RAF1

Chr 3AD

Raf-1 proto-oncogene, serine/threonine kinase

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

NCBI Gene: 5894 ENSG00000132155 UniProt: P04049 OMIM: 164760

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.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

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]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Cardiomyopathy, dilated, 1NNMIM #615916

LEOPARD syndrome 2MIM #611554

Noonan syndrome 5MIM #611553

Clinical highlights

Gene–disease validity (ClinGen · GenCC)

Definitive · Noonan syndrome · AD · ClinGen 2024
Definitive · Noonan syndrome 5 · AD · G2P
Strong · LEOPARD syndrome 2 · AD · Genomics England PanelApp
Strong · dilated cardiomyopathy 1NN · AD · Labcorp Genetics (formerly Invitae)
Limited · Noonan syndrome with multiple lentigines · AD · ClinGen 2018 — not for standalone diagnostic reporting
Disputed · Costello syndrome · AD · ClinGen 2018 — evidence questions this relationship
Disputed · cardiofaciocutaneous syndrome · AD · ClinGen 2018 — evidence questions this relationship

+1 more curated pair

Interpreting a novel variant

Gain of function is the curated mechanism (Gene2Phenotype), so a variant that simply removes the protein may not be the pathogenic class here — missense variants in functional domains often carry more weight.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

220

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.35

LOEUF

GOF*

Mechanism· G2P

📖

GeneReview available — RAF1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

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?

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?

LoF OE?0.19 (0.11–0.35)

0≤0.351.4

Missense OE?0.64 (0.57–0.71)

0≤0.61.4

Synonymous OE?0.99

0≤1.21.6

LoF obs/exp: 7 / 37.1Missense obs/exp: 234 / 366.7Syn Z: 0.06

Background carrier burden — how many people carry a rare variant somewhere in RAF1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 95

664 rare PASS variants

Rare truncating (LoF)

1 in 1,800

71 rare PASS variants

Rare synonymous (reference)

1 in 120

324 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for RAF1. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 120	1 in 2,900
South Asian	~43k	1 in 130	1 in 1,300
Remaining (unassigned)	~30k	1 in 110	1 in 3,400
European (Finnish)	~27k	1 in 520	≈ 1 in 6,700
Admixed American	~22k	1 in 93	1 in 2,200
African / African American	~21k	1 in 120	1 in 1,800
East Asian	~20k	1 in 170	1 in 1,800
Ashkenazi Jewish	~13k	1 in 340	≈ 1 in 6,500
Middle Eastern	~2,884	1 in 130	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 15 of 17 coding exons well covered in gnomAD exomes; exon 8 poorly covered; exon 12 marginal. Genomes: all 17.? see exons ↓