MAP2K2

mitogen-activated protein kinase kinase 2, the group of Mitogen-activated protein kinase kinases

Basic information

Region (hg38): 19:4090320-4124122

Previous symbols: [ "PRKMK2" ]

Links

ENSG00000126934 ∙ NCBI:5605 ∙ OMIM:601263 ∙ HGNC:6842 ∙ Uniprot:P36507 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• cardiofaciocutaneous syndrome 4 (Definitive), mode of inheritance: AD
• cardiofaciocutaneous syndrome 1 (Definitive), mode of inheritance: AD
• cardiofaciocutaneous syndrome 4 (Strong), mode of inheritance: AD
• cardiofaciocutaneous syndrome 4 (Strong), mode of inheritance: AD
• neurofibromatosis-Noonan syndrome (Supportive), mode of inheritance: AD
• cardiofaciocutaneous syndrome (Supportive), mode of inheritance: AD
• cardiofaciocutaneous syndrome 4 (Strong), mode of inheritance: AD
• Noonan syndrome (Limited), mode of inheritance: AD
• cardiofaciocutaneous syndrome (Definitive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Cardiofaciocutaneous syndrome 4	AD	Cardiovascular; Oncologic	Surveillance and treatment related to manifestations such as cardiac anomalies can be beneficial; Individuals with malignancies have been reported (eg, hematologic malignancies), and awareness of increased risk may be beneficial in order to allow prompt detection and management	Cardiovascular; Craniofacial; Musculoskeletal; Neurologic; Oncologic	16439621; 8456719; 18042262; 20301365; 20358587; 21178588; 21495173

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the MAP2K2 gene.

• RASopathy (474 variants)
• not provided (265 variants)
• not specified (173 variants)
• Cardiovascular phenotype (129 variants)
• Cardiofaciocutaneous syndrome 4 (42 variants)
• Noonan syndrome and Noonan-related syndrome (36 variants)
• Inborn genetic diseases (13 variants)
• Noonan syndrome (11 variants)
• MAP2K2-related condition (10 variants)
• Cardio-facio-cutaneous syndrome (8 variants)
• Noonan syndrome 1 (4 variants)
• Noonan syndrome with multiple lentigines (2 variants)
• Noonan syndrome;Cardio-facio-cutaneous syndrome (2 variants)
• Neurofibromatosis-Noonan syndrome (1 variants)
• Melanoma (1 variants)
• Gastric adenocarcinoma (1 variants)
• Squamous cell carcinoma of the head and neck (1 variants)
• Castleman-Kojima disease (1 variants)
• Cardiofaciocutaneous syndrome 1 (1 variants)
• Smith-Magenis Syndrome-like (1 variants)
• 9 conditions (1 variants)
• Pancreatic adenocarcinoma (1 variants)
• Hypertrophic cardiomyopathy (1 variants)
• Malignant melanoma of skin (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the MAP2K2 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			5	135	19	159
missense	6	14	228	8	3	259
nonsense			4			4
start loss						0
frameshift			14			14
inframe indel	1		2			3
splice donor/acceptor (+/-2bp)			6	1		7
splice region			15	20	4	39
non coding			4	111	71	186
Total	7	14	263	255	93

Highest pathogenic variant AF is 0.00000657

Variants in MAP2K2

This is a list of pathogenic ClinVar variants found in the MAP2K2 region.

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

Position	Type	Phenotype	Significance	ClinVar
19-4090424-G-T			Benign (Mar 03, 2015)
19-4090574-G-A		not specified	Benign (Mar 03, 2015)
19-4090574-G-C			Benign (Mar 06, 2020)
19-4090578-C-T		not specified	Benign/Likely benign (Jul 04, 2021)
19-4090579-G-A		not specified	Benign (Nov 25, 2019)
19-4090584-G-A		not specified	Likely benign (Apr 10, 2017)
19-4090589-C-T		not specified	Likely benign (Jul 13, 2012)
19-4090590-G-A		not specified • RASopathy • Noonan syndrome and Noonan-related syndrome	Likely benign (May 09, 2017)
19-4090596-T-A		not specified	Likely benign (Jan 28, 2016)
19-4090603-C-A		Cardiovascular phenotype	Uncertain significance (May 18, 2023)
19-4090603-C-T		not specified • RASopathy • Noonan syndrome and Noonan-related syndrome	Benign/Likely benign (Jan 07, 2024)
19-4090604-G-A		not specified • RASopathy • Cardiovascular phenotype	Likely benign (Aug 05, 2021)
19-4090604-G-C		RASopathy	Likely benign (Feb 27, 2023)
19-4090605-G-A		RASopathy	Uncertain significance (Feb 26, 2023)
19-4090606-C-T		not specified • RASopathy	Uncertain significance (Sep 01, 2023)
19-4090607-G-A		not specified • RASopathy • Cardiovascular phenotype	Benign (May 09, 2017)
19-4090608-G-C		RASopathy	Uncertain significance (Jan 19, 2024)
19-4090609-T-G			Uncertain significance (Apr 16, 2022)
19-4090610-G-A		RASopathy • not specified • Cardiovascular phenotype	Likely benign (Jan 29, 2024)
19-4090611-C-A		RASopathy	Uncertain significance (Dec 16, 2022)
19-4090611-C-T		RASopathy	Uncertain significance (Aug 05, 2023)
19-4090612-G-A		RASopathy	Uncertain significance (Sep 23, 2022)
19-4090613-C-T		RASopathy	Likely benign (Nov 30, 2023)
19-4090614-G-A		not specified • Cardiofaciocutaneous syndrome 4 • Noonan syndrome • RASopathy	Uncertain significance (Dec 05, 2019)
19-4090615-TG-T		RASopathy	Uncertain significance (Jul 06, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
MAP2K2	protein_coding	protein_coding	ENST00000262948	11	33808

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.967	0.0333	125727	0	14	125741	0.0000557

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.87	175	260	0.674	0.0000179	2568
Missense in Polyphen		49	81.796	0.59905		856
Synonymous	-0.453	126	120	1.05	0.00000968	791
Loss of Function	3.66	2	19.4	0.103	0.00000102	222

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000275	0.000275
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.0000938	0.0000924
European (Non-Finnish)	0.0000383	0.0000352
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Catalyzes the concomitant phosphorylation of a threonine and a tyrosine residue in a Thr-Glu-Tyr sequence located in MAP kinases. Activates the ERK1 and ERK2 MAP kinases (By similarity). {ECO:0000250}.
• Disease: DISEASE: Cardiofaciocutaneous syndrome 4 (CFC4) [MIM:615280]: A form of cardiofaciocutaneous syndrome, a multiple congenital anomaly disorder characterized by a distinctive facial appearance, heart defects and mental retardation. Heart defects include pulmonic stenosis, atrial septal defects and hypertrophic cardiomyopathy. Some affected individuals present with ectodermal abnormalities such as sparse, friable hair, hyperkeratotic skin lesions and a generalized ichthyosis-like condition. Typical facial features are similar to Noonan syndrome. They include high forehead with bitemporal constriction, hypoplastic supraorbital ridges, downslanting palpebral fissures, a depressed nasal bridge, and posteriorly angulated ears with prominent helices. {ECO:0000269|PubMed:16439621, ECO:0000269|PubMed:18042262, ECO:0000269|PubMed:20358587}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Prion diseases - Homo sapiens (human);PI3K-Akt signaling pathway - Homo sapiens (human);Non-small cell lung cancer - Homo sapiens (human);Chronic myeloid leukemia - Homo sapiens (human);Gastric cancer - Homo sapiens (human);mTOR signaling pathway - Homo sapiens (human);Relaxin signaling pathway - Homo sapiens (human);Oxytocin signaling pathway - Homo sapiens (human);T cell receptor signaling pathway - Homo sapiens (human);B cell receptor signaling pathway - Homo sapiens (human);Fc epsilon RI signaling pathway - Homo sapiens (human);Kaposi,s sarcoma-associated herpesvirus infection - Homo sapiens (human);Renal cell carcinoma - Homo sapiens (human);VEGF signaling pathway - Homo sapiens (human);Long-term potentiation - Homo sapiens (human);Neurotrophin signaling pathway - Homo sapiens (human);Central carbon metabolism in cancer - Homo sapiens (human);Choline metabolism in cancer - Homo sapiens (human);Melanoma - Homo sapiens (human);Cushing,s syndrome - Homo sapiens (human);Bladder cancer - Homo sapiens (human);HIF-1 signaling pathway - Homo sapiens (human);Long-term depression - Homo sapiens (human);Influenza A - Homo sapiens (human);Acute myeloid leukemia - Homo sapiens (human);GnRH signaling pathway - Homo sapiens (human);Breast cancer - Homo sapiens (human);ErbB signaling pathway - Homo sapiens (human);Autophagy - animal - Homo sapiens (human);Gap junction - Homo sapiens (human);FoxO signaling pathway - Homo sapiens (human);Regulation of actin cytoskeleton - Homo sapiens (human);Signaling pathways regulating pluripotency of stem cells - Homo sapiens (human);Hepatocellular carcinoma - Homo sapiens (human);Glioma - Homo sapiens (human);Thyroid hormone signaling pathway - Homo sapiens (human);Prostate cancer - Homo sapiens (human);Toll-like receptor signaling pathway - Homo sapiens (human);cAMP signaling pathway - Homo sapiens (human);Apelin signaling pathway - Homo sapiens (human);Estrogen signaling pathway - Homo sapiens (human);Vascular smooth muscle contraction - Homo sapiens (human);Rap1 signaling pathway - Homo sapiens (human);Ras signaling pathway - Homo sapiens (human);MAPK signaling pathway - Homo sapiens (human);Natural killer cell mediated cytotoxicity - Homo sapiens (human);Sphingolipid signaling pathway - Homo sapiens (human);Phospholipase D signaling pathway - Homo sapiens (human);Proteoglycans in cancer - Homo sapiens (human);Prolactin signaling pathway - Homo sapiens (human);MicroRNAs in cancer - Homo sapiens (human);Pathways in cancer - Homo sapiens (human);Hepatitis B - Homo sapiens (human);cGMP-PKG signaling pathway - Homo sapiens (human);Apoptosis - Homo sapiens (human);Cellular senescence - Homo sapiens (human);Thyroid cancer - Homo sapiens (human);Endometrial cancer - Homo sapiens (human);Colorectal cancer - Homo sapiens (human);Insulin signaling pathway - Homo sapiens (human);Melanogenesis - Homo sapiens (human);Human papillomavirus infection - Homo sapiens (human);Pathway_PA165959425;Sorafenib Pharmacodynamics;Vemurafenib Pathway, Pharmacodynamics;update your name in edit mode;VEGF Signaling Pathway;Intracellular Signalling Through Adenosine Receptor A2b and Adenosine;Intracellular Signalling Through Adenosine Receptor A2a and Adenosine;Fc Epsilon Receptor I Signaling in Mast Cells;Insulin Signalling;EGF-Core;IL-5 Signaling Pathway;Regulation of toll-like receptor signaling pathway;MicroRNAs in cardiomyocyte hypertrophy;IL-1 signaling pathway;Integrin-mediated Cell Adhesion;Leptin signaling pathway;Prolactin Signaling Pathway;IL-7 Signaling Pathway;IL-9 Signaling Pathway;Thymic Stromal LymphoPoietin (TSLP) Signaling Pathway;Signaling Pathways in Glioblastoma;Androgen Receptor Network in Prostate Cancer;B Cell Receptor Signaling Pathway;Interleukin-11 Signaling Pathway;Oncostatin M Signaling Pathway;Brain-Derived Neurotrophic Factor (BDNF) signaling pathway;Amyotrophic lateral sclerosis (ALS);JAK-STAT;Common Pathways Underlying Drug Addiction;Structural Pathway of Interleukin 1 (IL-1);Cardiac Hypertrophic Response;Bladder Cancer;Kit receptor signaling pathway;Signaling of Hepatocyte Growth Factor Receptor;IL-6 signaling pathway;Pathways Affected in Adenoid Cystic Carcinoma;TGF-beta Signaling Pathway;MAPK Signaling Pathway;T-Cell antigen Receptor (TCR) pathway during Staphylococcus aureus infection;4-hydroxytamoxifen, Dexamethasone, and Retinoic Acids Regulation of p27 Expression;VEGFA-VEGFR2 Signaling Pathway;Angiopoietin Like Protein 8 Regulatory Pathway;ESC Pluripotency Pathways;Focal Adhesion-PI3K-Akt-mTOR-signaling pathway;miRNA regulation of prostate cancer signaling pathways;Endometrial cancer;PI3K-Akt Signaling Pathway;MET in type 1 papillary renal cell carcinoma;MAPK Cascade;Ras Signaling;EMT transition in Colorectal Cancer;EGF-EGFR Signaling Pathway;Insulin Signaling;IL-2 Signaling Pathway;Regulation of Actin Cytoskeleton;EPO Receptor Signaling;T-Cell antigen Receptor (TCR) Signaling Pathway;Serotonin HTR1 Group and FOS Pathway;Serotonin Receptor 2 and ELK-SRF-GATA4 signaling;Serotonin Receptor 4-6-7 and NR3C Signaling;Toll-like Receptor Signaling Pathway;Developmental Biology;RAGE;MAP2K and MAPK activation;RAF activation;Disease;Signal Transduction;role of erk5 in neuronal survival pathway;links between pyk2 and map kinases;regulation of splicing through sam68;human cytomegalovirus and map kinase pathways;influence of ras and rho proteins on g1 to s transition;role of egf receptor transactivation by gpcrs in cardiac hypertrophy;trefoil factors initiate mucosal healing;anthrax toxin mechanism of action;melanocyte development and pigmentation pathway;angiotensin ii mediated activation of jnk pathway via pyk2 dependent signaling;il-2 receptor beta chain in t cell activation;phospholipids as signalling intermediaries;cadmium induces dna synthesis and proliferation in macrophages;mcalpain and friends in cell motility;sprouty regulation of tyrosine kinase signals;phosphorylation of mek1 by cdk5/p35 down regulates the map kinase pathway;role of -arrestins in the activation and targeting of map kinases;erk1/erk2 mapk signaling pathway;role of erbb2 in signal transduction and oncology;keratinocyte differentiation;mapkinase signaling pathway;Prolactin;B cell receptor signaling;GPCR Adenosine A2A receptor;GPCR GroupI metabotropic glutamate receptor;GPCR signaling-G alpha q;CD4 T cell receptor signaling-ERK cascade;HGF;Uptake and actions of bacterial toxins;TCR;Uptake and function of anthrax toxins;Infectious disease;IGF signaling;FGF;Negative feedback regulation of MAPK pathway;Fibroblast growth factor-1;insulin Mam;IL-1 p38;roles of arrestin dependent recruitment of src kinases in gpcr signaling;IL-1 JNK;ceramide signaling pathway;GPCR signaling-G alpha s Epac and ERK;MAPK1 (ERK2) activation;TLR p38;RAF-independent MAPK1/3 activation;IL-7 signaling;GPCR signaling-G alpha s PKA and ERK;Integrin;fc epsilon receptor i signaling in mast cells;EGFR1;SHP2 signaling;role of mal in rho-mediated activation of srf;ErbB1 downstream signaling;fmlp induced chemokine gene expression in hmc-1 cells;Negative regulation of MAPK pathway;RAF/MAP kinase cascade;MAPK1/MAPK3 signaling;MAPK family signaling cascades;JAK STAT pathway and regulation;PDGF;IL2;NGF;MAP kinase cascade;EPO signaling;Signal transduction by L1;IL2-mediated signaling events;L1CAM interactions;Axon guidance;IL5;TLR ECSIT MEKK1 JNK;IL6;TLR ECSIT MEKK1 p38;TLR JNK;IL-7;Signaling by RAS mutants;VEGF;Signaling by high-kinase activity BRAF mutants;ID;Signaling by moderate kinase activity BRAF mutants;EGF;Paradoxical activation of RAF signaling by kinase inactive BRAF;ErbB2/ErbB3 signaling events;GMCSF-mediated signaling events;mTOR signaling pathway;Signaling by BRAF and RAF fusions;Oncogenic MAPK signaling;Diseases of signal transduction;Signaling events mediated by Hepatocyte Growth Factor Receptor (c-Met);Downstream signaling in naïve CD8+ T cells;Fc-epsilon receptor I signaling in mast cells;Netrin-mediated signaling events;CXCR3-mediated signaling events;Signaling events mediated by Stem cell factor receptor (c-Kit);Nongenotropic Androgen signaling;PDGFR-beta signaling pathway;Endothelins;Signaling events mediated by VEGFR1 and VEGFR2;Ceramide signaling pathway;Cellular roles of Anthrax toxin;CD4 T cell receptor signaling-JNK cascade;insulin;FSH;CD4 T cell receptor signaling (Consensus)

Recessive Scores

• pRec: 0.512

Intolerance Scores

• loftool: 0.0513
• rvis_EVS: -0.8
• rvis_percentile_EVS: 12.33

Haploinsufficiency Scores

• pHI: 0.885
• hipred: Y
• hipred_score: 0.825
• ghis: 0.570

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.999

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Map2k2
• Phenotype: skeleton phenotype; hearing/vestibular/ear phenotype; digestive/alimentary phenotype; vision/eye phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); normal 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); neoplasm; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); cellular phenotype; homeostasis/metabolism phenotype; craniofacial phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); growth/size/body region phenotype; endocrine/exocrine gland phenotype; adipose tissue phenotype (the observable morphological and physiological characteristics of mammalian fat tissue that are manifested through development and lifespan)

Gene ontology

• Biological process: MAPK cascade;activation of MAPK activity;negative regulation of gene expression;peptidyl-tyrosine phosphorylation;signal transduction by protein phosphorylation;stress-activated protein kinase signaling cascade;activation of protein kinase activity;regulation of stress-activated MAPK cascade;peptidyl-serine autophosphorylation;positive regulation of transcription, DNA-templated;ERK1 and ERK2 cascade;positive regulation of protein serine/threonine kinase activity;regulation of Golgi inheritance;positive regulation of production of miRNAs involved in gene silencing by miRNA;regulation of early endosome to late endosome transport
• Cellular component: extracellular region;nucleus;cytoplasm;mitochondrion;early endosome;late endosome;peroxisomal membrane;endoplasmic reticulum;Golgi apparatus;cytosol;microtubule;cell-cell junction;focal adhesion;cytoplasmic side of plasma membrane;perinuclear region of cytoplasm
• Molecular function: protein serine/threonine kinase activity;MAP kinase kinase activity;protein serine/threonine/tyrosine kinase activity;protein tyrosine kinase activity;protein binding;ATP binding;PDZ domain binding;protein serine/threonine kinase activator activity;metal ion binding;scaffold protein binding