BRAF
Chr 7ADB-Raf proto-oncogene, serine/threonine kinase
Also known as: B-RAF1, B-raf, BRAF-1, BRAF1, NS7, RAFB1
BRAF encodes a serine/threonine protein kinase that regulates the MAP kinase/ERK signaling pathway controlling cell division, differentiation, and secretion. Loss-of-function mutations cause autosomal dominant cardiofaciocutaneous syndrome, Noonan syndrome 7, and LEOPARD syndrome 3, which present with overlapping phenotypes including developmental delays, cardiac abnormalities, and distinctive facial features. The gene is extremely intolerant to loss-of-function variation, indicating that haploinsufficiency is the likely pathogenic mechanism in these developmental disorders.
Moderate evidence — consider for supplementary testing
4 total gene-disease associations curated
Population Genetics & Constraint
gnomAD v4 — loss-of-function & missense intolerance
Highly LoF-intolerant (top ~10% of genes)
Highly missense-constrained (top ~0.1%)
This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.
Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.
Literature Evidence
Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.
ClinVar Variant Classifications
500 submitted variants in ClinVar
Classification Summary
Curated Variants Distribution
Classified variants from ClinVar · 5 ACMG categories
| Classification | LoF | Missense + Inframe | Non-coding | Synonymous | Total |
|---|---|---|---|---|---|
Pathogenic | 0 | 2 | 8 | 0 | 10 |
Likely Pathogenic | 0 | 7 | 0 | 0 | 7 |
VUS | 16 | 170 | 42 | 10 | 238 |
Likely Benign | 2 | 3 | 59 | 136 | 200 |
Benign | 0 | 0 | 3 | 1 | 4 |
Conflicting | — | 5 | |||
| Total | 18 | 182 | 112 | 147 | 464 |
LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly
View in ClinVar →Protein Context — Lollipop Plot
BRAF · protein map & ClinVar variants
Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.
3D Protein StructureAlphaFold
External Resources
Links to major genomics databases and tools
Clinical Trials
Active and recruiting trials from ClinicalTrials.gov
CongenItal Naevus Cohort for Longitudinal Evaluation
RECRUITINGA Study to Investigate the Safety and Efficacy of NST-628 Oral Tablets in Subjects With Solid Tumors
RECRUITINGA Study to Learn About the Study Medicine Called PF-07799933 in People With Advanced Solid Tumors With BRAF Alterations.
RECRUITINGBinimetinib for People With Relapsed/Refractory BRAF Wild Type Hairy Cell Leukemia and Variant
RECRUITINGOptimization of the Time and Dosage of Vemurafenib in BRAF Positive Juvenile Patients With Refractory Histiocytosis
RECRUITINGDecision-making of ctDNA in Patients With mCRC After Failure of First-line Treatment Containing Cetuximab - a Single-center, Phase II Clinical Study
NOT YET RECRUITINGIntermittent or Continuous Panitumumab Plus FOLFIRI for Left Sided RAS/B-RAF Wild-type Metastatic Colorectal Cancer
RECRUITINGRET-US Study - Ultrasound-Based Prediction of RET Alterations and Lateral-Neck Metastasis in Thyroid Cancer
NOT YET RECRUITINGStudy of Cemiplimab Combined With Dabrafenib and Trametinib in People With Anaplastic Thyroid Cancer
ACTIVE NOT RECRUITINGEarly Rebiopsy to Identify Biomarkers of Tumor Cell Survival Following EGFR, ALK, ROS1 or BRAF TKI Therapy
RECRUITINGDabrafenib and Trametinib Before and After Surgery in Treating Patients With Stage IIIB-C Melanoma With BRAF V600 Mutation
ACTIVE NOT RECRUITINGDabrafenib and Lapatinib in Treating Patients With Refractory Thyroid Cancer That Cannot Be Removed by Surgery
ACTIVE NOT RECRUITINGExternal Resources
Links to major genomics databases and tools