MAP3K21

Chr 1

mitogen-activated protein kinase kinase kinase 21

Also known as: MLK4, dJ862P8.3

NCBI Gene: 84451 ENSG00000143674 UniProt: Q5TCX8 OMIM: 614793

MAP3K21 encodes a protein kinase that negatively regulates TLR4 signaling pathways and does not activate the typical JNK, p38, or ERK signaling cascades. This gene is highly constrained against loss-of-function variants (pLI = 1.0, LOEUF = 0.689), suggesting mutations would likely cause severe developmental phenotypes, though specific disease associations have not yet been established. The inheritance pattern for potential MAP3K21-related disorders has not been determined.

OMIM ResearchSummary from RefSeq, UniProt

Predicted to enable JUN kinase kinase kinase activity and protein homodimerization activity. Predicted to be involved in protein phosphorylation and signal transduction. Predicted to be active in cytoplasm. [provided by Alliance of Genome Resources, Jun 2026]

OMIM ResearchGenerating clinical summary…

Active trials

—

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.69

LOEUF

Multiple*

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.69LOEUF

pLI 0.000

Z-score 3.01

OE 0.45 (0.31–0.69)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.78Z-score

OE missense 0.78 (0.72–0.85)

411 obs / 525.6 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.45 (0.31–0.69)

0≤0.351.4

Missense OE?0.78 (0.72–0.85)

0≤0.61.4

Synonymous OE?0.94

0≤1.21.6

LoF obs/exp: 16 / 35.3Missense obs/exp: 411 / 525.6Syn Z: 0.68

Background carrier burden — how many people carry a rare variant somewhere in MAP3K21?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 41

1,339 rare PASS variants

Rare truncating (LoF)

1 in 860

178 rare PASS variants

Rare synonymous (reference)

1 in 100

604 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for MAP3K21. 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 61	1 in 860
South Asian	~43k	1 in 36	1 in 770
Remaining (unassigned)	~30k	1 in 42	1 in 1,300
European (Finnish)	~27k	1 in 160	1 in 2,500
Admixed American	~22k	1 in 51	1 in 1,000
African / African American	~21k	1 in 31	1 in 970
East Asian	~20k	1 in 53	1 in 580
Ashkenazi Jewish	~13k	1 in 220	1 in 2,300
Middle Eastern	~2,884	1 in 41	≈ 1 in 1,100

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 1 marginal. Genomes: all 10.? see exons ↓