MAPKAPK3

MAPK activated protein kinase 3, the group of MAPK activated protein kinases

Basic information

Region (hg38): 3:50611519-50649291

Links

ENSG00000114738 ∙ NCBI:7867 ∙ OMIM:602130 ∙ HGNC:6888 ∙ Uniprot:Q16644 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• patterned macular dystrophy 3 (Supportive), mode of inheritance: AD
• patterned macular dystrophy 3 (Strong), mode of inheritance: AD
• patterned macular dystrophy 3 (Limited), mode of inheritance: Unknown

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Macular dystrophy, patterned, 3	AD	General	Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing	Ophthalmologic	23370609; 26744326

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the MAPKAPK3 gene.

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the MAPKAPK3 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	50	3	57
missense			121	2		123
nonsense			5			5
start loss						0
frameshift			5			5
inframe indel			2			2
splice donor/acceptor (+/-2bp)			2			2
splice region			7	6	3	16
non coding			5	29	1	35
Total	0	0	144	81	4

Variants in MAPKAPK3

This is a list of pathogenic ClinVar variants found in the MAPKAPK3 region.

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

Position	Type	Phenotype	Significance	ClinVar
3-50612068-A-T		Tuberculosis, susceptibility to • Malaria, susceptibility to • Bacteremia, susceptibility to, 2	risk factor (Jun 03, 2010)
3-50617567-TG-T			Uncertain significance (Dec 21, 2023)
3-50617572-G-A			Uncertain significance (Jul 05, 2022)
3-50617575-G-C			Uncertain significance (Nov 27, 2023)
3-50617587-GAGCAGGGGGGCCC-G			Uncertain significance (Aug 17, 2023)
3-50617589-G-A			Likely benign (Oct 22, 2023)
3-50617594-G-A		not specified	Uncertain significance (Oct 05, 2022)
3-50617596-G-C			Uncertain significance (Oct 03, 2022)
3-50617596-G-T			Uncertain significance (Jan 15, 2024)
3-50617598-C-T			Likely benign (Aug 30, 2021)
3-50617598-CCCTGTG-C			Uncertain significance (Jul 23, 2022)
3-50617599-C-A			Uncertain significance (Nov 22, 2022)
3-50617601-T-C			Likely benign (Jul 21, 2022)
3-50617618-C-T			Uncertain significance (Jun 08, 2022)
3-50617620-C-A			Uncertain significance (Dec 11, 2023)
3-50617622-C-G			Likely benign (Mar 18, 2022)
3-50617623-G-A			Uncertain significance (Jun 29, 2021)
3-50617625-C-G			Likely benign (May 08, 2023)
3-50617627-G-A			Uncertain significance (Mar 01, 2023)
3-50617633-G-A			Uncertain significance (Mar 22, 2022)
3-50617634-C-T			Uncertain significance (Jan 14, 2021)
3-50617640-C-T			Benign (Dec 01, 2023)
3-50617647-C-G			Likely benign (Oct 04, 2023)
3-50617648-C-G			Uncertain significance (Feb 20, 2023)
3-50617648-C-CG			Uncertain significance (Sep 08, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
MAPKAPK3	protein_coding	protein_coding	ENST00000446044	10	37770

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
3.72e-9	0.552	125716	0	32	125748	0.000127

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.44	165	226	0.731	0.0000120	2496
Missense in Polyphen		48	67.414	0.71202		763
Synonymous	0.746	78	86.8	0.898	0.00000454	728
Loss of Function	1.15	16	21.8	0.734	0.00000120	230

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000202	0.000202
Ashkenazi Jewish	0.000102	0.0000992
East Asian	0.00	0.00
Finnish	0.0000462	0.0000462
European (Non-Finnish)	0.000135	0.000132
Middle Eastern	0.00	0.00
South Asian	0.000262	0.000261
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Stress-activated serine/threonine-protein kinase involved in cytokines production, endocytosis, cell migration, chromatin remodeling and transcriptional regulation. Following stress, it is phosphorylated and activated by MAP kinase p38- alpha/MAPK14, leading to phosphorylation of substrates. Phosphorylates serine in the peptide sequence, Hyd-X-R-X(2)-S, where Hyd is a large hydrophobic residue. MAPKAPK2 and MAPKAPK3, share the same function and substrate specificity, but MAPKAPK3 kinase activity and level in protein expression are lower compared to MAPKAPK2. Phosphorylates HSP27/HSPB1, KRT18, KRT20, RCSD1, RPS6KA3, TAB3 and TTP/ZFP36. Mediates phosphorylation of HSP27/HSPB1 in response to stress, leading to dissociate HSP27/HSPB1 from large small heat-shock protein (sHsps) oligomers and impair their chaperone activities and ability to protect against oxidative stress effectively. Involved in inflammatory response by regulating tumor necrosis factor (TNF) and IL6 production post-transcriptionally: acts by phosphorylating AU-rich elements (AREs)-binding proteins, such as TTP/ZFP36, leading to regulate the stability and translation of TNF and IL6 mRNAs. Phosphorylation of TTP/ZFP36, a major post-transcriptional regulator of TNF, promotes its binding to 14-3-3 proteins and reduces its ARE mRNA affinity leading to inhibition of dependent degradation of ARE-containing transcript. Involved in toll-like receptor signaling pathway (TLR) in dendritic cells: required for acute TLR-induced macropinocytosis by phosphorylating and activating RPS6KA3. Also acts as a modulator of Polycomb-mediated repression. {ECO:0000269|PubMed:10383393, ECO:0000269|PubMed:15563468, ECO:0000269|PubMed:18021073, ECO:0000269|PubMed:20599781, ECO:0000269|PubMed:8626550, ECO:0000269|PubMed:8774846}.
• Disease: DISEASE: Macular dystrophy, patterned, 3 (MDPT3) [MIM:617111]: A form of retinal patterned dystrophy, characterized by retinal pigment epithelium and Bruch's membrane changes resembling a 'dry desert land'. It begins around the age of 30 and progresses to retinitis pigmentosa. MDPT3 inheritance is autosomal dominant. {ECO:0000269|PubMed:26744326}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: VEGF signaling pathway - Homo sapiens (human);MAPK signaling pathway - Homo sapiens (human);EGF-Core;Fas Ligand (FasL) pathway and Stress induction of Heat Shock Proteins (HSP) regulation;MAPK Signaling Pathway;Serotonin HTR1 Group and FOS Pathway;Toll Like Receptor 7/8 (TLR7/8) Cascade;Interleukin-17 signaling;Signal Transduction;Signaling by Interleukins;VEGFA-VEGFR2 Pathway;stress induction of hsp regulation;Cytokine Signaling in Immune system;Toll Like Receptor 9 (TLR9) Cascade;Oxidative Stress Induced Senescence;MyD88 cascade initiated on plasma membrane;Toll Like Receptor 10 (TLR10) Cascade;Toll Like Receptor 3 (TLR3) Cascade;Toll Like Receptor 5 (TLR5) Cascade;Toll-Like Receptors Cascades;Cellular Senescence;Cellular responses to stress;Innate Immune System;Immune System;p38MAPK events;Signalling to RAS;Cellular responses to external stimuli;IL-7 signaling;Signalling to ERKs;Signaling by NTRK1 (TRKA);activated TAK1 mediates p38 MAPK activation;Signaling by NTRKs;MAP kinase activation;TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activation;MyD88 dependent cascade initiated on endosome;JAK STAT pathway and regulation;EPO signaling;Signaling by VEGF;TRIF(TICAM1)-mediated TLR4 signaling ;MyD88-independent TLR4 cascade ;Toll Like Receptor 4 (TLR4) Cascade;Signaling by Receptor Tyrosine Kinases;VEGF;MyD88:Mal cascade initiated on plasma membrane;Toll Like Receptor TLR1:TLR2 Cascade;Toll Like Receptor TLR6:TLR2 Cascade;Toll Like Receptor 2 (TLR2) Cascade;Signaling mediated by p38-alpha and p38-beta;p38 signaling mediated by MAPKAP kinases (Consensus)

Recessive Scores

• pRec: 0.166

Intolerance Scores

• loftool: 0.600
• rvis_EVS: -0.25
• rvis_percentile_EVS: 35.75

Haploinsufficiency Scores

• pHI: 0.172
• hipred: Y
• hipred_score: 0.771
• ghis: 0.516

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.998

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Mapkapk3
• Phenotype: immune system phenotype

Gene ontology

• Biological process: MAPK cascade;activation of MAPK activity;toll-like receptor signaling pathway;signal transduction;peptidyl-serine phosphorylation;response to lipopolysaccharide;response to cytokine;intracellular signal transduction;macropinocytosis;protein autophosphorylation;vascular endothelial growth factor receptor signaling pathway
• Cellular component: nucleus;nucleoplasm;cytoplasm;cytosol
• Molecular function: protein serine/threonine kinase activity;calmodulin-dependent protein kinase activity;MAP kinase kinase activity;protein binding;calmodulin binding;ATP binding;calcium-dependent protein serine/threonine kinase activity;mitogen-activated protein kinase binding