# NM_004333.6(BRAF):c.739T>G (p.Phe247Val)

https://sugi.bio/variant/braf-p-phe247val

## Summary

**BRAF p.Phe247Val (c.739T>G)** is classified **Likely pathogenic** in BRAF (ClinVar, Expert panel, 6 submitters; last evaluated 2019-05-10). AlphaMissense: likely pathogenic (0.9949); Absent from gnomAD v4.1; Associated with Noonan syndrome and Noonan-related syndrome.

**At a glance:** Likely pathogenic · review: Expert panel · rsID rs397516903 · 6 submitters · 4 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 likely disease-causing, submitted by 6 submitters, and is linked to Noonan syndrome and Noonan-related syndrome.

*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.*

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0019561/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.Phe247Val |
| Coding change (HGVS c.) | c.739T>G |
| MANE Select transcript | [NM_004333](https://www.ncbi.nlm.nih.gov/nuccore/NM_004333) |
| dbSNP | [rs397516903](https://www.ncbi.nlm.nih.gov/snp/rs397516903/) |
| Variant type | single nucleotide variant |
| Location | chr7:140801533-140801533 (GRCh38) |
| ClinVar | [VCV44830](https://www.ncbi.nlm.nih.gov/clinvar/variation/44830/) |

**All HGVS expressions:** `LRG_299:g.128232T>G`, `LRG_299t1:c.739T>G`, `NC_000007.13:g.140501333A>C`, `NC_000007.14:g.140801533A>C`, `NG_007873.3:g.128232T>G`, `NM_001354609.2:c.739T>G`, `NM_001374244.1:c.739T>G`, `NM_001374258.1:c.739T>G`, `NM_001378467.1:c.748T>G`, `NM_001378468.1:c.739T>G`, `NM_001378469.1:c.739T>G`, `NM_001378470.1:c.637T>G`, `NM_001378471.1:c.739T>G`, `NM_001378472.1:c.583T>G`, `NM_001378473.1:c.583T>G`, `NM_001378474.1:c.739T>G`, `NM_001378475.1:c.475T>G`, `NM_004333.6:c.739T>G`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.9949) — concordant with the pathogenic call
- REVEL 0.921 (moderately pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -15.532 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- SpliceAI predicts **acceptor loss** (Δ 0.20) — consistent with the pathogenic call
- Conservation: phyloP 11.143, GERP 3.75, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 26.6**. 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 deltas (raw): acceptor loss **0.20**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**. Largest is acceptor loss, 21 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- 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}


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. 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}

**Likely pathogenic** — review status Expert panel *(reviewed by expert panel)*, last evaluated 2019-05-10.

**Submitter consensus:** conflicting (3 Likely pathogenic, 2 Pathogenic, 1 Uncertain significance).

**Submission history:** 6 submissions (2013–2025); classifications have differed over time.

**ClinGen expert panel:** Likely Pathogenic — RASopathy VCEP (RASopathy). *Expert-panel curated (ACMG); the highest ClinVar review tier.*
**Applied ACMG criteria (met):** `PM2`, `PS4_Supporting`, `PM1`, `PP2`, `PP3`.
*Considered but not met:* `PM6`, `PS1`, `PS2`, `PS3`, `PP1`, `BS2`, `BS1`, `BS4`, `BS3`, `BP5`, `BP7`, `PM5`, `BP4`, `BP3`, `BP1`, `BP2`, `BA1`, `PM4`.
Inheritance: Autosomal dominant inheritance.

> **Curation rationale (ClinGen, verbatim):** The c.739T>G (p.Phe247Val) variant in BRAF has been identified in at least 2 independent occurrences in patients with clinical features of a RASopathy (PS4_Supporting; Partners LMM, GeneDx internal data; GTR Lab IDs 21766, 26957; ClinVar SCV000061624.5, SCV000330320.6). This variant was absent from large population studies (PM2; gnomAD, http://gnomad.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). 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). A different pathogenic missense variant (p.Phe247Leu) has been previously identified at this codon of BRAF which may indicate that this residue is critical to the function of the protein (PM5 not usable due to PM1 application; ClinVar 180784, 55793). Computational prediction tools and conservation analysis suggest that the p.Phe247Val variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for RASopathies in an autosomal dominant manner. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS4_Supporting, PM2, PM1, PP2, PP3.
*Source: https://cspec.clinicalgenome.org/cspec/ui/svi/affiliation/50021 · approved 2019-05-10 · [ClinGen Evidence Repository](https://erepo.genome.network/evrepo/ui/classification/d691f327-120d-4c5c-b56e-fbfdc3f820f3).*
*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 |
| --- | --- | --- | --- | --- |
| Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Uncertain significance | flagged submission | clinical testing | 2013-01-10 |
| ClinGen RASopathy Variant Curation Expert Panel | Likely pathogenic | reviewed by expert panel | curation | 2019-05-10 |
| Service de Génétique Moléculaire, Hôpital Robert Debré | Likely pathogenic | no assertion criteria provided | clinical testing |  |
| GeneDx | Pathogenic | criteria provided, single submitter | clinical testing | 2021-08-01 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely pathogenic | criteria provided, single submitter | clinical testing | 2025-04-02 |
| CeGaT Center for Human Genetics Tuebingen | Pathogenic | criteria provided, single submitter | clinical testing | 2022-02-01 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Noonan syndrome and Noonan-related syndrome, not specified, not provided, Cardio-facio-cutaneous syndrome, Noonan syndrome, RASopathy, Noonan's syndrome, Cardiofaciocutaneous syndrome, CFC syndrome, AllHighlyPenetrant.

## Same-residue context {#hotspot}

Residue **247** carries **2 other pathogenic ClinVar variants** — a recurrently-mutated position: [BRAF p.Phe247Leu](/variant/braf-p-phe247leu), [BRAF p.Phe247Ser](/variant/braf-p-phe247ser). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related BRAF variant pages (same residue, condition, or type): [BRAF p.Phe247Leu](/variant/braf-p-phe247leu), [BRAF p.Phe247Ser](/variant/braf-p-phe247ser), [BRAF p.Phe247Cys](/variant/braf-p-phe247cys), [BRAF p.Ala246Pro](/variant/braf-p-ala246pro), [BRAF p.Asn581Asp](/variant/braf-p-asn581asp), [BRAF p.Asp594Val](/variant/braf-p-asp594val), [BRAF p.Cys532Tyr](/variant/braf-p-cys532tyr), [BRAF p.Gln257Arg](/variant/braf-p-gln257arg).

### 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 44830). 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.*