MAP3K11

Chr 11

mitogen-activated protein kinase kinase kinase 11

ENSG00000173327 UniProt: Q16584 OMIM: 600050

This serine/threonine kinase activates the JUN N-terminal (JNK) signaling pathway and is required for serum-stimulated cell proliferation and activation of p38, ERK, and JNK1 through phosphorylation of downstream kinases. MAP3K11 is highly constrained against loss-of-function variants and mutations cause autosomal dominant intellectual disability with developmental delay. The protein also influences microtubule organization during the cell cycle and plays a role in NF-kappaB transcriptional activity.

OMIM ResearchSummary from RefSeq, UniProt

Activates the JUN N-terminal pathway. Required for serum-stimulated cell proliferation and for mitogen and cytokine activation of MAPK14 (p38), MAPK3 (ERK) and MAPK8 (JNK1) through phosphorylation and activation of MAP2K4/MKK4 and MAP2K7/MKK7. Plays a role in mitogen-stimulated phosphorylation and activation of BRAF, but does not phosphorylate BRAF directly. Influences microtubule organization during the cell cycle

OMIM ResearchGenerating clinical summary…

Clinical highlights

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.48

LOEUF

Multiple*

Mechanism· predicted

Some data sources returned errors (1)

ncbi: Error: NCBI fetch failed: 429 https://eutils.ncbi.nlm.nih.gov/entrez/eutils/esearch.fcgi

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.48LOEUF

pLI 0.011

Z-score 4.06

OE 0.29 (0.18–0.48)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.90Z-score

OE missense 0.77 (0.70–0.83)

401 obs / 523.6 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.29 (0.18–0.48)

0≤0.351.4

Missense OE?0.77 (0.70–0.83)

0≤0.61.4

Synonymous OE?1.07

0≤1.21.6

LoF obs/exp: 11 / 38.0Missense obs/exp: 401 / 523.6Syn Z: -0.83

Background carrier burden — how many people carry a rare variant somewhere in MAP3K11?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 55

1,110 rare PASS variants

Rare truncating (LoF)

1 in 1,300

124 rare PASS variants

Rare synonymous (reference)

1 in 89

568 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for MAP3K11. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 67	1 in 1,300
South Asian	~43k	1 in 49	1 in 2,300
Remaining (unassigned)	~30k	1 in 56	1 in 2,800
European (Finnish)	~27k	1 in 140	1 in 740
Admixed American	~22k	1 in 48	1 in 800
African / African American	~21k	1 in 53	1 in 1,400
East Asian	~20k	1 in 57	≈ 1 in 4,900
Ashkenazi Jewish	~13k	1 in 500	1 in 2,400
Middle Eastern	~2,884	1 in 80	≈ 1 in 2,900

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 9 of 10 coding exons well covered in gnomAD exomes; exon 5 marginal. Genomes: all 10.? see exons ↓