MAP2K4

Chr 17

mitogen-activated protein kinase kinase 4

Also known as: JNKK, JNKK1, MAPKK4, MEK4, MKK4, PRKMK4, SAPKK-1, SAPKK1

NCBI Gene: 6416ENSG00000065559UniProt: P45985

This gene encodes a member of the mitogen-activated protein kinase (MAPK) family. Members of this family act as an integration point for multiple biochemical signals and are involved in a wide variety of cellular processes such as proliferation, differentiation, transcription regulation, and development. They form a three-tiered signaling module composed of MAPKKKs, MAPKKs, and MAPKs. This protein is phosphorylated at serine and threonine residues by MAPKKKs and subsequently phosphorylates downstream MAPK targets at threonine and tyrosine residues. A similar protein in mouse has been reported to play a role in liver organogenesis. A pseudogene of this gene is located on the long arm of chromosome X. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]

44
ClinVar variants
10
Pathogenic / LP
1.00
pLI score· haploinsufficient
5
Active trials
Clinical Summary— MAP2K4
⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
10 Pathogenic / Likely Pathogenic· 34 VUS of 44 total submissions
💊
Clinical Trials
5 active or recruiting trials — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Dual constrained — LoF & missense intolerant
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.
0.22LOEUF
pLI 0.997
Z-score 4.10
OE 0.05 (0.01–0.22)
Highly constrained

Highly LoF-intolerant (top ~10% 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.
3.23Z-score
OE missense 0.36 (0.29–0.43)
71 obs / 199.4 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.0.05 (0.01–0.22)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.36 (0.29–0.43)
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.0.99
0≤1.21.6
LoF obs/exp: 1 / 21.6Missense obs/exp: 71 / 199.4Syn Z: 0.09

ClinVar Variant Classifications

44 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic10
VUS34
10
Pathogenic
34
VUS

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
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
Total03113044

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.

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups.
Curtis C et al.·Nature
2012
Single-cell transcriptome analysis reveals subtype-specific clonal evolution and microenvironmental changes in liver metastasis of pancreatic adenocarcinoma and their clinical implications.
Park JK et al.·Mol Cancer
2024
Small-molecule inhibition of MAP2K4 is synergistic with RAS inhibitors in KRAS-mutant cancers.
Jansen RA et al.·Proc Natl Acad Sci U S A
2024
Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes.
Biankin AV et al.·Nature
2012
Map2k4δ - identification and functional characterization of a novel Map2k4 splice variant.
Haeusgen W et al.·Biochim Biophys Acta
2014Functional
Large-Scale Multiomic Analysis Identifies Anatomic Differences and Immunogenic Potential in Subtypes of Leiomyosarcoma.
Lagos G et al.·Clin Cancer Res
2025
[Expressions of MAP2K4 and estrogen receptor and their clinical significance in invasive breast cancer].
Liu S et al.·Nan Fang Yi Ke Da Xue Xue Bao
2016
MAP3K1/MAP2K4 mutations drive breast cancer progression by compensating for TP53 loss through inactivation of the JNK2-p53-FOSL1 axis.
Hu S et al.·Breast Cancer Res
2025
MAP2K4 interacts with Vimentin to activate the PI3K/AKT pathway and promotes breast cancer pathogenesis.
Liu S et al.·Aging (Albany NY)
2019
Lactucopicrin promotes the autophagic degradation of MAP2K4/MKK4 by mediating CCDC50 palmitoylation to alleviate osteoarthritis progression.
Li W et al.·Autophagy
2026
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
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
Hairy Cell Leukemia

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

RECRUITING
NCT04324112Phase PHASE2National Cancer Institute (NCI)Started 2020-10-28
binimetinibEncorafenib
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
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
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

External Resources

Links to major genomics databases and tools