MAPK4

Summary

MAPK4 (mitogen-activated protein kinase 4, HGNC:6878) is a protein-coding gene on chromosome 18q21.1-q21.2, encoding Mitogen-activated protein kinase 4 (P31152). Atypical MAPK protein.

Mitogen-activated protein kinase 4 is a member of the mitogen-activated protein kinase family. Tyrosine kinase growth factor receptors activate mitogen-activated protein kinases which then translocate into the nucleus and phosphorylate nuclear targets. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 5596 — RefSeq curated summary.

At a glance

• GWAS associations: 21
• Clinical variants (ClinVar): 99 total
• Druggable target: yes — 4 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_002747

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6878
Approved symbol	MAPK4
Name	mitogen-activated protein kinase 4
Location	18q21.1-q21.2
Locus type	gene with protein product
Status	Approved
Aliases	Erk3-related, Erk4
Ensembl gene	ENSG00000141639
Ensembl biotype	protein_coding
OMIM	176949
Entrez	5596

Gene structure

Transcript identifiers

Ensembl transcripts: 15 — 13 protein_coding, 2 protein_coding_CDS_not_defined

ENST00000400384, ENST00000540640, ENST00000586735, ENST00000587823, ENST00000588540, ENST00000592595, ENST00000903334, ENST00000903337, ENST00000903340, ENST00000903342, ENST00000903345, ENST00000903347, ENST00000903348, ENST00000942366, ENST00000942367

RefSeq mRNA: 3 — MANE Select: NM_002747 NM_001292039, NM_001292040, NM_002747

CCDS: CCDS42437, CCDS77188, CCDS77189

Canonical transcript exons

ENST00000400384 — 6 exons

Exon	Start	End
ENSE00001151712	50725962	50726175
ENSE00001151719	50721938	50722099
ENSE00001173112	50663089	50664504
ENSE00002771820	50560087	50560243
ENSE00003597280	50729158	50731826
ENSE00003614662	50715079	50715223

Expression profiles

Bgee: expression breadth ubiquitous, 154 present calls, max score 92.48.

FANTOM5 (CAGE): breadth broad, TPM avg 3.4179 / max 150.9758, expressed in 386 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
170257	3.4179	386

Top tissues by expression

287 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
caudate nucleus	UBERON:0001873	92.48	gold quality
nucleus accumbens	UBERON:0001882	90.66	gold quality
right frontal lobe	UBERON:0002810	90.45	gold quality
anterior cingulate cortex	UBERON:0009835	89.45	gold quality
putamen	UBERON:0001874	89.42	gold quality
cingulate cortex	UBERON:0003027	89.29	gold quality
adrenal tissue	UBERON:0018303	89.05	gold quality
right adrenal gland cortex	UBERON:0035827	88.97	gold quality
right hemisphere of cerebellum	UBERON:0014890	87.91	gold quality
left adrenal gland cortex	UBERON:0035825	87.33	gold quality
amygdala	UBERON:0001876	87.16	gold quality
cerebellar hemisphere	UBERON:0002245	87.03	gold quality
prefrontal cortex	UBERON:0000451	86.96	gold quality
cerebellar cortex	UBERON:0002129	86.96	gold quality
right adrenal gland	UBERON:0001233	86.86	gold quality
left adrenal gland	UBERON:0001234	86.19	gold quality
right atrium auricular region	UBERON:0006631	85.87	gold quality
Brodmann (1909) area 9	UBERON:0013540	85.68	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	84.66	gold quality
adrenal gland	UBERON:0002369	84.42	gold quality
adrenal cortex	UBERON:0001235	84.39	gold quality
cerebellum	UBERON:0002037	83.68	gold quality
heart left ventricle	UBERON:0002084	83.56	gold quality
cardiac atrium	UBERON:0002081	82.87	gold quality
cardiac ventricle	UBERON:0002082	82.59	gold quality
neocortex	UBERON:0001950	82.44	gold quality
hypothalamus	UBERON:0001898	82.06	gold quality
frontal cortex	UBERON:0001870	82.02	gold quality
ventricular zone	UBERON:0003053	81.65	gold quality
ganglionic eminence	UBERON:0004023	81.01	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	3.38

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

94 targeting MAPK4, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-223-3P	99.99	70.14	1140
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-3910	99.95	71.13	2227
HSA-MIR-145-5P	99.92	71.13	1836
HSA-MIR-5195-3P	99.92	70.92	1877
HSA-MIR-5680	99.91	69.83	3421
HSA-MIR-106A-5P	99.90	73.94	2683
HSA-MIR-4302	99.89	67.94	1187
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057
HSA-MIR-17-5P	99.89	73.83	2665
HSA-MIR-4697-3P	99.89	67.09	1123
HSA-MIR-95-5P	99.89	72.17	3973
HSA-MIR-106B-5P	99.88	74.72	2795
HSA-MIR-20A-5P	99.88	74.76	2769
HSA-MIR-20B-5P	99.88	74.01	2621
HSA-MIR-519D-3P	99.88	73.97	2607
HSA-MIR-93-5P	99.88	73.98	2606
HSA-MIR-526B-3P	99.88	74.06	2587
HSA-MIR-5582-3P	99.86	72.48	4221
HSA-MIR-3151-5P	99.86	63.83	1069
HSA-MIR-548AR-3P	99.85	71.26	3889
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-576-5P	99.84	70.46	2582
HSA-MIR-548AZ-3P	99.82	70.56	3549
HSA-MIR-548BC	99.82	70.61	3524
HSA-MIR-548E-3P	99.82	70.59	3514
HSA-MIR-548F-3P	99.82	70.59	3540
HSA-MIR-3133	99.81	70.92	3506

Literature-anchored findings (GeneRIF, showing 12)

• Data show that in contrast to ERK3, ERK4 (MAPK4) is a stable protein and binds to MAPKAPK-5. Interaction of ERK4 with MAPKAPK-5 leads to translocation of MAPKAPK-5 to the cytoplasm and to its activation by phosphorylation. ERK4 can form dimers with ERK3. (PMID:16973613)
• Data defined a novel MK5 interaction motif (FRIEDE) within both ERK4 and ERK3 that is essential for binding to the C-terminal region of MK5. (PMID:19473979)
• Activation loop phosphorylation of ERK3/ERK4 by group I p21-activated kinases (PAKs) defines a novel PAK-ERK3/4-MAPK-activated protein kinase 5 signaling pathway. (PMID:21177870)
• MAPK4 can promote cancer by activating the AKT/mTOR signaling pathway and that targeting MAPK4 may provide a novel therapeutic approach for cancer. (PMID:30688659)
• MAPK4 deletion enhances radiation effects and triggers synergistic lethality with simultaneous PARP1 inhibition in cervical cancer. (PMID:32711558)
• MiR-127-3p inhibits proliferation of ovarian cancer in rats through down-regulating MAPK4. (PMID:33155194)
• MAPK4 promotes prostate cancer by concerted activation of androgen receptor and AKT. (PMID:33586682)
• MAPK4 promotes triple negative breast cancer growth and reduces tumor sensitivity to PI3K blockade. (PMID:35017531)
• Promotor methylation status of MAPK4 is a novel epigenetic biomarker for prognosis of recurrence in patients with thymic epithelial tumors. (PMID:36073321)
• Genetic Polymorphisms of rs9949644 in MAPK4 Are Associated with Clinical Response to Methotrexate in Patients with Psoriasis. (PMID:37494889)
• Cooperative activation of PDK1 and AKT by MAPK4 enhances cancer growth and resistance to therapy. (PMID:37531320)
• LINC00467 enhanced the proliferative, migratory and invasive ability of breast cancer cells by targeting miR-18a/b-5p/MAPK4 axis. (PMID:38279470)

Cross-species orthologs

12 orthologs

Organism	Symbol	Gene ID
danio_rerio	mapk4	ENSDARG00000110581
mus_musculus	Mapk4	ENSMUSG00000024558
rattus_norvegicus	Mapk4	ENSRNOG00000015401
drosophila_melanogaster	CG8565	FBGN0030697
drosophila_melanogaster	SRPK	FBGN0286813
caenorhabditis_elegans		WBGENE00002187
caenorhabditis_elegans		WBGENE00002188
caenorhabditis_elegans		WBGENE00004055
caenorhabditis_elegans		WBGENE00004056
caenorhabditis_elegans		WBGENE00004980
caenorhabditis_elegans	gskl-2	WBGENE00007977
caenorhabditis_elegans	Y106G6E.1	WBGENE00013705

Paralogs (19): MAPK9 (ENSG00000050748), MAPK6 (ENSG00000069956), MOK (ENSG00000080823), NLK (ENSG00000087095), SRPK1 (ENSG00000096063), MAPK1 (ENSG00000100030), MAPK3 (ENSG00000102882), MAPK8 (ENSG00000107643), MAPK10 (ENSG00000109339), MAK (ENSG00000111837), MAPK14 (ENSG00000112062), CILK1 (ENSG00000112144), SRPK2 (ENSG00000135250), MAPK13 (ENSG00000156711), MAPK7 (ENSG00000166484), MAPK15 (ENSG00000181085), SRPK3 (ENSG00000184343), MAPK11 (ENSG00000185386), MAPK12 (ENSG00000188130)

Protein

Protein identifiers

Mitogen-activated protein kinase 4 — P31152 (reviewed: P31152)

Alternative names: Extracellular signal-regulated kinase 4, MAP kinase isoform p63

All UniProt accessions (4): B4DEW2, P31152, K7ELV1, K7EN18

UniProt curated annotations — full annotation on UniProt →

Function. Atypical MAPK protein. Phosphorylates microtubule-associated protein 2 (MAP2) and MAPKAPK5. The precise role of the complex formed with MAPKAPK5 is still unclear, but the complex follows a complex set of phosphorylation events: upon interaction with atypical MAPKAPK5, ERK4/MAPK4 is phosphorylated at Ser-186 and then mediates phosphorylation and activation of MAPKAPK5, which in turn phosphorylates ERK4/MAPK4. May promote entry in the cell cycle.

Subunit / interactions. Homodimer. Heterodimer with ERK3/MAPK6. Interacts with (via FRIEDE motif) MAPKAPK5.

Subcellular location. Cytoplasm. Nucleus.

Tissue specificity. High expression in heart and brain.

Post-translational modifications. Phosphorylated at Ser-186 by PAK1, PAK2 and PAK3 resulting in catalytic activation. Phosphorylated by MAPKAPK5 at other sites.

Activity regulation. Activated by phosphorylation at Ser-186.

Domain organisation. The FRIEDE motif is required for docking MAPKAPK5. In contrast to classical MAPKs, the TXY motif within the activation loop is replaced by the SEG motif, whose phosphorylation activates the MAP kinases.

Similarity. Belongs to the protein kinase superfamily. CMGC Ser/Thr protein kinase family. MAP kinase subfamily.

RefSeq proteins (3): NP_001278968, NP_001278969, NP_002738* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000719	Prot_kinase_dom	Domain
IPR008271	Ser/Thr_kinase_AS	Active_site
IPR008350	MAPK_ERK3/4	Family
IPR011009	Kinase-like_dom_sf	Homologous_superfamily
IPR017441	Protein_kinase_ATP_BS	Binding_site
IPR050117	MAPK	Family

Pfam: PF00069

Enzyme classification (BRENDA):

• EC 2.7.11.24 — mitogen-activated protein kinase (BRENDA: 48 organisms, 305 substrates, 720 inhibitors, 27 Km, 20 kcat entries)

Substrate kinetics (BRENDA)

13 substrates with measured Km, best-characterized 13. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ATP	0.048–0.096	4
ATF2DELTA109	0.002–0.02	2
EGF RECEPTOR PEPTIDE	0.656–2.8	2
ERKSUB	0.127–1.2	2
MEK1ERK	0.0037–0.065	2
MEK2ERK	0.0056–0.03	2
ELKERK	0.0044	1
ERKMEK1	0.344	1
ERKMEK2	0.388	1
ERKSTE7	0.173	1
PROTEIN ATF2	0.0019	1
SCRAMMMEK2	0.096	1
STE7ERK	0.0006	1

Catalyzed reactions (Rhea), 2 shown:

• L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H(+) (RHEA:17989)
• L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H(+) (RHEA:46608)

UniProt features (16 total): binding site 2, modified residue 2, sequence variant 2, region of interest 2, short sequence motif 2, compositionally biased region 2, chain 1, domain 1, sequence conflict 1, active site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P31152-F1	64.04	0.30

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 149 (proton acceptor)

Ligand- & substrate-binding residues (2): 49; 26–34

Post-translational modifications (2): 186, 434

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-5687128	MAPK6/MAPK4 signaling
R-HSA-162582	Signal Transduction
R-HSA-5683057	MAPK family signaling cascades

MSigDB gene sets: 155 (showing top): BENPORATH_ES_WITH_H3K27ME3, MODULE_255, TGCACTT_MIR519C_MIR519B_MIR519A, MODULE_64, MODULE_317, CTATGCA_MIR153, CAGCTG_AP4_Q5, MODULE_195, BIOCARTA_MAPK_PATHWAY, TGCCTTA_MIR124A, MODULE_356, MARIADASON_RESPONSE_TO_BUTYRATE_SULINDAC_6, TGGAAA_NFAT_Q4_01, MODULE_69, SANSOM_APC_TARGETS

GO Biological Process (15): protein phosphorylation (GO:0006468), intracellular signal transduction (GO:0035556), MAPK cascade (GO:0000165), epidermal growth factor receptor signaling pathway (GO:0007173), positive regulation of macrophage chemotaxis (GO:0010759), positive regulation of telomere maintenance (GO:0032206), regulation of stress-activated MAPK cascade (GO:0032872), cellular response to amino acid starvation (GO:0034198), stress-activated MAPK cascade (GO:0051403), regulation of cytoskeleton organization (GO:0051493), response to epidermal growth factor (GO:0070849), caveolin-mediated endocytosis (GO:0072584), regulation of Golgi inheritance (GO:0090170), positive regulation of macrophage proliferation (GO:0120041), regulation of early endosome to late endosome transport (GO:2000641)

GO Molecular Function (13): protein serine/threonine kinase activity (GO:0004674), MAP kinase activity (GO:0004707), ATP binding (GO:0005524), protein kinase binding (GO:0019901), protein homodimerization activity (GO:0042803), protein heterodimerization activity (GO:0046982), protein serine kinase activity (GO:0106310), nucleotide binding (GO:0000166), protein kinase activity (GO:0004672), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740), phosphatase binding (GO:0019902)

GO Cellular Component (9): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), early endosome (GO:0005769), late endosome (GO:0005770), Golgi apparatus (GO:0005794), caveola (GO:0005901), focal adhesion (GO:0005925)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
MAPK family signaling cascades	1
Signal Transduction	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
intracellular anatomical structure	2
MAPK cascade	2
protein kinase activity	2
protein dimerization activity	2
intracellular membrane-bounded organelle	2
cytoplasm	2
endosome	2
phosphorylation	1
protein modification process	1
signal transduction	1
intracellular signaling cassette	1
ERBB signaling pathway	1
positive regulation of leukocyte chemotaxis	1
regulation of macrophage chemotaxis	1
macrophage chemotaxis	1
regulation of granulocyte chemotaxis	1
positive regulation of macrophage migration	1
telomere maintenance	1
regulation of telomere maintenance	1
positive regulation of DNA metabolic process	1
positive regulation of chromosome organization	1
regulation of MAPK cascade	1
stress-activated MAPK cascade	1
regulation of stress-activated protein kinase signaling cascade	1
cellular response to starvation	1
response to amino acid starvation	1
stress-activated protein kinase signaling cascade	1
cytoskeleton organization	1
regulation of organelle organization	1
response to growth factor	1
endocytosis	1
Golgi inheritance	1
regulation of Golgi organization	1
macrophage proliferation	1
positive regulation of leukocyte proliferation	1
regulation of macrophage proliferation	1
regulation of intracellular transport	1
early endosome to late endosome transport	1
regulation of vesicle-mediated transport	1

Protein interactions and networks

STRING

3134 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MAPK4	MAP2K4	P45985	600
MAPK4	H1-0	P07305	502
MAPK4	MBP	P02686	485
MAPK4	STRN3	Q13033	483
MAPK4	STRN	O43815	464
MAPK4	DUSP1	P28562	453
MAPK4	MAPK8	P45983	452
MAPK4	TRPM7	Q96QT4	432
MAPK4	PTEN	P60484	430
MAPK4	EXOC2	Q96KP1	425
MAPK4	MKS1	Q9NXB0	415
MAPK4	MYBL2	P10244	413
MAPK4	CPLX4	Q7Z7G2	403
MAPK4	STARD6	P59095	396
MAPK4	CCDC68	Q9H2F9	385

IntAct

36 interactions, top by confidence:

A	B	Type	Score
MAPK4	HSP90AB1	psi-mi:“MI:0915”(physical association)	0.640
HSP90AB1	MAPK4	psi-mi:“MI:0915”(physical association)	0.640
YWHAE	MAPK4	psi-mi:“MI:0915”(physical association)	0.400
SFN	MAPK4	psi-mi:“MI:0915”(physical association)	0.400
	TK2	psi-mi:“MI:0915”(physical association)	0.400
CALML3	MAPK4	psi-mi:“MI:0915”(physical association)	0.370
MAPK4	CRK	psi-mi:“MI:0915”(physical association)	0.370
MAPK4	ILVBL	psi-mi:“MI:0914”(association)	0.350
MAPKAPK5	HERC2	psi-mi:“MI:0914”(association)	0.350
DYRK2	RBM47	psi-mi:“MI:0914”(association)	0.350
PRG2	ZSWIM8	psi-mi:“MI:0914”(association)	0.350
MAPK4	INPPL1	psi-mi:“MI:0914”(association)	0.350
CREB3L3	AP3B1	psi-mi:“MI:0914”(association)	0.350
MAPK4	PSMA7	psi-mi:“MI:0914”(association)	0.350
BRAF	MAPK4	psi-mi:“MI:2364”(proximity)	0.270
FBXW7	MAPK4	psi-mi:“MI:2364”(proximity)	0.270
SMAD4	MAPK4	psi-mi:“MI:2364”(proximity)	0.270
MAPK4	SMARCA4	psi-mi:“MI:2364”(proximity)	0.270
SMARCA4	MAPK4	psi-mi:“MI:2364”(proximity)	0.270
SPOP	MAPK4	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (84): MAPK4 (Affinity Capture-MS), MAPK4 (Affinity Capture-MS), AKT1 (Biochemical Activity), MAPK4 (Affinity Capture-Western), AKT1 (Affinity Capture-Western), AKT1 (Reconstituted Complex), AKT1 (PCA), PLEKHH3 (Affinity Capture-MS), AHCYL1 (Affinity Capture-MS), AHCYL2 (Affinity Capture-MS), RPS6KA4 (Affinity Capture-MS), MAPK6 (Affinity Capture-MS), FASTKD5 (Affinity Capture-MS), INPPL1 (Affinity Capture-MS), MAPK4 (Affinity Capture-MS)

ESM2 similar proteins: A2VE78, A5PK16, A6QP29, B1AVH7, B5DFA1, C0HAC0, D2H0G5, D2HNY3, O15040, P31152, P41002, P51944, Q13615, Q2YDQ5, Q32NM1, Q3UMR0, Q400C9, Q5F479, Q5M9H0, Q5PQT2, Q5REW9, Q5RF77, Q5XGG5, Q69ZT1, Q6NYX6, Q6R653, Q6ZW76, Q7T0L6, Q7TNH6, Q80TI1, Q810L3, Q86XL3, Q8BVF9, Q8C2S5, Q8IV13, Q8IV45, Q8JZL1, Q8K296, Q8K4F8, Q8NFM7

Diamond homologs: A0A075F7E9, A0A509AMC3, A8XSC1, A9S9Q8, C6KTB8, D0Z5N4, G1XJZ4, O02812, O14132, O43948, O65238, P27704, P31152, P42525, P46551, P47811, P47812, P52304, P54665, P70618, Q09892, Q16539, Q16659, Q25AG2, Q38775, Q40531, Q4PKS0, Q4PNJ1, Q55F45, Q5AP97, Q5F3W3, Q5I6M2, Q5R7U1, Q61532, Q63184, Q63454, Q6P5G0, Q75JN1, Q7FAZ0, Q7FAZ3

SIGNOR signaling

5 interactions.

A	Effect	B	Mechanism
MAPKAPK5	up-regulates	MAPK4	phosphorylation
MAPK4	“up-regulates activity”	AKT1	phosphorylation
DUSP2	“down-regulates activity”	MAPK4	dephosphorylation
MAPK4	“up-regulates activity”	DUSP2	phosphorylation
MAPK4	“up-regulates activity”	MAPKAPK5	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 24 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

GO biological processes:

GO term	Partners	Fold	FDR
proteasome-mediated ubiquitin-dependent protein catabolic process	6	13.6×	7e-04
protein ubiquitination	5	9.0×	8e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

99 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	85
Likely benign	5
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1859 predictions. Top by Δscore:

Variant	Effect	Δscore
18:50729153:T:TA	acceptor_gain	1.0000
18:50729153:TGCA:T	acceptor_loss	1.0000
18:50729154:GCAG:G	acceptor_loss	1.0000
18:50729155:CAG:C	acceptor_loss	1.0000
18:50729156:A:AG	acceptor_gain	1.0000
18:50729156:AG:A	acceptor_gain	1.0000
18:50729157:G:GT	acceptor_gain	1.0000
18:50729157:GG:G	acceptor_gain	1.0000
18:50729157:GGT:G	acceptor_gain	1.0000
18:50729157:GGTA:G	acceptor_gain	1.0000
18:50729157:GGTAC:G	acceptor_gain	1.0000
18:50560241:TCGG:T	donor_loss	0.9900
18:50560242:CGGT:C	donor_loss	0.9900
18:50560243:GGT:G	donor_loss	0.9900
18:50560244:G:GG	donor_gain	0.9900
18:50560244:GT:G	donor_loss	0.9900
18:50560245:T:TC	donor_loss	0.9900
18:50649591:G:GT	donor_gain	0.9900
18:50704596:G:T	donor_gain	0.9900
18:50721932:CCCCA:C	acceptor_loss	0.9900
18:50721933:CCCAG:C	acceptor_loss	0.9900
18:50721934:CCA:C	acceptor_loss	0.9900
18:50721935:CA:C	acceptor_loss	0.9900
18:50721936:A:AT	acceptor_loss	0.9900
18:50721936:AG:A	acceptor_gain	0.9900
18:50721936:AGG:A	acceptor_gain	0.9900
18:50721936:AGGG:A	acceptor_gain	0.9900
18:50721937:GG:G	acceptor_gain	0.9900
18:50721937:GGG:G	acceptor_gain	0.9900
18:50721937:GGGG:G	acceptor_gain	0.9900

AlphaMissense

3862 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
18:50715169:T:A	W213R	1.000
18:50715169:T:C	W213R	1.000
18:50715171:G:C	W213C	1.000
18:50715171:G:T	W213C	1.000
18:50715179:G:A	G216D	1.000
18:50664105:G:C	K49N	0.999
18:50664105:G:T	K49N	0.999
18:50664186:C:A	N76K	0.999
18:50664186:C:G	N76K	0.999
18:50664356:T:C	L133P	0.999
18:50664362:G:C	R135P	0.999
18:50664364:G:A	G136R	0.999
18:50664364:G:C	G136R	0.999
18:50664364:G:T	G136W	0.999
18:50664365:G:A	G136E	0.999
18:50664368:T:C	L137P	0.999
18:50664401:G:T	R148M	0.999
18:50664404:A:C	D149A	0.999
18:50664404:A:G	D149G	0.999
18:50664404:A:T	D149V	0.999
18:50664405:C:A	D149E	0.999
18:50664405:C:G	D149E	0.999
18:50664407:T:C	L150P	0.999
18:50664449:T:A	L164H	0.999
18:50664460:G:C	D168H	0.999
18:50664461:A:C	D168A	0.999
18:50664461:A:G	D168G	0.999
18:50664461:A:T	D168V	0.999
18:50664462:T:A	D168E	0.999
18:50664462:T:G	D168E	0.999

dbSNP variants (sampled 300 via entrez): RS1000004893 (18:50727284 G>A,C,T), RS1000027746 (18:50641264 T>C), RS1000043491 (18:50604367 T>G), RS1000052926 (18:50637979 C>T), RS1000066151 (18:50599655 G>A), RS1000070674 (18:50728548 C>G), RS1000113319 (18:50720728 G>A), RS1000116454 (18:50662954 G>A), RS1000134264 (18:50647592 T>C), RS1000163682 (18:50647817 C>T), RS1000166426 (18:50701248 G>A), RS1000172975 (18:50624738 ATGGTGTCAT>A), RS1000180229 (18:50580356 C>G), RS1000194172 (18:50606278 G>A), RS1000196733 (18:50616796 C>A,T)

Disease associations

OMIM: gene MIM:176949 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

21 associations (top):

Study	Trait	p-value
GCST002875_63	Diisocyanate-induced asthma	1.000000e-06
GCST004280_35	Diastolic blood pressure	1.000000e-09
GCST004613_70	Sum neutrophil eosinophil counts	2.000000e-09
GCST004614_70	Granulocyte count	2.000000e-09
GCST004620_34	Sum basophil neutrophil counts	4.000000e-10
GCST004626_153	Myeloid white cell count	1.000000e-09
GCST004629_39	Neutrophil count	4.000000e-10
GCST005497_2	Large HDL particle concentration	3.000000e-08
GCST005499_5	Phospholipid levels in large HDL	3.000000e-08
GCST005504_17	Phospholipid levels in medium HDL	4.000000e-08
GCST007096_242	Pulse pressure	4.000000e-12
GCST007097_85	Pulse pressure	9.000000e-06
GCST007099_179	Systolic blood pressure	3.000000e-07
GCST007267_249	Systolic blood pressure	4.000000e-08
GCST007448_1	Normal facial asymmetry (angle of surface orientation score)	3.000000e-15
GCST007448_16	Normal facial asymmetry (angle of surface orientation score)	1.000000e-11
GCST90002393_619	Monocyte count	4.000000e-11
GCST90002398_324	Neutrophil count	9.000000e-21
GCST90002407_164	White blood cell count	3.000000e-21
GCST90020025_1473	Waist-to-hip ratio adjusted for BMI	3.000000e-08
GCST90020027_183	Waist-hip index	4.000000e-08

EFO canonical traits (12, from GWAS)

EFO ID	Trait name
EFO:0006995	response to diisocyanate
EFO:0006336	diastolic blood pressure
EFO:0004833	neutrophil count
EFO:0004842	eosinophil count
EFO:0007987	granulocyte count
EFO:0005090	basophil count
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0005763	pulse pressure measurement
EFO:0006335	systolic blood pressure
EFO:0009751	facial asymmetry measurement
EFO:0005091	monocyte count
EFO:0007788	BMI-adjusted waist-hip ratio

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5759 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

4 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 236,272 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL553	ERLOTINIB	4	108,300
CHEMBL939	GEFITINIB	4	117,814
CHEMBL31965	CANERTINIB	3	8,083
CHEMBL296468	BMS-387032	1	2,075

PharmGKB: 1 entry (VIP=true, CPIC=false)

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — ERK subfamily

Binding affinities (BindingDB)

4 measured of 4 human assays (4 total across all organisms); most potent 4 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
ERLOTINIB HYDROCHLORIDE	KD	1200 nM
BMS-387072	KD	1800 nM
GEFITINIB	IC50	2300 nM	US-9416123: Kinase modulators for the treatment of cancer
1-Acyl-1H-[1,2,4]triazole-3,5-diamine Analogue 3b	KD	3100 nM

ChEMBL bioactivities

12 potent at pChembl≥5 of 14 total, top 9 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.00	IC50	1000	nM	TP-030-1
6.00	IC50	1000	nM	TP-030-2
5.96	Kd	1100	nM	CHEMBL386051
5.80	Kd	1600	nM	JNJ-7706621
5.60	Kd	2500	nM	ERLOTINIB
5.51	Kd	3100	nM	GEFITINIB
5.39	Kd	4100	nM	BMS-387032
5.27	Kd	5320	nM	CHEMBL4445812
5.27	Kd	5400	nM	CANERTINIB

PubChem BioAssay actives

10 with measured affinity, of 175 total; 7 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
6-(2,6-dichlorophenyl)-8-methyl-2-(3-methylsulfanylanilino)pyrido[2,3-d]pyrimidin-7-one	624886: Binding constant for ERK4 kinase domain	kd	1.1000	uM
4-[[5-amino-1-(2,6-difluorobenzoyl)-1,2,4-triazol-3-yl]amino]benzenesulfonamide	436017: Binding constant for ERK4 kinase domain	kd	1.6000	uM
Erlotinib	436017: Binding constant for ERK4 kinase domain	kd	2.5000	uM
Gefitinib	436017: Binding constant for ERK4 kinase domain	kd	3.1000	uM
N-[5-[(5-tert-butyl-1,3-oxazol-2-yl)methylsulfanyl]-1,3-thiazol-2-yl]piperidine-4-carboxamide	436017: Binding constant for ERK4 kinase domain	kd	4.1000	uM
6-[(3,4-dichlorobenzoyl)amino]-N-(1,3-thiazol-2-yl)naphthalene-2-carboxamide	1577090: Binding affinity to wild-type human partial length ERK4 (M1 to L365 residues) expressed in bacterial expression system measured after 1 hr by kinomescan method	kd	5.3200	uM
N-[4-(3-chloro-4-fluoroanilino)-7-(3-morpholin-4-ylpropoxy)quinazolin-6-yl]prop-2-enamide	624886: Binding constant for ERK4 kinase domain	kd	5.4000	uM

CTD chemical–gene interactions

26 total (human), top 26 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases methylation, affects methylation	2
propionaldehyde	decreases expression	1
bisphenol A	affects cotreatment, decreases methylation, increases methylation	1
lead acetate	affects cotreatment, decreases expression	1
hydroxyhydroquinone	decreases expression	1
sulforaphane	decreases expression	1
chromous chloride	affects cotreatment, decreases expression	1
sodium arsenite	affects cotreatment, decreases expression	1
butyraldehyde	decreases expression	1
chromic oxide	affects cotreatment, decreases expression	1
ochratoxin A	increases acetylation	1
AGN 194204	decreases expression	1
Resveratrol	decreases expression, affects cotreatment	1
Sunitinib	decreases expression	1
Fulvestrant	affects cotreatment, decreases methylation	1
Atrazine	increases expression	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Estradiol	decreases expression	1
Flame Retardants	decreases expression	1
Methylnitronitrosoguanidine	increases expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Tretinoin	decreases expression	1
Aflatoxin B1	increases methylation	1
Cadmium Chloride	affects cotreatment, decreases expression	1
Permethrin	decreases expression	1
Halogenated Diphenyl Ethers	decreases expression	1

ChEMBL screening assays

79 unique, capped per target: 79 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1034134	Binding	Inhibition of ERK4 at 3 uM	Discovery of substituted 4-(pyrazol-4-yl)-phenylbenzodioxane-2-carboxamides as potent and highly selective Rho kinase (ROCK-II) inhibitors. — J Med Chem

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_SW92	HAP1 MAPK4 (-) 1	Cancer cell line	Male
CVCL_SW93	HAP1 MAPK4 (-) 2	Cancer cell line	Male
CVCL_SW94	HAP1 MAPK4 (-) 3	Cancer cell line	Male

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.