MAP2K1

Chr 15AD

mitogen-activated protein kinase kinase 1

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

NCBI Gene: 5604ENSG00000169032UniProt: Q02750OMIM: 176872

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]

GeneReviewsOMIMResearchGenerating clinical summary…
GOFmechanismADLOEUF 0.382 OMIM phenotypes
VCEP Guidelines: RASopathyReleased
View SpecificationsClinGen Panel
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
57 unique Pathogenic / Likely Pathogenic· 298 VUS of 743 total submissions
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Clinical Trials
10 active or recruiting trials — potential therapeutic options may be available
Explore recent and relevant literature in Research Assistant →
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GeneReview available — MAP2K1
Authoritative clinical overview · Recommended first read
Open GeneReview ↗

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
Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗
definitiveMAP2K1-related cardiofaciocutaneous syndromeGOFAD

This gene — mechanism propensity

DN
0.4686th %ile
GOF
0.6248th %ile
LOF
0.62top 25%

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

GOF1 literature citation · 100% of P/LP are missense
LOFLOEUF 0.38

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

GOFMutations activating the MAPK pathway are found in more than 80% of patients with ECD, mainly the BRAFV600E activating mutation in 57% to 70% of cases, followed by MAP2K1 in close to 20%.1

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

References

  1. 1.PMID 32107533 ↗

ClinVar Variant Classifications

743 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic24
Likely Pathogenic33
VUS298
Likely Benign286
Benign56
Conflicting23
24
Pathogenic
33
Likely Pathogenic
298
VUS
286
Likely Benign
56
Benign
23
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
24
0
0
24
Likely Pathogenic
0
33
0
0
33
VUS
29
222
41
6
298
Likely Benign
0
3
147
136
286
Benign
0
1
49
6
56
Conflicting
—23
Total29283237148720

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

8 pathogenic / likely-pathogenic (of 13) ClinVar copy-number / structural variants overlap MAP2K1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →

Protein Context — Lollipop Plot

MAP2K1 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Breast Cancer, Metastatic Breast Cancer

Next Generation Sequencing-based "Oncochip" for Therapeutic Decision in Metastatic Breast Cancer. Study SHARP

ACTIVE NOT RECRUITING
NCT06727357Phase PHASE2European Institute of OncologyStarted 2019-09-26
Chemotherapy
Non Small Cell Lung CancerEGFR Gene MutationALK Gene Mutation

Treatment Strategies and Survival Outcome for Non-small Cell Lung Cancer With Oncogenic Mutation

RECRUITING
NCT04322890Phase PHASE2Hunan Province Tumor HospitalStarted 2020-04-16
OsimertinibAlectinib 150 MGCrizotinib 250 MG
EGFR NP_005219.2:p.S492RKRAS Gene MutationMAP2K1 Gene Mutation

Panitumumab With or Without Trametinib in Treating Patients With Stage IV Colorectal Cancer

ACTIVE NOT RECRUITING
NCT03087071Phase PHASE2M.D. Anderson Cancer CenterStarted 2017-12-29
Laboratory Biomarker AnalysisPanitumumabTrametinib
Solid TumorPrecision Medicine

Precision Medicine Trial Based on Molecular Matching Therapy for Patients With Standard Treatment Exhaustion

RECRUITING
NCT06739395Phase PHASE2Tianjin Medical University Second HospitalStarted 2024-11-01
Olaparib tabletTemozolomide capsuleAnlotinib
Hairy Cell Leukemia

Encorafenib Plus Binimetinib for People With BRAF V600 Mutated Relapsed/Refractory HCL

ACTIVE NOT RECRUITING
NCT04324112Phase PHASE2National Cancer Institute (NCI)Started 2020-10-28
binimetinibEncorafenib
Hairy Cell Leukemia

Binimetinib for People With Relapsed/Refractory BRAF Wild Type Hairy Cell Leukemia and Variant

RECRUITING
NCT04322383Phase PHASE2National Cancer Institute (NCI)Started 2021-01-07
binimetinib
RASopathy

Study of the Thyroid Function and Echostructural Morphology in Patients Affected With Rasopathies (ECORAS2023)

RECRUITING
NCT06489067University of Bari Aldo MoroStarted 2024-01-15
Slow-Flow Vascular MalformationFast-Flow Vascular MalformationVascular Malformations

A Trial of Targeted Therapies for Patients With Slow-Flow or Fast-Flow Vascular Malformations

RECRUITING
NCT05983159Phase PHASE2Murdoch Childrens Research InstituteStarted 2024-09-13
AlpelisibMirdametinib
Hormone-Resistant Prostate CancerMetastatic Prostate CarcinomaRecurrent Prostate Carcinoma

Trametinib in Treating Patients With Progressive Metastatic Hormone-Resistant Prostate Cancer

ACTIVE NOT RECRUITING
NCT02881242Phase PHASE2Jonsson Comprehensive Cancer CenterStarted 2018-01-30
Laboratory Biomarker AnalysisQuality-of-Life AssessmentTrametinib
Refractory Differentiated Thyroid Gland Carcinoma

Study of Targeted Therapy vs. Chemotherapy in Patients With Thyroid Cancer

RECRUITING
NCT06475989Phase PHASE3ECOG-ACRIN Cancer Research GroupStarted 2024-08-22
Biospecimen CollectionCabozantinibComputed Tomography

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients