MAP2K2

Chr 19AD

mitogen-activated protein kinase kinase 2

Also known as: CFC4, MAPKK2, MEK2, MKK2, PRKMK2

NCBI Gene: 5605 ENSG00000126934 UniProt: P36507 OMIM: 601263

This dual specificity protein kinase phosphorylates and activates MAPK1/ERK2 and MAPK2/ERK3 as part of the mitogen growth factor signal transduction pathway. Mutations cause cardiofaciocutaneous syndrome type 4, an autosomal dominant disorder characterized by heart defects, cognitive disability, and distinctive facial features similar to Noonan syndrome. The high pLI score (0.97) indicates the gene is highly intolerant to loss-of-function variants.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

GOFmechanismADLOEUF 0.331 OMIM phenotype

VCEP Guidelines: RASopathyReleased

View Specifications ClinGen Panel

Clinical Summary— MAP2K2

🧬

Gene-Disease Validity (ClinGen)

Noonan syndrome · ADLimited

Limited evidence — not for standalone diagnostic reporting

2 total gene-disease associations curated

⚡

Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.97). One damaged copy is likely sufficient to cause disease.

💊

Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

📖

GeneReview available — MAP2K2

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint

0.33LOEUF

pLI 0.967

Z-score 3.66

OE 0.10 (0.04–0.33)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint

1.87Z-score

OE missense 0.67 (0.59–0.76)

175 obs / 259.6 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios

LoF OE0.10 (0.04–0.33)

0≤0.351.4

Missense OE0.67 (0.59–0.76)

0≤0.61.4

Synonymous OE1.05

0≤1.21.6

LoF obs/exp: 2 / 19.4Missense obs/exp: 175 / 259.6Syn Z: -0.45

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveMAP2K2-related cardiofaciocutaneous syndromeGOFAD

0.4884th %ile

GOF

0.6735th %ile

LOF

0.60top 25%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and gain-of-function). The Badonyi & Marsh model scores gain-of-function highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports loss-of-function (haploinsufficiency). Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOF1 literature citation · LOEUF 0.33

GOFprediction above median · 1 literature citation

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

GOFTwo melanomas with non-canonical BRAF mutations harbored gain-of-function MAP2K1 and MAP2K2 (MEK1 and MEK2, respectively) mutations, resulting in constitutive ERK phosphorylation and higher resistance to MEK inhibitors.PMID:22197931

LOFThis is the first report suggesting that, in addition to activating mutations, MEK2 haploinsufficiency can lead to dysregulation of the MAPK pathway.PMID:23379592

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.