MAP3K5

Chr 6

mitogen-activated protein kinase kinase kinase 5

Also known as: ASK1, MAPKKK5, MEKK5

NCBI Gene: 4217ENSG00000197442UniProt: Q99683

Mitogen-activated protein kinase (MAPK) signaling cascades include MAPK or extracellular signal-regulated kinase (ERK), MAPK kinase (MKK or MEK), and MAPK kinase kinase (MAPKKK or MEKK). MAPKK kinase/MEKK phosphorylates and activates its downstream protein kinase, MAPK kinase/MEK, which in turn activates MAPK. The kinases of these signaling cascades are highly conserved, and homologs exist in yeast, Drosophila, and mammalian cells. MAPKKK5 contains 1,374 amino acids with all 11 kinase subdomains. Northern blot analysis shows that MAPKKK5 transcript is abundantly expressed in human heart and pancreas. The MAPKKK5 protein phosphorylates and activates MKK4 (aliases SERK1, MAPKK4) in vitro, and activates c-Jun N-terminal kinase (JNK)/stress-activated protein kinase (SAPK) during transient expression in COS and 293 cells; MAPKKK5 does not activate MAPK/ERK. [provided by RefSeq, Jul 2008]

151
ClinVar variants
18
Pathogenic / LP
0.52
pLI score
0
Active trials
Clinical Summary— MAP3K5
⚡
Population Constraint (gnomAD)
Moderately constrained gene (pLI 0.52) — some intolerance to loss-of-function variants.
📋
ClinVar Variants
18 Pathogenic / Likely Pathogenic· 117 VUS of 151 total submissions

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.
0.34LOEUF
pLI 0.520
Z-score 5.95
OE 0.22 (0.15–0.34)
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.
3.28Z-score
OE missense 0.66 (0.61–0.71)
483 obs / 733.3 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.0.22 (0.15–0.34)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.66 (0.61–0.71)
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.0.97
0≤1.21.6
LoF obs/exp: 15 / 67.9Missense obs/exp: 483 / 733.3Syn Z: 0.34

ClinVar Variant Classifications

151 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic18
VUS117
Likely Benign7
Benign9
18
Pathogenic
117
VUS
7
Likely Benign
9
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
18
0
18
Likely Pathogenic
0
0
0
0
0
VUS
0
116
1
0
117
Likely Benign
0
4
1
2
7
Benign
0
1
4
4
9
Total0121246151

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

View in ClinVar →

Protein Context — Lollipop Plot

MAP3K5 · 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
MAP3K kinases and kidney injury.
Cuarental L et al.·Nefrologia (Engl Ed)
2019Review
Multi-omics analysis reveals the genetic aging landscape of Parkinson's disease.
Wang Z et al.·Sci Rep
2024
Epigenetic Insights and Potential Modifiers as Therapeutic Targets in β-Thalassemia.
Zakaria NA et al.·Biomolecules
2021Review
Multi-omic human pancreatic islet endoplasmic reticulum and cytokine stress response mapping provides type 2 diabetes genetic insights.
Sokolowski EK et al.·Cell Metab
2024
ASK1 inhibition: a therapeutic strategy with multi-system benefits.
Ogier JM et al.·J Mol Med (Berl)
2020Review
Identification of subtypes and biomarkers associated with disulfidptosis-related ferroptosis in ulcerative colitis.
Jiang Y et al.·Hereditas
2025
Genomic variation in the MAP3K5 gene is associated with β-thalassemia disease severity and hydroxyurea treatment efficacy.
Tafrali C et al.·Pharmacogenomics
2013
Construction of an ER stress-related prognostic signature for predicting prognosis and screening the effective anti-tumor drug in osteosarcoma.
Chen W et al.·J Transl Med
2024
Circ_0001060 Upregulates and Encourages Progression in Osteosarcoma.
Liu H et al.·DNA Cell Biol
2023
Clinical significance and immune landscape of a novel ferroptosis-related prognosis signature in osteosarcoma.
Yang L et al.·BMC Cancer
2023
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Role of OCT1 and MAP3K5 Genetic Polymorphisms in Hydroxyurea Pharmacokinetics.
Allegra S et al.·Life (Basel)
2025🔓 Open Access
Aerobic exercise modulates RIPK1-mediated MAP3K5/JNK and NF-κB pathways to suppress microglia activation and neuroinflammation in the hippocampus of D-gal-induced accelerated aging mice.
Liu Y et al.·Physiol Behav
2024
Cetylpyridinium chloride triggers paraptosis to suppress pancreatic tumor growth via the ERN1-MAP3K5-p38 pathway.
Tang H et al.·iScience
2024🔓 Open Access
FOXP1‑induced DUSP12 alleviates vascular endothelial cell inflammation and oxidative stress injury induced by ox‑LDL via MAP3K5 signaling pathway.
Li Y et al.·Exp Ther Med
2023🔓 Open Access
Exosome-mediated delivery of gga-miR-20a-5p regulates immune response of chicken macrophages by targeting IFNGR2, MAPK1, MAP3K5, and MAP3K14.
Hong Y et al.·Anim Biosci
2023🔓 Open Access
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

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External Resources

Links to major genomics databases and tools