage (PS2). The c.1781A>T (p.Asp594Val) variant is located in the CR3 activation segment of BRAF, which has been defined by the ClinGen RASopathy Expert Panel as a region important for protein function (PM1; PMID 29493581). Computational prediction tools and conservation analysis suggest that the variant may impact protein function (PP3). Finally, c.1781A>T (p.Asp594Val) 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). 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, PS4_Moderate, PM1, PM2, PP2, PP3,
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 1 | likely pathogenic ✓ concordant with ClinVar · top 7% in BRAF |
|---|---|---|
| REVEL | 0.977 | strongly pathogenic-leaning |
| SaProt | LLR -14.07 | damaging |
| ⇒ AlphaMissense, REVEL and SaProt all call this damaging. | ||
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
| Pangolin | Δ0.25 | loss · gain 0.22 · not in the SpliceAI release · independent |
| Constraint at this position | ||
| Conservation | phyloP 7.9 | GERP 6.8, phastCons 1 |
| Overall | ||
| CADD | 32.0 | 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 |
|---|---|---|---|
| Skin Melanoma | Sorafenib,Trametinib | E | Sensitivity/Response |
Variant & gene context
- Gene
- BRAF
- Protein
- p.Asp594Val
- Coding
- c.1781A>T
- MANE Select
- NM_004333
- dbSNP
- rs121913338
- Type
- single nucleotide variant
- Location
- chr7:140753354 (GRCh38)
- Gene constraint
- LOEUF 0.237 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
- Structure
- AlphaFold pLDDT 67.87 · 135 PDB
- Residue 594
- the protein kinase domain; a UniProt-annotated variant site (in nhl)
Similar variants
- BRAF p.Asp594Gly Conflicting classifications of pathogenicity ★ ⚠ same residue
- BRAF p.Asp594Glu Likely pathogenic same residue
- BRAF p.Ala246Pro Pathogenic ★★★ same condition
- BRAF p.Asn581Asp Pathogenic ★★★ same condition
- BRAF p.Cys532Tyr Likely pathogenic ★★★ same condition
- BRAF p.Gln257Arg Pathogenic ★★★ same condition
- BRAF p.Gly265Arg Likely pathogenic ★★★ same condition
- BRAF p.Gly464Glu 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-asp594val (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown