MAP2K1

Chr 15

mitogen-activated protein kinase kinase 1

Also known as: CFC3, MAPKK1, MEK1, MEL, MKK1, PRKMK1

NCBI Gene: 5604 ENSG00000169032 UniProt: Q02750

The encoded protein is a dual specificity kinase that phosphorylates and activates MAP kinases (ERKs), serving as an essential component of the MAP kinase signaling pathway that regulates cellular proliferation, differentiation, and development. Mutations cause cardiofaciocutaneous syndrome 3 and isolated melorheostosis in somatic mosaic form through autosomal dominant inheritance. The high pLI score (0.90) and low LOEUF score (0.38) indicate this gene is highly intolerant to loss-of-function variants.

GeneReviews ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene is a member of the dual specificity protein kinase family, which acts as a mitogen-activated protein (MAP) kinase kinase. MAP kinases, also known as extracellular signal-regulated kinases (ERKs), act as an integration point for multiple biochemical signals. This protein kinase lies upstream of MAP kinases and stimulates the enzymatic activity of MAP kinases upon wide variety of extra- and intracellular signals. As an essential component of MAP kinase signal transduction pathway, this kinase is involved in many cellular processes such as proliferation, differentiation, transcription regulation and development. [provided by RefSeq, Jul 2008]

GeneReviews ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

UniProtCardiofaciocutaneous syndrome 3

UniProtMelorheostosis, isolated

Clinical highlights

Gene–disease validity (ClinGen · GenCC)

Definitive · cardiofaciocutaneous syndrome · AD · ClinGen 2018
Definitive · cardiofaciocutaneous syndrome 3 · AD · G2P
Strong · Noonan syndrome with multiple lentigines · AD · Genomics England PanelApp
Limited · Noonan syndrome · AD · ClinGen 2018 — not for standalone diagnostic reporting
Disputed · Costello syndrome · AD · ClinGen 2018 — evidence questions this relationship

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

209

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.38

LOEUF

GOF*

Mechanism· G2P

📖

GeneReview available — MAP2K1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Missense constrained — critical functional residues

LoF Constraint?

0.38LOEUF

pLI 0.897

Z-score 3.59

OE 0.15 (0.07–0.38)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

3.11Z-score

OE missense 0.41 (0.34–0.48)

88 obs / 216.8 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.15 (0.07–0.38)

0≤0.351.4

Missense OE?0.41 (0.34–0.48)

0≤0.61.4

Synonymous OE?1.09

0≤1.21.6

LoF obs/exp: 3 / 20.6Missense obs/exp: 88 / 216.8Syn Z: -0.65

Background carrier burden — how many people carry a rare variant somewhere in MAP2K1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 210

378 rare PASS variants

Rare truncating (LoF)

1 in 3,300

57 rare PASS variants

Rare synonymous (reference)

1 in 130

187 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for MAP2K1. 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 320	1 in 3,100
South Asian	~43k	1 in 170	≈ 1 in 13,000
Remaining (unassigned)	~30k	1 in 260	≈ 1 in 6,100
European (Finnish)	~27k	1 in 2,200	≈ 1 in 27,000
Admixed American	~22k	1 in 200	1 in 1,500
African / African American	~21k	1 in 170	1 in 3,200
East Asian	~20k	1 in 150	1 in 1,500
Ashkenazi Jewish	~13k	≈ 1 in 4,400	≈ 1 in 13,000
Middle Eastern	~2,884	1 in 250	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): All 11 coding exons well covered in gnomAD exomes and genomes.? see exons ↓