RAF1
Chr 3ADRaf-1 proto-oncogene, serine/threonine kinase
Also known as: CMD1NN, CRAF, NS5, Raf-1, c-Raf
The protein is a MAP kinase kinase kinase (MAP3K) that functions downstream of Ras GTPases and phosphorylates MEK1 and MEK2 to activate the ERK1/2 pathway, which controls gene expression involved in cell division, apoptosis, differentiation, and migration. Loss-of-function mutations cause autosomal dominant Noonan syndrome 5, LEOPARD syndrome 2, and dilated cardiomyopathy through disruption of this critical signaling cascade. The gene shows strong intolerance to loss-of-function variants, consistent with its essential role in development and cellular regulation.
Disputed — evidence questions this relationship
4 total gene-disease associations curated
Population Genetics & Constraint
gnomAD v4 — loss-of-function & missense intolerance
More LoF-intolerant than ~75% of genes
Moderately missense-constrained (top ~2.5%)
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
0 submitted variants in ClinVar
Protein Context — Lollipop Plot
RAF1 · 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
Phase 1/2 Trial of S241656 in Selected RAS/MAPK Mutation- Positive Malignancies
RECRUITINGStudy of the Thyroid Function and Echostructural Morphology in Patients Affected With Rasopathies (ECORAS2023)
RECRUITINGTreatment Strategies and Survival Outcome for Non-small Cell Lung Cancer With Oncogenic Mutation
RECRUITINGEfficacy and Safety of Stapokibart in Non-Allergic Rhinitis With Eosinophilia Syndrome
NOT YET RECRUITINGTAPUR: Testing the Use of Food and Drug Administration (FDA) Approved Drugs That Target a Specific Abnormality in a Tumor Gene in People With Advanced Stage Cancer
RECRUITINGExternal Resources
Links to major genomics databases and tools