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 autophosphorylation and signal transduction. Predicted to be active in cytoplasm. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.69

Clinical Summary— MAP3K21

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

6 VUS of 24 total submissions

Explore recent and relevant literature in Research Assistant →

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

This gene — mechanism propensity

0.7132th %ile

GOF

0.72top 25%

LOF

0.4825th %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

24 submitted variants in ClinVar

ClinVar

Classification Summary

VUS6

Likely Benign1

Benign1

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Non-coding	Total
Pathogenic	0	0	0
Likely Pathogenic	0	0	0
VUS	6	0	6
Likely Benign	1	0	1
Benign	0	1	1
Total	7	1	8

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

View in ClinVar →

38 pathogenic / likely-pathogenic (of 48) ClinVar copy-number / structural variants overlap MAP3K21 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →