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.

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]

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)

Costello syndrome · ADDisputedevidence questions this relationship4 gene-disease associations curated in total

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

205

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.35

LOEUF

GOF*

Mechanism· G2P