# NM_004333.6(BRAF):c.1208del (p.Pro403fs)

https://sugi.bio/variant/braf-p-pro403fs

## Summary

**BRAF p.Pro403fs (c.1208del)** is classified **Uncertain significance** in BRAF (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-06-30). No allele count reported in gnomAD v4.1 (AN 1,613,998); Associated with RASopathy.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs777474487 · 2 submitters · 1 linked condition · no allele count reported in gnomAD v4.1 (AN 1,613,998)

## For patients & families {#patients}

This is a change in the BRAF gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 2 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.Pro403fs |
| Coding change (HGVS c.) | c.1208del |
| MANE Select transcript | [NM_004333](https://www.ncbi.nlm.nih.gov/nuccore/NM_004333) |
| dbSNP | [rs777474487](https://www.ncbi.nlm.nih.gov/snp/rs777474487/) |
| Variant type | Deletion |
| Location | chr7:140783127-140783127 (GRCh38) |
| ClinVar | [VCV2077036](https://www.ncbi.nlm.nih.gov/clinvar/variation/2077036/) |

**All HGVS expressions:** `LRG_299:g.146638del`, `LRG_299t1:c.1202del`, `NC_000007.13:g.140482933del`, `NC_000007.14:g.140783133del`, `NG_007873.3:g.146638del`, `NM_001354609.2:c.1208del`, `NM_001374244.1:c.1328del`, `NM_001374258.1:c.1328del`, `NM_001378467.1:c.1217del`, `NM_001378468.1:c.1208del`, `NM_001378469.1:c.1178-36del`, `NM_001378470.1:c.1106del`, `NM_001378471.1:c.1141-44del`, `NM_001378472.1:c.1052del`, `NM_001378473.1:c.1052del`, `NM_001378474.1:c.1208del`, `NM_001378475.1:c.944del`, `NM_004333.6:c.1208del`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 3.017, GERP 0.788, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. the gene is **loss-of-function-intolerant** (LOEUF 0.237, pLI 1), supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 10 of 18**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency: **no allele count reported in gnomAD v4.1 (AN 1,613,998)** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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 0/3, triplosensitivity 0/3. *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 **403** lies in the 'disordered' region.

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.Pro403fs falls in the disordered region. 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}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-06-30.

**Submitter consensus:** unanimous (2/2 Uncertain significance).

**Submission history:** 2 submissions (2021–2024); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-06-30 |
| Blueprint Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-04-15 |

## Associated conditions {#conditions}

[RASopathy](https://sugi.bio/atlas/disease/rasopathy/).

**Reported phenotype names (ClinVar):** RASopathy, not provided, Noonan spectrum disorder, rasopathies, none provided.

## Similar variants {#similar}

Related BRAF variant pages (same residue, condition, or type): [BRAF p.Pro403Ala](/variant/braf-p-pro403ala), [BRAF p.Pro403Thr](/variant/braf-p-pro403thr), [BRAF p.Ala404fs](/variant/braf-p-ala404fs), [BRAF c.139-9del](/variant/braf-c-139-minus-9del), [BRAF c.2128-16_2128-7del](/variant/braf-c-2128-minus-16-2128-minus-7del), [BRAF c.2128-27_2128-19del](/variant/braf-c-2128-minus-27-2128-minus-19del), [BRAF c.2128-5del](/variant/braf-c-2128-minus-5del), [BRAF c.138+6_138+11del](/variant/braf-c-138-plus-6-138-plus-11del).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 2026-10-14); 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 2077036). 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.*