MAP2K1

Chr 15AD

mitogen-activated protein kinase kinase 1

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

NCBI Gene: 5604 ENSG00000169032 UniProt: Q02750

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]

Primary Disease Associations & Inheritance

Cardiofaciocutaneous syndrome 3MIM #615279

Melorheostosis, isolated, somatic mosaicMIM #155950

528

ClinVar variants

Pathogenic / LP

0.90

pLI score

Active trials

Clinical Summary— MAP2K1

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Gene-Disease Validity (ClinGen)

Noonan syndrome · ADLimited

Limited evidence — not for standalone diagnostic reporting

4 total gene-disease associations curated

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Population Constraint (gnomAD)

Moderately constrained gene (pLI 0.90) — some intolerance to loss-of-function variants.

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ClinVar Variants

55 Pathogenic / Likely Pathogenic· 214 VUS of 528 total submissions

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Clinical Trials

11 active or recruiting trials — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Missense constrained — critical functional residues

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.

0.38LOEUF

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?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.

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?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.0.15 (0.07–0.38)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.41 (0.34–0.48)

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.1.09

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	18	9	0	27
Likely Pathogenic	0	19	9	0	28
VUS	17	153	38	6	214
Likely Benign	0	1	106	88	195
Benign	0	1	38	6	45
Conflicting	—				19
Total	17	192	200	100	528

MAP2K1

Primary Disease Associations & Inheritance

Population Genetics & Constraint

ClinVar Variant Classifications

Classification Summary

Curated Variants Distribution

Protein Context — Lollipop Plot

DECIPHER · Gene2Phenotype

Gene2Phenotype Curations

OMIM — Genotype-Phenotype Relationships

Gene Overview

ClinGen Curation

Disease Associations

External Resources

Variant Interpretation

Population Databases

Gene Resources