MAP2K3

Chr 17

mitogen-activated protein kinase kinase 3

Also known as: MAPKK3, MEK3, MKK3, PRKMK3, SAPKK-2, SAPKK2

NCBI Gene: 5606ENSG00000034152UniProt: P46734

The encoded protein is a dual specificity kinase that phosphorylates threonine and tyrosine residues to activate p38-MAPK in response to cytokines and environmental stress. Gain-of-function mutations cause an unspecified neurological disorder with autosomal dominant inheritance. The pathogenic mechanism involves constitutive activation of the p38-MAPK signaling cascade.

Summary from RefSeq, UniProt, Mechanism
0
Active trials
14
Pubs (1 yr)
5
P/LP submissions
0%
P/LP missense
0.66
LOEUF
GOF
Mechanism· predicted
Clinical Summary— MAP2K3
⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.34) despite low pLI — interpret in context.
📋
ClinVar Variants
5 unique Pathogenic / Likely Pathogenic· 29 VUS of 89 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint
0.66LOEUF
pLI 0.022
Z-score 2.60
OE 0.34 (0.18–0.66)
Tolerant

Typical tolerance to LoF variation

Missense Constraint
1.80Z-score
OE missense 0.62 (0.53–0.73)
111 obs / 178.9 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios
LoF OE0.34 (0.18–0.66)
0≤0.351.4
Missense OE0.62 (0.53–0.73)
0≤0.61.4
Synonymous OE0.80
0≤1.21.6
LoF obs/exp: 6 / 17.9Missense obs/exp: 111 / 178.9Syn Z: 1.31
DN
0.75top 25%
GOF
0.78top 25%
LOF
0.3067th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median
DNprediction 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.

ClinVar Variant Classifications

89 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic5
VUS29
Likely Benign17
Benign20
Conflicting1
5
Pathogenic
29
VUS
17
Likely Benign
20
Benign
1
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
5
0
5
Likely Pathogenic
0
0
0
0
0
VUS
0
19
10
0
29
Likely Benign
0
5
2
10
17
Benign
0
10
4
6
20
Conflicting
—1
Total034211672

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

View in ClinVar →

Protein Context — Lollipop Plot

MAP2K3 · 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
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
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