MAP3K5

mitogen-activated protein kinase kinase kinase 5, the group of Mitogen-activated protein kinase kinase kinases

Basic information

Region (hg38): 6:136557045-136793097

Previous symbols: [ "MEKK5" ]

Links

ENSG00000197442 ∙ NCBI:4217 ∙ OMIM:602448 ∙ HGNC:6857 ∙ Uniprot:Q99683 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

No genCC data.

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the MAP3K5 gene.

• Inborn genetic diseases (31 variants)
• not provided (9 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the MAP3K5 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous					4	4
missense			28	3	2	33
nonsense						0
start loss						0
frameshift						0
inframe indel						0
splice donor/acceptor (+/-2bp)						0
splice region					1	1
non coding					2	2
Total	0	0	28	3	8

Variants in MAP3K5

This is a list of pathogenic ClinVar variants found in the MAP3K5 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
6-136557783-A-G		not specified	Likely benign (Jan 19, 2022)
6-136557787-T-G		not specified	Uncertain significance (Aug 02, 2023)
6-136558807-T-C		not specified	Uncertain significance (Jul 25, 2023)
6-136558846-C-T		not specified	Uncertain significance (Mar 06, 2023)
6-136567644-T-C			Benign (Jul 12, 2018)
6-136567677-G-A		not specified	Uncertain significance (Nov 18, 2022)
6-136567685-C-T		not specified	Likely benign (May 13, 2022)
6-136567691-G-A		not specified	Uncertain significance (Jan 29, 2024)
6-136567725-C-T		not specified	Uncertain significance (Jan 10, 2023)
6-136580400-T-C		not specified	Uncertain significance (Jun 29, 2023)
6-136583645-G-A			Benign (Aug 09, 2018)
6-136583695-T-C		not specified	Likely benign (May 30, 2023)
6-136592452-C-T		not specified	Uncertain significance (Aug 28, 2023)
6-136592478-G-A			Benign (Jul 26, 2018)
6-136592546-C-T		not specified	Uncertain significance (Oct 13, 2023)
6-136592561-T-C		not specified	Uncertain significance (Jul 13, 2022)
6-136601831-T-C		not specified	Uncertain significance (Jun 26, 2023)
6-136601844-T-C		not specified	Uncertain significance (Jan 02, 2024)
6-136601936-G-A		not specified	Uncertain significance (Jan 25, 2023)
6-136611309-T-C		not specified	Uncertain significance (Feb 05, 2024)
6-136611312-C-T		not specified	Uncertain significance (Jan 16, 2024)
6-136613130-C-T		not specified	Uncertain significance (Oct 12, 2021)
6-136613131-G-A		not specified	Uncertain significance (Aug 02, 2022)
6-136613251-G-C		not specified	Uncertain significance (Nov 18, 2022)
6-136614151-T-C			Benign (Jul 23, 2018)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
MAP3K5	protein_coding	protein_coding	ENST00000359015	30	235472

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.520	0.480	125712	0	36	125748	0.000143

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	3.28	483	733	0.659	0.0000369	9044
Missense in Polyphen		149	291.26	0.51157		3603
Synonymous	0.336	267	274	0.974	0.0000145	2596
Loss of Function	5.95	15	67.9	0.221	0.00000328	856

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000116	0.000116
Ashkenazi Jewish	0.0000992	0.0000992
East Asian	0.000113	0.000109
Finnish	0.0000462	0.0000462
European (Non-Finnish)	0.000116	0.000114
Middle Eastern	0.000113	0.000109
South Asian	0.000508	0.000490
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. Plays an important role in the cascades of cellular responses evoked by changes in the environment. Mediates signaling for determination of cell fate such as differentiation and survival. Plays a crucial role in the apoptosis signal transduction pathway through mitochondria-dependent caspase activation. MAP3K5/ASK1 is required for the innate immune response, which is essential for host defense against a wide range of pathogens. Mediates signal transduction of various stressors like oxidative stress as well as by receptor-mediated inflammatory signals, such as the tumor necrosis factor (TNF) or lipopolysaccharide (LPS). Once activated, acts as an upstream activator of the MKK/JNK signal transduction cascade and the p38 MAPK signal transduction cascade through the phosphorylation and activation of several MAP kinase kinases like MAP2K4/SEK1, MAP2K3/MKK3, MAP2K6/MKK6 and MAP2K7/MKK7. These MAP2Ks in turn activate p38 MAPKs and c-jun N-terminal kinases (JNKs). Both p38 MAPK and JNKs control the transcription factors activator protein-1 (AP-1). {ECO:0000269|PubMed:10411906, ECO:0000269|PubMed:10688666, ECO:0000269|PubMed:10849426, ECO:0000269|PubMed:11029458, ECO:0000269|PubMed:11154276, ECO:0000269|PubMed:11689443, ECO:0000269|PubMed:11920685, ECO:0000269|PubMed:12697749, ECO:0000269|PubMed:14688258, ECO:0000269|PubMed:14749717, ECO:0000269|PubMed:15023544, ECO:0000269|PubMed:16129676, ECO:0000269|PubMed:17220297, ECO:0000269|PubMed:23102700, ECO:0000269|PubMed:8940179, ECO:0000269|PubMed:8974401, ECO:0000269|PubMed:9564042, ECO:0000269|PubMed:9774977}.
• Pathway: Neurotrophin signaling pathway - Homo sapiens (human);Non-alcoholic fatty liver disease (NAFLD) - Homo sapiens (human);Tight junction - Homo sapiens (human);Protein processing in endoplasmic reticulum - Homo sapiens (human);Amyotrophic lateral sclerosis (ALS) - Homo sapiens (human);TNF signaling pathway - Homo sapiens (human);Thermogenesis - Homo sapiens (human);Fluid shear stress and atherosclerosis - Homo sapiens (human);MAPK signaling pathway - Homo sapiens (human);Sphingolipid signaling pathway - Homo sapiens (human);Apoptosis - Homo sapiens (human);EGF-Core;Apoptosis Modulation and Signaling;Integrated Cancer Pathway;TNF alpha Signaling Pathway;Corticotropin-releasing hormone signaling pathway;Amyotrophic lateral sclerosis (ALS);Photodynamic therapy-induced AP-1 survival signaling.;MAPK Signaling Pathway;ATM Signaling Network in Development and Disease;4-hydroxytamoxifen, Dexamethasone, and Retinoic Acids Regulation of p27 Expression;VEGFA-VEGFR2 Signaling Pathway;Angiopoietin Like Protein 8 Regulatory Pathway;p38 MAPK Signaling Pathway;Insulin Signaling;p38 mapk signaling pathway;il-10 anti-inflammatory signaling pathway;hiv-1 nef: negative effector of fas and tnf;the 41bb-dependent immune response;keratinocyte differentiation;mapkinase signaling pathway;Oxidative Stress Induced Senescence;Cellular Senescence;Fas;Cellular responses to stress;Cellular responses to external stimuli;IL-7 signaling;JAK STAT pathway and regulation;EPO signaling;TNFalpha;TNF;VEGF;HIV-1 Nef: Negative effector of Fas and TNF-alpha;TNF receptor signaling pathway ;p38 MAPK signaling pathway;Class I PI3K signaling events mediated by Akt (Consensus)

Recessive Scores

• pRec: 0.557

Intolerance Scores

• loftool: 0.567
• rvis_EVS: -0.71
• rvis_percentile_EVS: 14.78

Haploinsufficiency Scores

• pHI: 0.538
• hipred: Y
• hipred_score: 0.756
• ghis: 0.499

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 1.00

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Map3k5
• Phenotype: cellular phenotype; homeostasis/metabolism phenotype; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan)

Gene ontology

• Biological process: MAPK cascade;activation of MAPKK activity;response to ischemia;protein phosphorylation;JNK cascade;activation of JUN kinase activity;intrinsic apoptotic signaling pathway in response to oxidative stress;positive regulation of cardiac muscle cell apoptotic process;viral process;cellular response to amino acid starvation;response to endoplasmic reticulum stress;p38MAPK cascade;wound healing;positive regulation of apoptotic process;positive regulation of cysteine-type endopeptidase activity involved in apoptotic process;positive regulation of JUN kinase activity;innate immune response;positive regulation of myoblast differentiation;positive regulation of transcription, DNA-templated;positive regulation of JNK cascade;stress-activated MAPK cascade;intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress;cellular response to hydrogen peroxide;cellular response to tumor necrosis factor;endothelial cell apoptotic process;apoptotic signaling pathway;programmed necrotic cell death;positive regulation of p38MAPK cascade;positive regulation of neuron death;cellular response to reactive nitrogen species;positive regulation of vascular smooth muscle cell proliferation
• Cellular component: cytosol;external side of plasma membrane;protein-containing complex;protein kinase complex;IRE1-TRAF2-ASK1 complex
• Molecular function: magnesium ion binding;protein kinase activity;protein serine/threonine kinase activity;MAP kinase kinase kinase activity;protein binding;ATP binding;protein kinase binding;protein phosphatase binding;protein domain specific binding;identical protein binding;protein homodimerization activity