MAP2K4

Chr 17

mitogen-activated protein kinase kinase 4

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

NCBI Gene: 6416 ENSG00000065559 UniProt: P45985 OMIM: 601335

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.

OMIM ResearchSummary from RefSeq, UniProt

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]

OMIM ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.22

Clinical Summary— MAP2K4

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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.

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ClinVar Variants

31 VUS of 59 total submissions

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Clinical Trials

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

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

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?

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?

LoF OE?0.05 (0.01–0.22)

0≤0.351.4

Missense OE?0.36 (0.29–0.43)

0≤0.61.4

Synonymous OE?0.99

0≤1.21.6

LoF obs/exp: 1 / 21.6Missense obs/exp: 71 / 199.4Syn Z: 0.09

This gene — mechanism propensity

0.3792th %ile

GOF

0.5171th %ile

LOF

0.75top 10%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · LOEUF 0.22

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

59 submitted variants in ClinVar

ClinVar

Classification Summary

VUS31

VUS

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Total
Pathogenic	0	0
Likely Pathogenic	0	0
VUS	31	31
Likely Benign	0	0
Benign	0	0
Total	31	31

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

View in ClinVar →

10 pathogenic / likely-pathogenic (of 13) ClinVar copy-number / structural variants overlap MAP2K4 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →