MAP2K1
Chr 15ADmitogen-activated protein kinase kinase 1
Also known as: CFC3, MAPKK1, MEK1, MEL, MKK1, PRKMK1
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.
Limited evidence — not for standalone diagnostic reporting
4 total gene-disease associations curated
Population Genetics & Constraint
gnomAD v4 — loss-of-function & missense intolerance
More LoF-intolerant than ~75% of genes
Highly missense-constrained (top ~0.1%)
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.
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
Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.
ClinVar Variant Classifications
0 submitted variants in ClinVar
Protein Context — Lollipop Plot
MAP2K1 · protein map & ClinVar variants
Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.
3D Protein StructureAlphaFold
External Resources
Links to major genomics databases and tools
Clinical Trials
Active and recruiting trials from ClinicalTrials.gov
Study of the Thyroid Function and Echostructural Morphology in Patients Affected With Rasopathies (ECORAS2023)
RECRUITINGPrecision Medicine Trial Based on Molecular Matching Therapy for Patients With Standard Treatment Exhaustion
RECRUITINGBinimetinib for People With Relapsed/Refractory BRAF Wild Type Hairy Cell Leukemia and Variant
RECRUITINGTreatment Strategies and Survival Outcome for Non-small Cell Lung Cancer With Oncogenic Mutation
RECRUITINGA Trial of Targeted Therapies for Patients With Slow-Flow or Fast-Flow Vascular Malformations
RECRUITINGStudy of Targeted Therapy vs. Chemotherapy in Patients With Thyroid Cancer
RECRUITINGTrametinib in Treating Patients With Progressive Metastatic Hormone-Resistant Prostate Cancer
ACTIVE NOT RECRUITINGPanitumumab With or Without Trametinib in Treating Patients With Stage IV Colorectal Cancer
ACTIVE NOT RECRUITINGNext Generation Sequencing-based "Oncochip" for Therapeutic Decision in Metastatic Breast Cancer. Study SHARP
ACTIVE NOT RECRUITINGEncorafenib Plus Binimetinib for People With BRAF V600 Mutated Relapsed/Refractory HCL
RECRUITINGExternal Resources
Links to major genomics databases and tools