RAF1

Chr 3AD

Raf-1 proto-oncogene, serine/threonine kinase

Also known as: CMD1NN, CRAF, NS5, Raf-1, c-Raf

NCBI Gene: 5894ENSG00000132155UniProt: P04049

This gene is the cellular homolog of viral raf gene (v-raf). The encoded protein is a MAP kinase kinase kinase (MAP3K), which functions downstream of the Ras family of membrane associated GTPases to which it binds directly. Once activated, the cellular RAF1 protein can phosphorylate to activate the dual specificity protein kinases MEK1 and MEK2, which in turn phosphorylate to activate the serine/threonine specific protein kinases, ERK1 and ERK2. Activated ERKs are pleiotropic effectors of cell physiology and play an important role in the control of gene expression involved in the cell division cycle, apoptosis, cell differentiation and cell migration. Mutations in this gene are associated with Noonan syndrome 5 and LEOPARD syndrome 2. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

Cardiomyopathy, dilated, 1NNMIM #615916
AD
LEOPARD syndrome 2MIM #611554
AD
Noonan syndrome 5MIM #611553
AD
498
ClinVar variants
43
Pathogenic / LP
0.85
pLI score
5
Active trials
Clinical Summary— RAF1
🧬
Gene-Disease Validity (ClinGen)
Costello syndrome · ADDisputed

Disputed — evidence questions this relationship

4 total gene-disease associations curated

⚡
Population Constraint (gnomAD)
Moderately constrained gene (pLI 0.85) — some intolerance to loss-of-function variants.
📋
ClinVar Variants
43 Pathogenic / Likely Pathogenic· 211 VUS of 498 total submissions
💊
Clinical Trials
5 active or recruiting trials — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.35LOEUF
pLI 0.853
Z-score 4.58
OE 0.19 (0.11–0.35)
Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
2.46Z-score
OE missense 0.64 (0.57–0.71)
234 obs / 366.7 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.19 (0.11–0.35)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.64 (0.57–0.71)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.99
0≤1.21.6
LoF obs/exp: 7 / 37.1Missense obs/exp: 234 / 366.7Syn Z: 0.06

ClinVar Variant Classifications

498 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic16
Likely Pathogenic27
VUS211
Likely Benign188
Benign27
Conflicting29
16
Pathogenic
27
Likely Pathogenic
211
VUS
188
Likely Benign
27
Benign
29
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
6
10
0
16
Likely Pathogenic
0
26
1
0
27
VUS
3
171
36
1
211
Likely Benign
1
11
85
91
188
Benign
0
5
15
7
27
Conflicting
—29
Total421914799498

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View 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.

Gene2Phenotype Curations

RAF1-related Noonan syndrome

definitive
ADGain Of FunctionAltered Gene Product Structure
Dev. DisordersCardiac
G2P ↗
missense variantinframe deletion

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Cardiomyopathy, dilated, 1NN

MIM #615916

Molecular basis of disorder known

Autosomal dominant

LEOPARD syndrome 2

MIM #611554

Molecular basis of disorder known

Autosomal dominant

Noonan syndrome 5

MIM #611553

Molecular basis of disorder known

Autosomal dominant
📖
GeneReview available — RAF1
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Integrative clinical genomics of advanced prostate cancer.
Robinson D et al.·Cell
2015
Acquired Resistance to KRAS(G12C) Inhibition in Cancer.
Awad MM et al.·N Engl J Med
2021
Anticancer drug resistance: An update and perspective.
Nussinov R et al.·Drug Resist Updat
2021Review
Rare molecular subtypes of lung cancer.
Harada G et al.·Nat Rev Clin Oncol
2023Review
Targeting the MAPK Pathway in KRAS-Driven Tumors.
Drosten M et al.·Cancer Cell
2020Review
A targeted combination therapy achieves effective pancreatic cancer regression and prevents tumor resistance.
Liaki V et al.·Proc Natl Acad Sci U S A
2025
Disruption of cTnT-Mediated Sarcomere-Mitochondrial Communication Results in Dilated Cardiomyopathy.
Ye L et al.·Circulation
2025
LPA(2) Contributes to Vascular Endothelium Homeostasis and Cardiac Remodeling After Myocardial Infarction.
Pei J et al.·Circ Res
2022Functional
Comparative assessment of gene-specific variant distribution in prenatal and postnatal cohorts tested for Noonan syndrome and related conditions.
Leach NT et al.·Genet Med
2019Cohort
Clinical features and molecular genetics of patients with RASopathies: expanding the phenotype with rare genes and novel variants.
Yılmaz Uzman C et al.·Eur J Pediatr
2024Cohort
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
RASopathy

Study of the Thyroid Function and Echostructural Morphology in Patients Affected With Rasopathies (ECORAS2023)

RECRUITING
NCT06489067University of Bari Aldo MoroStarted 2024-01-15
Non-Allergic Rhinitis With Eosinophilia Syndrome

Efficacy and Safety of Stapokibart in Non-Allergic Rhinitis With Eosinophilia Syndrome

NOT YET RECRUITING
NCT07240376Phase NAHuazhong University of Science and TechnologyStarted 2025-11-25
Stapokibart (CM310)Placebo
Non-small Cell Lung CancerHistiocytic NeoplasmHistiocytosis

Phase 1/2 Trial of S241656 in Selected RAS/MAPK Mutation- Positive Malignancies

RECRUITING
NCT05786924Phase PHASE1, PHASE2Institut de Recherches Internationales ServierStarted 2023-04-18
S241656FOLFOX6/FOLFOX7FOLFIRI
Lymphoma, Non-HodgkinMultiple MyelomaAdvanced Solid Tumors

TAPUR: 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

RECRUITING
NCT02693535Phase PHASE2American Society of Clinical OncologyStarted 2016-03-14
PalbociclibSunitinibTemsirolimus
Non Small Cell Lung CancerEGFR Gene MutationALK Gene Mutation

Treatment Strategies and Survival Outcome for Non-small Cell Lung Cancer With Oncogenic Mutation

RECRUITING
NCT04322890Phase PHASE2Hunan Province Tumor HospitalStarted 2020-04-16
OsimertinibAlectinib 150 MGCrizotinib 250 MG

External Resources

Links to major genomics databases and tools