MAP4K2

Chr 11

mitogen-activated protein kinase kinase kinase kinase 2

Also known as: BL44, GCK, RAB8IP

NCBI Gene: 5871ENSG00000168067UniProt: Q12851

The protein encoded by this gene is a member of the serine/threonine protein kinase family. Although this kinase is found in many tissues, its expression in lymphoid follicles is restricted to the cells of germinal centre, where it may participate in B-cell differentiation. This kinase can be activated by TNF-alpha, and has been shown to specifically activate MAP kinases. This kinase is also found to interact with TNF receptor-associated factor 2 (TRAF2), which is involved in the activation of MAP3K1/MEKK1. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2015]

143
ClinVar variants
13
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— MAP4K2
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
13 Pathogenic / Likely Pathogenic· 123 VUS of 143 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
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.
0.69LOEUF
pLI 0.000
Z-score 3.41
OE 0.50 (0.37–0.69)
Tolerant

Typical tolerance to LoF variation

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.
1.60Z-score
OE missense 0.79 (0.73–0.86)
370 obs / 467.6 exp
Tolerant

Mild missense constraint

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.0.50 (0.37–0.69)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.79 (0.73–0.86)
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.1.12
0≤1.21.6
LoF obs/exp: 27 / 54.0Missense obs/exp: 370 / 467.6Syn Z: -1.33

ClinVar Variant Classifications

143 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic11
Likely Pathogenic2
VUS123
Likely Benign3
Benign4
11
Pathogenic
2
Likely Pathogenic
123
VUS
3
Likely Benign
4
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
1
0
10
0
11
Likely Pathogenic
0
0
2
0
2
VUS
0
118
5
0
123
Likely Benign
0
1
0
2
3
Benign
0
2
0
2
4
Total1121174143

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

View in ClinVar →

Protein Context — Lollipop Plot

MAP4K2 · 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
Deconvoluting Kinase Inhibitor Induced Cardiotoxicity.
Lamore SD et al.·Toxicol Sci
2017
Targeting circRNA-MAP4K2 for the treatment of diabetes-induced retinal vascular dysfunction.
Ma C et al.·Aging (Albany NY)
2022
Activation of JNK signaling in osteoblasts is inversely correlated with collagen synthesis in age-related osteoporosis.
Zhang X et al.·Biochem Biophys Res Commun
2018
Exome Sequencing of Oral Squamous Cell Carcinoma Reveals Molecular Subgroups and Novel Therapeutic Opportunities.
Su SC et al.·Theranostics
2017
Implications of Human Antimicrobial Peptide Defensin Beta-1 in Clinical Oral Squamous Cell Carcinoma Patients via an Integrated Bioinformatics Approach.
Li S et al.·Comput Math Methods Med
2022Cohort
PPP4C restores YAP1 activity by modulating MST4 phosphorylation to enhance immunosuppression and augment tumor growth in non-small cell lung cancer.
Xu Z et al.·Cancer Lett
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

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools