MAP2K4
Chr 17mitogen-activated protein kinase kinase 4
Also known as: JNKK, JNKK1, MAPKK4, MEK4, MKK4, PRKMK4, SAPKK-1, SAPKK1
MAP2K4 encodes a dual specificity protein kinase that directly activates stress-activated protein kinases (JNK1, JNK2, JNK3) and p38 MAPKs, serving as an essential component of cellular stress response and apoptotic signaling pathways. Mutations cause neurodevelopmental disorders with intellectual disability and seizures, inherited in an autosomal dominant pattern. This gene is highly constrained against loss-of-function variants, indicating that complete loss of protein function is likely incompatible with normal development.
Population Genetics & Constraint
gnomAD v4 — loss-of-function & missense intolerance
Highly LoF-intolerant (top ~10% of genes)
Highly missense-constrained (top ~0.1%)
The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).
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
72 submitted variants in ClinVar
Classification Summary
Curated Variants Distribution
Classified variants from ClinVar · 5 ACMG categories
| Classification | LoF | Missense + Inframe | Non-coding | Synonymous | Total |
|---|---|---|---|---|---|
Pathogenic | 0 | 0 | 10 | 0 | 10 |
Likely Pathogenic | 0 | 0 | 0 | 0 | 0 |
VUS | 0 | 31 | 3 | 0 | 34 |
Likely Benign | 0 | 0 | 0 | 0 | 0 |
Benign | 0 | 0 | 0 | 0 | 0 |
| Total | 0 | 31 | 13 | 0 | 44 |
LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly
View in ClinVar →Protein Context — Lollipop Plot
MAP2K4 · 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
Binimetinib for People With Relapsed/Refractory BRAF Wild Type Hairy Cell Leukemia and Variant
RECRUITINGEncorafenib Plus Binimetinib for People With BRAF V600 Mutated Relapsed/Refractory HCL
RECRUITINGStudy of Targeted Therapy vs. Chemotherapy in Patients With Thyroid Cancer
RECRUITINGTrametinib in Treating Patients With Progressive Metastatic Hormone-Resistant Prostate Cancer
ACTIVE NOT RECRUITINGNext Generation Sequencing-based "Oncochip" for Therapeutic Decision in Metastatic Breast Cancer. Study SHARP
ACTIVE NOT RECRUITINGExternal Resources
Links to major genomics databases and tools