# NM_004333.6(BRAF):c.1781A>T (p.Asp594Val)

https://sugi.bio/variant/braf-p-asp594val

## Summary

**BRAF p.Asp594Val (c.1781A>T)** is classified **Pathogenic** in BRAF (ClinVar, Expert panel, 3 submitters; last evaluated 2020-05-18). AlphaMissense: likely pathogenic (1); Absent from gnomAD v4.1; Associated with RASopathy.

**At a glance:** Pathogenic · review: Expert panel · rsID rs121913338 · 3 submitters · 2 linked conditions · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the BRAF gene that is considered disease-causing, submitted by 3 submitters, and is linked to RASopathy.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Clinical trials | 9 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0022213/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [BRAF](https://sugi.bio/atlas/gene/BRAF/) |
| Protein change (HGVS p.) | p.Asp594Val |
| Coding change (HGVS c.) | c.1781A>T |
| MANE Select transcript | [NM_004333](https://www.ncbi.nlm.nih.gov/nuccore/NM_004333) |
| dbSNP | [rs121913338](https://www.ncbi.nlm.nih.gov/snp/rs121913338/) |
| Variant type | single nucleotide variant |
| Location | chr7:140753354-140753354 (GRCh38) |
| ClinVar | [VCV375946](https://www.ncbi.nlm.nih.gov/clinvar/variation/375946/) |

**All HGVS expressions:** `LRG_299:g.176411A>T`, `LRG_299t1:c.1781A>T`, `NC_000007.13:g.140453154T>A`, `NC_000007.14:g.140753354T>A`, `NG_007873.3:g.176411A>T`, `NM_001354609.2:c.1781A>T`, `NM_001374244.1:c.1901A>T`, `NM_001374258.1:c.1901A>T`, `NM_001378467.1:c.1790A>T`, `NM_001378468.1:c.1781A>T`, `NM_001378469.1:c.1715A>T`, `NM_001378470.1:c.1679A>T`, `NM_001378471.1:c.1670A>T`, `NM_001378472.1:c.1625A>T`, `NM_001378473.1:c.1625A>T`, `NM_001378474.1:c.1781A>T`, `NM_001378475.1:c.1517A>T`, `NM_004333.6(BRAF):c.1781A>T`, `NM_004333.6:c.1781A>T`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- AlphaMissense **likely pathogenic** (1) — concordant with the pathogenic call
- REVEL 0.977 (strongly pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -14.073 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 7.89, GERP 6.79, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 7%** most-pathogenic-predicted substitutions in BRAF (of 4,469 modeled).
- CADD: **PHRED 32.0**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Pangolin: Δ**0.25** (loss), gain 0.22 / loss 0.25. Not in the SpliceAI release. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**BRAF** population constraint: LOEUF 0.237, pLI 1, missense-Z 4.9103; ClinGen dosage — haploinsufficiency 0, triplosensitivity 0 (0–3 scale). *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **Noonan syndrome** — Moderate (AD)
- **Noonan syndrome with multiple lentigines** — Limited (AD)
- **cardiofaciocutaneous syndrome** — Definitive (AD)
- **Costello syndrome** — Disputed (AD)

## Protein context {#protein}

Residue **594** lies in the protein kinase domain; a UniProt-annotated variant site (in nhl).

AlphaFold model confidence (whole protein): pLDDT 67.87, 31% of residues very-high.

**135 experimental structure(s)** (PDB): [1UWH](https://www.rcsb.org/structure/1UWH), [1UWJ](https://www.rcsb.org/structure/1UWJ), [2FB8](https://www.rcsb.org/structure/2FB8), [2L05](https://www.rcsb.org/structure/2L05), [3C4C](https://www.rcsb.org/structure/3C4C), [3D4Q](https://www.rcsb.org/structure/3D4Q) — incl. mutant structure 1UWJ.

## What this gene does {#gene-function}

*Describes the biological roles of BRAF (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** BRAF's established molecular role includes protein kinase activity. p.Asp594Val falls in the protein kinase domain. In Reactome, BRAF is annotated in disease pathway(s) including **Gain-of-function MRAS complexes activate RAF signaling**, **Paradoxical activation of RAF signaling by kinase inactive BRAF**.

**Disease mechanism (Reactome):** BRAF loss or alteration is curated in [Gain-of-function MRAS complexes activate RAF signaling](https://reactome.org/content/detail/R-HSA-9726842), [Paradoxical activation of RAF signaling by kinase inactive BRAF](https://reactome.org/content/detail/R-HSA-6802955), [SHOC2 M1731 mutant abolishes MRAS complex function](https://reactome.org/content/detail/R-HSA-9726840).

### Pathways affected {#pathways}

BRAF participates in **16 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Gain-of-function MRAS complexes activate RAF signaling](https://reactome.org/content/detail/R-HSA-9726842) | curated |
| ⚕ [Paradoxical activation of RAF signaling by kinase inactive BRAF](https://reactome.org/content/detail/R-HSA-6802955) | curated |
| ⚕ [SHOC2 M1731 mutant abolishes MRAS complex function](https://reactome.org/content/detail/R-HSA-9726840) | curated |
| ⚕ [Signaling by BRAF and RAF1 fusions](https://reactome.org/content/detail/R-HSA-6802952) | curated |
| ⚕ [Signaling by RAF1 mutants](https://reactome.org/content/detail/R-HSA-9656223) | curated |
| ⚕ [Signaling by high-kinase activity BRAF mutants](https://reactome.org/content/detail/R-HSA-6802948) | curated |
| ⚕ [Signaling by moderate kinase activity BRAF mutants](https://reactome.org/content/detail/R-HSA-6802946) | curated |
| ⚕ [Signaling downstream of RAS mutants](https://reactome.org/content/detail/R-HSA-9649948) | curated |
| [MAP2K and MAPK activation](https://reactome.org/content/detail/R-HSA-5674135) | curated |
| [Negative feedback regulation of MAPK pathway](https://reactome.org/content/detail/R-HSA-5674499) | curated |
| [Negative regulation of MAPK pathway](https://reactome.org/content/detail/R-HSA-5675221) | curated |
| [RAF activation](https://reactome.org/content/detail/R-HSA-5673000) | curated |
| [Spry regulation of FGF signaling](https://reactome.org/content/detail/R-HSA-1295596) | curated |
| [ARMS-mediated activation](https://reactome.org/content/detail/R-HSA-170984) | electronic |
| [Frs2-mediated activation](https://reactome.org/content/detail/R-HSA-170968) | electronic |
| [Signalling to p38 via RIT and RIN](https://reactome.org/content/detail/R-HSA-187706) | electronic |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** protein kinase activity, protein serine/threonine kinase activity, MAP kinase kinase activity, calcium ion binding, identical protein binding, scaffold protein binding.

**Biological process:** MAPK cascade, epidermal growth factor receptor signaling pathway, positive regulation of gene expression, positive regulation of D-glucose transmembrane transport, positive regulation of peptidyl-serine phosphorylation, negative regulation of apoptotic process.

## Clinical significance {#significance}

**Pathogenic** — review status Expert panel *(reviewed by expert panel)*, last evaluated 2020-05-18.

**Submitter consensus:** conflicting (2 Uncertain significance, 1 Pathogenic).

**Submission history:** 3 submissions (2018–2020); classifications have differed over time.

**ClinGen expert panel:** Pathogenic — RASopathy VCEP (RASopathy). *Expert-panel curated (ACMG); the highest ClinVar review tier.*
**Applied ACMG criteria (met):** `PM2`, `PS2`, `PS4_Moderate`, `PM1`, `PP2`, `PP3`.
Inheritance: Autosomal dominant inheritance.

> **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,
*Source: https://cspec.clinicalgenome.org/cspec/ui/svi/affiliation/50021 · approved 2020-05-18 · [ClinGen Evidence Repository](https://erepo.genome.network/evrepo/ui/classification/8d88d5d7-5d83-4298-8db6-00da7b7db528).*
*These are ClinGen's applied codes, reported verbatim — Sugi Variant does not re-tally or combine them into its own classification.*

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Service de Génétique Moléculaire, Hôpital Robert Debré | Uncertain significance | no assertion criteria provided | clinical testing |  |
| ClinGen RASopathy Variant Curation Expert Panel | Pathogenic | reviewed by expert panel | curation | 2020-05-18 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-12-15 |

## Associated conditions {#conditions}

[RASopathy](https://sugi.bio/atlas/disease/rasopathy/), [cardiofaciocutaneous syndrome](https://sugi.bio/atlas/disease/cardiofaciocutaneous-syndrome/).

**Reported phenotype names (ClinVar):** RASopathy, Cardio-facio-cutaneous syndrome, Cardiofaciocutaneous syndrome, CFC syndrome, rasopathies, Noonan spectrum disorder.

## Same-residue context {#hotspot}

Residue **594** carries **2 other pathogenic ClinVar variants** — a recurrently-mutated position: [BRAF p.Asp594Glu](/variant/braf-p-asp594glu), [BRAF p.Asp594Asn](/variant/braf-p-asp594asn). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Cancer therapy associations (CIViC) {#civic}

Curated clinical evidence for this variant from CIViC (profile *D594V*):

| Disease | Therapies | Type | Level | Significance |
| --- | --- | --- | --- | --- |
| Skin Melanoma | Sorafenib,Trametinib | Predictive | E | Sensitivity/Response |
*CIViC evidence levels A–E (A strongest). Therapy associations are context-specific — not a treatment recommendation.*

## Similar variants {#similar}

Related BRAF variant pages (same residue, condition, or type): [BRAF p.Asp594Gly](/variant/braf-p-asp594gly), [BRAF p.Asp594Glu](/variant/braf-p-asp594glu), [BRAF p.Ala246Pro](/variant/braf-p-ala246pro), [BRAF p.Asn581Asp](/variant/braf-p-asn581asp), [BRAF p.Cys532Tyr](/variant/braf-p-cys532tyr), [BRAF p.Gln257Arg](/variant/braf-p-gln257arg), [BRAF p.Gly265Arg](/variant/braf-p-gly265arg), [BRAF p.Gly464Glu](/variant/braf-p-gly464glu).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-07-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 375946). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*