MAP2K6

Chr 17

mitogen-activated protein kinase kinase 6

Also known as: CRCMSL, MAPKK6, MEK6, MKK6, PRKMK6, SAPKK-3, SAPKK3

NCBI Gene: 5608ENSG00000108984UniProt: P52564

This gene encodes a member of the dual specificity protein kinase family, which functions 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 phosphorylates and activates p38 MAP kinase in response to inflammatory cytokines or environmental stress. As an essential component of p38 MAP kinase mediated signal transduction pathway, this gene is involved in many cellular processes such as stress induced cell cycle arrest, transcription activation and apoptosis. [provided by RefSeq, Jul 2008]

0
Active trials
11
Pathogenic / LP
30
ClinVar variants
17
Pubs (1 yr)
3.0
Missense Z
0.36
LOEUF
Clinical Summary— MAP2K6
⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.91). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
11 Pathogenic / Likely Pathogenic· 19 VUS of 30 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
LoF Constraint
0.36LOEUF
pLI 0.913
Z-score 3.94
OE 0.16 (0.08–0.36)
Highly constrained

More LoF-intolerant than ~75% of genes

Missense Constraint
3.01Z-score
OE missense 0.38 (0.31–0.46)
71 obs / 186.8 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios
LoF OE0.16 (0.08–0.36)
0≤0.351.4
Missense OE0.38 (0.31–0.46)
0≤0.61.4
Synonymous OE0.91
0≤1.21.6
LoF obs/exp: 4 / 25.5Missense obs/exp: 71 / 186.8Syn Z: 0.55
LOFGOF
DN
0.5378th %ile
GOF
0.6344th %ile
LOF
0.58top 25%

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

LOFLOEUF 0.36
GOFprediction above median

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.

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

30 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic10
Likely Pathogenic1
VUS19
10
Pathogenic
1
Likely Pathogenic
19
VUS

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
10
0
10
Likely Pathogenic
0
0
1
0
1
VUS
0
17
2
0
19
Likely Benign
0
0
0
0
0
Benign
0
0
0
0
0
Total01713030

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

View in ClinVar →

MAP2K6 · 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

No active trials found for this gene.

Search ClinicalTrials.gov →
Clinical Literature
Landmark / reviewRecent case evidence
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Identification of Ten-Gene Related to Lipid Metabolism for Predicting Overall Survival of Breast Invasive Carcinoma
Wang Z et al.·Contrast Media Mol Imaging
2022
The endogenous association among MMP2/miR-1248/Circ_0087558/miR-643/ MAP2K6 axis can contribute to brain metastasis in basal-like subtype of breast cancer
Khoshbakht S et al.·Heliyon
2024
Omilancor mitigates the senescence of nucleus pulposus cells induced by DDP through targeting MAP2K6
Yafeng F et al.·Aging (Albany NY)
2024
MAP2K6 remodels chromatin and facilitates reprogramming by activating Gatad2b-phosphorylation dependent heterochromatin loosening.
Xing G et al.·Cell Death Differ
2022Functional
Identification of potential Mitogen-Activated Protein Kinase-related key genes and regulation networks in molecular subtypes of major depressive disorder
Chen Y et al.·Front Psychiatry
2022
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Map2k6 is a potent genetic modifier of arterial rupture in vascular Ehlers-Danlos syndrome mice.
Bowen CJ et al.·JCI Insight
2025
APEX1 promotes the oncogenicity of hepatocellular carcinoma via regulation of MAP2K6.
Sun Z et al.·Aging (Albany NY)
2022
METTL14 mediates the m6A methylation of miR-29a-3p, thereby activating the MAP2K6 signaling pathway and exacerbating the inflammatory response associated with spinal tuberculosis.
Feng L et al.·J Orthop Surg Res
2025
miR-625-3p regulates oxaliplatin resistance by targeting MAP2K6-p38 signalling in human colorectal adenocarcinoma cells.
Rasmussen MH et al.·Nat Commun
2016
A de novo 1.58 Mb deletion, including MAP2K6 and mapping 1.28 Mb upstream to SOX9, identified in a patient with Pierre Robin sequence and osteopenia with multiple fractures.
Smyk M et al.·Am J Med Genet A
2015
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

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