MAP3K21

protein-coding

mitogen-activated protein kinase kinase kinase 21, the group of Mitogen-activated protein kinase kinase kinases

Gene summary

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]

MANE transcript

NM_032435.3

Inheritance

—

ClinVar variants

U:17B:1

Top phenotype

—

gnomAD constraint

pLI —, LoF o/e 0.45

Max pathogenic AF

—

Genomic locus

chr1:233,327,724-233,385,148

External References & Databases

Ensembl (ENSG00000143674)

Transcript & Mutation Effects

hg38 • Region Span ~57.4 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

No GenCC data available for this gene.

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to MAP3K21 variants in ClinVar

2 Conditions Cataloged

not specifiedTotal: 6

not providedTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_032435.3. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			2 clinvar			2
missense			10 clinvar	1 clinvar		11
nonsense			2 clinvar			2
start loss						0
frameshift			1 clinvar			1
splice donor/acceptor (+/-2bp)			2 clinvar			2
Total	0	0	17	1	0	18

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 23 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_032435.3	RefSeq	NP_115811.2	10	MANE Select
ENST00000366624.8	Ensembl	ENSP00000355583.3	10	MANE Select
ENST00000366622.1	Ensembl	ENSP00000355581.1	4	Standard
ENST00000366622.2	Ensembl	ENSP00000355581.1	4	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

IL-7 signaling
JAK STAT pathway and regulation
EPO signaling
VEGF

Biological Process

activation of MAPKK activity
protein phosphorylation
activation of JUN kinase activity
protein autophosphorylation

Molecular Function

MAP kinase kinase kinase activity
protein binding
ATP binding
protein homodimerization activity

Cellular Component

cellular_component

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000366624
Coding exons: 10
Length: 57381
Individuals with no LoFs: 125684
Homozygous LoFs: 0
Heterozygous LoFs: 64
Defined: 125748
p: 0.000255

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.78	411	526	0.782	0.0000291	6592
Missense (PolyPhen)		127	213.6	0.59457		2730
Synonymous	0.681	197	210	0.940	0.0000117	2166
Loss of Function	3.01	16	35.3	0.454	0.00000191	424

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00025	0.00025	rare
Latino/Admixed American	0.00032	0.00032	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.00076	0.00076	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.00026	0.00025	rare
South Asian	0.00013	0.000098	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Negative regulator of TLR4 signaling. Does not activate JNK1/MAPK8 pathway, p38/MAPK14, nor ERK2/MAPK1 pathways. {ECO:0000269|PubMed:21602844}.;

Intolerance Scores

RVIS EVS: 0.16
RVIS percentile EVS: 64.92

Essentials

Essential (gene trap): N