MAP4K4

protein-coding

mitogen-activated protein kinase kinase kinase kinase 4, the group of Mitogen-activated protein kinase kinase kinase kinases

Gene summary

The protein encoded by this gene is a member of the serine/threonine protein kinase family. This kinase has been shown to specifically activate MAPK8/JNK. The activation of MAPK8 by this kinase is found to be inhibited by the dominant-negative mutants of MAP3K7/TAK1, MAP2K4/MKK4, and MAP2K7/MKK7, which suggests that this kinase may function through the MAP3K7-MAP2K4-MAP2K7 kinase cascade, and mediate the TNF-alpha signaling pathway. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

MANE transcript

NM_001395002.1

Inheritance

ClinVar variants

P:16U:217B:13

Top phenotype

RASopathy

gnomAD constraint

pLI —, LoF o/e 0.09

Max pathogenic AF

—

Genomic locus

chr2:101,696,850-101,894,690

External References & Databases

Ensembl (ENSG00000071054)

Transcript & Mutation Effects

hg38 • Region Span ~197.8 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

RASopathySTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0021060

Submitter: PanelApp Australia

complex neurodevelopmental disorderMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: G2P

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to MAP4K4 variants in ClinVar

11 Conditions Cataloged

Inborn genetic diseasesTotal: 122

not providedTotal: 115

not specifiedTotal: 3

MAP4K4-related disorderTotal: 2

Early-onset non-syndromic cataractTotal: 1

RASopathyTotal: 1

MAP4K4-related neurodevelopmental delayTotal: 1

Imperforate anusTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001395002.1. 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			6 clinvar	2 clinvar	2 clinvar	10
missense	2 clinvar	6 clinvar	188 clinvar	9 clinvar		205
nonsense	1 clinvar	3 clinvar	3 clinvar			7
start loss						0
frameshift	1 clinvar	2 clinvar	8 clinvar			11
splice donor/acceptor (+/-2bp)		1 clinvar	12 clinvar			13
Total	4	12	217	11	2	246

Highest pathogenic variant AF is 0.000009369378

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 138 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001395002.1	RefSeq	NP_001381931.1	33	MANE Select
ENST00000324219.9	Ensembl	ENSP00000313644.6	33	MANE Select
NM_001242559.2	RefSeq	NP_001229488.1	30	Standard
NM_001242560.2	RefSeq	NP_001229489.1	31	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
map4k4	Danio rerio	Structure: gastrulation Quality: disrupted abnormal

Gene / Model

Organism

Observed Phenotype

map4k4

Danio rerio

Structure: gastrulation

Quality: disrupted

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

MAPK signaling pathway - Homo sapiens (human)
EGF-Core
Oxidative Stress Induced Senescence
MAPK Signaling Pathway
Angiopoietin Like Protein 8 Regulatory Pathway

Biological Process

MAPK cascade
negative regulation of cell-matrix adhesion
protein phosphorylation
signal transduction by protein phosphorylation
microvillus assembly

Molecular Function

creatine kinase activity
protein serine/threonine kinase activity
protein binding
ATP binding
microtubule binding

Cellular Component

cytoplasm
focal adhesion

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000347699
Coding exons: 30
Length: 197838
Individuals with no LoFs: 124644
Homozygous LoFs: 0
Heterozygous LoFs: 12
Defined: 124656
p: 0.0000481

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	4.74	320	664	0.482	0.0000369	8035
Missense (PolyPhen)		105	235.05	0.44672		2791
Synonymous	0.755	229	244	0.939	0.0000134	2344
Loss of Function	7.29	7	75.3	0.0930	0.00000445	857

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000066	0.000065	rare
Latino/Admixed American	0.000059	0.000058	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000053	0.000053	rare
South Asian	0.000038	0.000033	rare
Other	0.00017	0.00017	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Serine/threonine kinase that may play a role in the response to environmental stress and cytokines such as TNF-alpha. Appears to act upstream of the JUN N-terminal pathway. Phosphorylates SMAD1 on Thr-322. {ECO:0000269|PubMed:21690388, ECO:0000269|PubMed:9890973}.;

Recessive Scores

pRec: 0.226

Intolerance Scores

LoFtool: 0.258
RVIS EVS: -1.44
RVIS percentile EVS: 3.95

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.961

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium