PRKCH

Summary

PRKCH (protein kinase C eta, HGNC:9403) is a protein-coding gene on chromosome 14q23.1, encoding PRKCH upstream open reading frame 2 (C0HM02). Product of an upstream open reading frame (ORF) of PRKCH which regulates translation of the downstream protein kinase C eta (PKC-eta) ORF.

Protein kinase C (PKC) is a family of serine- and threonine-specific protein kinases that can be activated by calcium and the second messenger diacylglycerol. PKC family members phosphorylate a wide variety of protein targets and are known to be involved in diverse cellular signaling pathways. PKC family members also serve as major receptors for phorbol esters, a class of tumor promoters. Each member of the PKC family has a specific expression profile and is believed to play a distinct role in cells. The protein encoded by this gene is one of the PKC family members. It is a calcium-independent and phospholipids-dependent protein kinase. It is predominantly expressed in epithelial tissues and has been shown to reside specifically in the cell nucleus. This protein kinase can regulate keratinocyte differentiation by activating the MAP kinase MAPK13 (p38delta)-activated protein kinase cascade that targets CCAAT/enhancer-binding protein alpha (CEBPA). It is also found to mediate the transcription activation of the transglutaminase 1 (TGM1) gene. Mutations in this gene are associated with susceptibility to cerebral infarction.

Source: NCBI Gene 5583 — RefSeq curated summary.

At a glance

• GWAS associations: 11
• Clinical variants (ClinVar): 155 total
• MANE Select transcript: NM_006255

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9403
Approved symbol	PRKCH
Name	protein kinase C eta
Location	14q23.1
Locus type	gene with protein product
Status	Approved
Aliases	PKC-L, PKCL
Ensembl gene	ENSG00000027075
Ensembl biotype	protein_coding
OMIM	605437
Entrez	5583

Gene structure

Transcript identifiers

Ensembl transcripts: 27 — 14 protein_coding, 13 protein_coding_CDS_not_defined

ENST00000332981, ENST00000536400, ENST00000552875, ENST00000553265, ENST00000553726, ENST00000553830, ENST00000553831, ENST00000553846, ENST00000553889, ENST00000554835, ENST00000555082, ENST00000555110, ENST00000555185, ENST00000555233, ENST00000555382, ENST00000555542, ENST00000555604, ENST00000555628, ENST00000555906, ENST00000556164, ENST00000556245, ENST00000556778, ENST00000557294, ENST00000557473, ENST00000557559, ENST00000557585, ENST00000557599

RefSeq mRNA: 1 — MANE Select: NM_006255 NM_006255

CCDS: CCDS9752

Canonical transcript exons

ENST00000332981 — 14 exons

Exon	Start	End
ENSE00001313856	61321579	61322464
ENSE00002516287	61549685	61550976
ENSE00003468824	61450842	61450971
ENSE00003468881	61457506	61457679
ENSE00003468962	61485502	61485656
ENSE00003476188	61453226	61453353
ENSE00003512561	61457176	61457319
ENSE00003535166	61391225	61391288
ENSE00003566321	61547743	61547886
ENSE00003575400	61445692	61445726
ENSE00003584360	61530407	61530595
ENSE00003642436	61529075	61529213
ENSE00003683690	61443111	61443261
ENSE00003788450	61449164	61449252

Expression profiles

Bgee: expression breadth ubiquitous, 274 present calls, max score 97.62.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 20.9721 / max 3450.7001, expressed in 1110 samples.

FANTOM5 promoters (26 alternative TSS)

Promoter ID	TPM avg	Samples expressed
139911	8.7966	851
139931	5.0960	246
139934	2.3676	112
139908	1.6032	503
139933	0.8328	117
139912	0.4798	265
139932	0.2598	59
139915	0.2012	80
139913	0.1780	94
139943	0.1673	41

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
parotid gland	UBERON:0001831	97.62	gold quality
granulocyte	CL:0000094	97.16	gold quality
esophagus squamous epithelium	UBERON:0006920	95.18	gold quality
epithelium of esophagus	UBERON:0001976	94.64	gold quality
lymph node	UBERON:0000029	94.62	gold quality
blood	UBERON:0000178	94.62	gold quality
tonsil	UBERON:0002372	94.55	gold quality
lower esophagus mucosa	UBERON:0035834	93.91	gold quality
upper lobe of left lung	UBERON:0008952	93.62	gold quality
thymus	UBERON:0002370	93.42	gold quality
upper lobe of lung	UBERON:0008948	93.40	gold quality
right lung	UBERON:0002167	93.39	gold quality
visceral pleura	UBERON:0002401	93.34	gold quality
colonic epithelium	UBERON:0000397	93.10	gold quality
lung	UBERON:0002048	93.06	gold quality
spleen	UBERON:0002106	92.30	gold quality
sural nerve	UBERON:0015488	92.19	gold quality
mucosa of urinary bladder	UBERON:0001259	92.10	gold quality
amniotic fluid	UBERON:0000173	92.01	gold quality
squamous epithelium	UBERON:0006914	91.79	gold quality
esophagus mucosa	UBERON:0002469	91.61	gold quality
placenta	UBERON:0001987	91.56	gold quality
oral cavity	UBERON:0000167	91.52	gold quality
calcaneal tendon	UBERON:0003701	91.23	gold quality
bone marrow cell	CL:0002092	91.18	gold quality
palpebral conjunctiva	UBERON:0001812	91.09	gold quality
lower lobe of lung	UBERON:0008949	90.97	gold quality
pleura	UBERON:0000977	90.90	gold quality
left lobe of thyroid gland	UBERON:0001120	90.69	gold quality
gall bladder	UBERON:0002110	90.68	gold quality

Single-cell (SCXA)

Detected in 9 experiment(s), a significant marker in 9.

Experiment	Marker?	Max mean expression
E-GEOD-180759	yes	1288.40
E-MTAB-11268	yes	1212.49
E-CURD-112	yes	478.90
E-CURD-122	yes	44.30
E-CURD-119	yes	34.54
E-MTAB-6678	yes	26.25
E-HCAD-35	yes	22.43
E-ANND-3	yes	14.75
E-MTAB-9067	yes	5.08

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): GLI1, PITX2, STAT3

miRNA regulators (miRDB)

58 targeting PRKCH, 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-513A-5P	100.00	69.77	2465
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-1305	99.91	71.43	3443
HSA-MIR-576-5P	99.84	70.46	2582
HSA-MIR-944	99.82	70.85	3042
HSA-MIR-4799-5P	99.82	70.60	2663
HSA-MIR-181B-2-3P	99.81	70.06	1646
HSA-MIR-181B-3P	99.81	70.06	1646
HSA-MIR-204-5P	99.79	71.62	2439
HSA-MIR-211-5P	99.79	71.65	2440
HSA-MIR-6885-3P	99.75	70.36	3187
HSA-MIR-4766-5P	99.75	69.23	2662
HSA-MIR-187-5P	99.74	70.26	1404
HSA-MIR-4755-5P	99.71	70.34	2716
HSA-MIR-5006-3P	99.71	70.26	2728
HSA-MIR-33A-3P	99.70	70.27	3362
HSA-MIR-1283	99.69	72.42	3009
HSA-MIR-9851-3P	99.63	69.68	1110
HSA-MIR-24-3P	99.59	69.97	1934
HSA-MIR-4276	99.56	67.66	2514
HSA-MIR-3609	99.52	69.89	2587
HSA-MIR-548AH-5P	99.52	69.73	2626
HSA-MIR-548AV-3P	99.43	68.50	1721
HSA-MIR-6080	99.43	69.43	373
HSA-MIR-508-5P	99.41	64.25	1248

Literature-anchored findings (GeneRIF, showing 40)

• that PKC eta negatively regulates UV-induced apoptosis through its localization, resistance to cleavage, and the p38 MAPK pathway (PMID:12646210)
• The novel varepsilon and eta and atypical zeta, but not the conventional alpha and beta and the novel delta PKCs, may be involved in the signaling pathways involved in thrombin-induced human platelet P-selectin expression (PMID:12783114)
• Minute virus of mice infection causes accumulation of endogenous PKCeta in the nuclear periphery and regulaties this NS1 regulating kinase, thus underlining the tight interconnection between PKC-mediated signaling and the parvoviral life cycle (PMID:12829844)
• The major result is a clear correlation of PKC eta expression with tumor progression in renal cell carcinoma. (PMID:14666709)
• There was expression of protein kinase C eta in abnormal muscle fibers. Protein kinase C isoforms may play a role in the pathogenesis of myofibrillar myopathy. (PMID:15159477)
• PKC-eta targets the Akt and mTOR signaling pathways (PMID:15489897)
• These studies demonstrate translocation of PKCeta to the nuclear envelope, and suggest that the spatial regulation of PKCeta could be important for its cellular functions including effects on cell cycle control and involvement in tumor promotion. (PMID:16242915)
• PKC-eta-mediated glioblastoma proliferation involves MEK/mitogen-activated protein (MAP) kinase phosphorylation, activation of ERK and subsequently of Elk-1. (PMID:17146445)
• Our results provide evidence of the involvement of PRKCH as a susceptibility gene for rheumatoid arthritis in the Japanese population (PMID:17195206)
• We report that a nonsynonymous SNP in PRKCH increases the risk of cerebral infarction in the general Japanese population. We also found that PKCeta was expressed in vascular endothelial cells and foamy macrophages in human atherosclerotic lesions. (PMID:17206144)
• Fission of transport carriers at the trans-Golgi network is dependent on specifically PLCbeta3, which is necessary to activate PKCeta and PKD in that Golgi compartment, via diacylglycerol production. (PMID:17492941)
• PKCeta functions as an anti-apoptotic protein in Hodgkin’s lymphoma-derived cell lines (PMID:17786031)
• PRKCH mRNA was expressed at lower level in rheumatoid arthritis unrelated patients than in healthy controls, and is not a rheumatoid arthritis major susceptibility genetic factor in the French Caucasian population. (PMID:17957454)
• PRKCH gene polymorphisms have a role in subcortical silent brain infarction (PMID:18164711)
• Results establish PKCeta as a unique element in interferon signaling that plays a key and essential role in the generation of the regulatory effects of type I IFNs on normal and leukemic hematopoiesis. (PMID:19211565)
• nPKCeta positively regulates agonist-induced thromboxane generation with no effects on platelet aggregation. (PMID:19286657)
• The 1425G/A SNP in PRKCH increases the risk of both ischemic stroke and cerebral hemorrhage in the Chinese population. (PMID:19520989)
• Data show that PKCeta is an anti-apoptotic protein, acting as a negative regulator of JNK activity. (PMID:19523467)
• These results suggest that swiprosin-1 is a PKC-beta I/eta-inducible gene and it modulates mast cell activation through NF-kappaB-dependent pathway. (PMID:19693767)
• Translational regulation could provide an additional level for controlling the expression of PKC family members. (PMID:19797084)
• Reduced expression of PKCeta may represent a molecular lesion in the development of more aggressive disease of human hepatocellular carcinoma. (PMID:20001341)
• These findings suggest that inverse effects of PKCdelta and PKCeta on loricrin expression attributes to the expression of c-Jun and JunD. (PMID:20184865)
• Three different isotypes of protein kinase C, i.e. PKC-alpha, PKC-eta and PKC-theta, were found to be regulated and translocated in opposite directions upon apoptosis induction. (PMID:20486122)
• the AA genotype of PRKCH, relative to the G/G genotype, may be a higher risk genotype for severe gastric atrophy (PMID:20602195)
• Catalytic activity of protein kinase C eta (PKCeta) is not necessary for enlarged and flattened morphology of differentiated human keratinocytes, although it is important for gene expression of the marker proteins. (PMID:21346190)
• A remarkable association of minor alleles (1425G/A and _15) in the PRKCH gene with an elevated risk of coronary artery disease and increased levels of LDL-C in a Chinese population. (PMID:21625852)
• In the present study, a significant association between the PRKCH 1425G/A polymorphism and SSNHL risk was observed through a nested case-control analysis within the population-based study. (PMID:21756056)
• study suggests that PKCeta is involved in NF-kappaB signaling leading to drug resistance. (PMID:21820409)
• The present meta-analyses suggested that 1425G/A SNP in PRKCH was associated with ischemic stroke, particularly lacunar infarction, in Chinese and Japanese populations. (PMID:22044875)
• study demonstrates that type V collagen induces the down-regulation of protein kinase C eta (PMID:22213077)
• It was shown that the PKCeta isoform is a negative regulator of the AKT signaling pathway. The IGF-I induced phosphorylation on Ser473 of AKT was inhibited by the PKCeta-induced expression in MCF-7 breast adenocarcinoma cancer cells. (PMID:22305966)
• There was loss of the negative correlation in the expression levels of CD3eta and FcepsilonRIgamma genes in CLL patients. (PMID:22664044)
• The single nucleotide polymorphism (rs2230500) in PRKCH decreases the risk of carotid intima-media thickness. (PMID:22808203)
• these results suggest that the regulation of PKCeta is unique and PKCepsilon is required for the PKC activator-induced upregulation of PKCeta. (PMID:22892130)
• Protein kinase Ceta 1425G/A variant was not a risk locus for deep intracerebral hemorrhage phenotype. (PMID:22999931)
• Upregulation of PKCeta contributes to breast cancer cell growth and targeting either PKCepsilon or PDK1 triggers PKCeta downregulation (PMID:23562764)
• the PKC family genes may play a role in the pathogenesis of MS relapse through modulating the association between 25(OH)D and relapse. (PMID:23868949)
• The 1425G/A polymorphism in PRKCH is not a significant predictor of stroke recurrence in patients with acute ischemic stroke during a 2-year follow-up period. (PMID:24534126)
• These results suggest that siRNA-mediated silencing of PKCeta can be a potent tool to complement existing chemotherapy regimens for treating EBV(+) B lymphoma. (PMID:24784886)
• PKC-eta associates with NHE3 and gamma tubulin to promote the cell polarity during migration. (PMID:24788043)

Cross-species orthologs

11 orthologs

Organism	Symbol	Gene ID
danio_rerio	prkcha	ENSDARG00000018382
danio_rerio	prkchb	ENSDARG00000043243
mus_musculus	Prkch	ENSMUSG00000021108
rattus_norvegicus	Prkch	ENSRNOG00000004873
drosophila_melanogaster	Pkc53E	FBGN0003091
drosophila_melanogaster	inaC	FBGN0004784
drosophila_melanogaster	Pkn	FBGN0020621
drosophila_melanogaster	Pkcdelta	FBGN0287828
caenorhabditis_elegans		WBGENE00004033
caenorhabditis_elegans		WBGENE00006599
caenorhabditis_elegans		WBGENE00009793

Paralogs (9): PKN2 (ENSG00000065243), PRKCZ (ENSG00000067606), PKN1 (ENSG00000123143), PRKCG (ENSG00000126583), PRKCA (ENSG00000154229), PKN3 (ENSG00000160447), PRKCI (ENSG00000163558), PRKCB (ENSG00000166501), PRKCE (ENSG00000171132)

Protein

Protein identifiers

PRKCH upstream open reading frame 2 — C0HM02 (reviewed: C0HM02, P24723)

Alternative names: Protein uPEP2

All UniProt accessions (13): P24723, G3V304, G3V3E7, G3V4G6, G3V4H0, G3V4L3, G3V4Q6, G3V4Q9, G3V4X4, G3V520, G3V5F8, G3V5U5, G3V5Y6

UniProt curated annotations — full annotation on UniProt →

Function. Product of an upstream open reading frame (ORF) of PRKCH which regulates translation of the downstream protein kinase C eta (PKC-eta) ORF. Functions as a repressive element that maintains low basal levels of PKC-eta in growing cells but enhances its expression during stress conditions induced by amino acid starvation in a EIF2AK4/GCN2-dependent manner. In addition to its role in regulating PKC-eta translation, also inhibits the kinase activity of PKC-eta as well as other protein kinases including PRKCD, PRKCQ and PRKCE but not PRKCA, PRKCG or PRKCZ.

Subunit / interactions. Interacts with protein kinase C eta as well as other protein kinases including PRKCD, PRKCQ and PRKCE but not with PRKCG or PRKCZ; the interactions lead to inhibition of kinase activity.

Miscellaneous. Suppresses proliferation and migration of cancer cells.

RefSeq proteins (1): NP_006246* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR054137	PRKCH_uORF2	Family
IPR000008	C2_dom	Domain
IPR000719	Prot_kinase_dom	Domain
IPR000961	AGC-kinase_C	Domain
IPR002219	PKC_DAG/PE	Domain
IPR008271	Ser/Thr_kinase_AS	Active_site
IPR011009	Kinase-like_dom_sf	Homologous_superfamily
IPR014376	Prot_kin_PKC_delta	Family
IPR017441	Protein_kinase_ATP_BS	Binding_site
IPR017892	Pkinase_C	Domain
IPR020454	DAG/PE-bd	Domain
IPR027431	PKC_eta	Family
IPR034665	nPKC_eta	Domain
IPR035892	C2_domain_sf	Homologous_superfamily
IPR046349	C1-like_sf	Homologous_superfamily

Pfam: PF00069, PF00130, PF00168, PF00433, PF21952

Enzyme classification (BRENDA):

• EC 2.7.11.13 — protein kinase C (BRENDA: 25 organisms, 203 substrates, 258 inhibitors, 20 Km, 1 kcat entries)

Substrate kinetics (BRENDA)

4 substrates with measured Km, best-characterized 4. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
FKKQGSFAKKK	0.0166–0.0599	10
ATP	0.0001–0.0828	4
N6-PHENYL-ATP	0.0124	1
S6-(229-239) PEPTIDE	0.0036	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 (79 total): helix 21, strand 19, sequence variant 10, modified residue 6, sequence conflict 5, turn 5, domain 3, chain 2, zinc finger region 2, binding site 2, mutagenesis site 1, splice variant 1, region of interest 1, active site 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
2FK9	X-RAY DIFFRACTION	1.75
8FP1	X-RAY DIFFRACTION	1.85
3TXO	X-RAY DIFFRACTION	2.05
8FP3	X-RAY DIFFRACTION	2.3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-C0HM02-F1	67.75	0.00
AF-P24723-F1	81.85	0.48

Functional residue map

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

C0HM02 (canonical)

Mutagenesis-validated functional residues (1):

Position	Phenotype
6	abolishes kinase inhibitor activity and converts peptide to a substrate for prkch and prkce but not for prkca.

P24723

Catalytic / active sites (1): 479 (proton acceptor)

Ligand- & substrate-binding residues (2): 361–369; 384

Post-translational modifications (6): 28, 32, 317, 513, 656, 675

Function

Pathways and Gene Ontology

Reactome pathways

8 pathways

ID	Pathway
R-HSA-114508	Effects of PIP2 hydrolysis
R-HSA-418597	G alpha (z) signalling events
R-HSA-109582	Hemostasis
R-HSA-162582	Signal Transduction
R-HSA-372790	Signaling by GPCR
R-HSA-388396	GPCR downstream signalling
R-HSA-416476	G alpha (q) signalling events
R-HSA-76002	Platelet activation, signaling and aggregation

MSigDB gene sets: 475 (showing top): GOBP_POSITIVE_REGULATION_OF_EPITHELIAL_CELL_DIFFERENTIATION, GOBP_REGULATION_OF_B_CELL_RECEPTOR_SIGNALING_PATHWAY, GOBP_REGULATION_OF_ANTIGEN_RECEPTOR_MEDIATED_SIGNALING_PATHWAY, GOBP_EPITHELIUM_DEVELOPMENT, FREAC2_01, BENPORATH_ES_WITH_H3K27ME3, GOBP_REGULATION_OF_TRANSLATION_IN_RESPONSE_TO_STRESS, YAGI_AML_WITH_INV_16_TRANSLOCATION, GOBP_POSITIVE_REGULATION_OF_KERATINOCYTE_DIFFERENTIATION, GOBP_REGULATION_OF_EPIDERMIS_DEVELOPMENT, PEREZ_TP63_TARGETS, REACTOME_PLATELET_ACTIVATION_SIGNALING_AND_AGGREGATION, REACTOME_G_ALPHA_Z_SIGNALLING_EVENTS, SP3_Q3, MODULE_64

GO Biological Process (16): negative regulation of translation (GO:0017148), positive regulation of translation in response to stress (GO:0032056), cellular response to amino acid starvation (GO:0034198), protein phosphorylation (GO:0006468), signal transduction (GO:0007165), positive regulation of macrophage derived foam cell differentiation (GO:0010744), cell differentiation (GO:0030154), negative regulation of glial cell apoptotic process (GO:0034351), intracellular signal transduction (GO:0035556), positive regulation of keratinocyte differentiation (GO:0045618), positive regulation of B cell receptor signaling pathway (GO:0050861), obsolete positive regulation of NF-kappaB transcription factor activity (GO:0051092), positive regulation of glial cell proliferation (GO:0060252), phospholipase C/protein kinase C signal transduction (GO:0141212), positive regulation of protein localization to plasma membrane (GO:1903078), regulation of bicellular tight junction assembly (GO:2000810)

GO Molecular Function (17): protein serine/threonine kinase inhibitor activity (GO:0030291), translation regulator activity (GO:0045182), protein serine/threonine kinase binding (GO:0120283), protein kinase activity (GO:0004672), protein serine/threonine kinase activity (GO:0004674), diacylglycerol-dependent serine/threonine kinase activity (GO:0004697), diacylglycerol-dependent, calcium-independent serine/threonine kinase activity (GO:0004699), ATP binding (GO:0005524), zinc ion binding (GO:0008270), enzyme binding (GO:0019899), small GTPase binding (GO:0031267), protein serine kinase activity (GO:0106310), nucleotide binding (GO:0000166), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740), metal ion binding (GO:0046872)

GO Cellular Component (7): cytoplasm (GO:0005737), cytosol (GO:0005829), plasma membrane (GO:0005886), cell-cell junction (GO:0005911), extracellular exosome (GO:0070062), membrane (GO:0016020), sarcolemma (GO:0042383)

Reactome top-level categories

Rollup of top-6 pathways:

Category	Pathways
GPCR downstream signalling	2
G alpha (q) signalling events	1
Platelet activation, signaling and aggregation	1
Signal Transduction	1
Signaling by GPCR	1
Hemostasis	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
translation	2
regulation of translation	2
intracellular anatomical structure	2
protein serine/threonine kinase activity	2
protein kinase activity	2
negative regulation of gene expression	1
negative regulation of protein metabolic process	1
cellular response to stress	1
regulation of translation in response to stress	1
positive regulation of translation	1
cellular response to starvation	1
response to amino acid starvation	1
phosphorylation	1
protein modification process	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
macrophage derived foam cell differentiation	1
regulation of macrophage derived foam cell differentiation	1
positive regulation of cell differentiation	1
cellular developmental process	1
glial cell apoptotic process	1
regulation of glial cell apoptotic process	1
negative regulation of apoptotic process	1
signal transduction	1
keratinocyte differentiation	1
positive regulation of epidermal cell differentiation	1
regulation of keratinocyte differentiation	1
positive regulation of multicellular organismal process	1
B cell receptor signaling pathway	1
regulation of B cell receptor signaling pathway	1
positive regulation of antigen receptor-mediated signaling pathway	1
positive regulation of cell population proliferation	1
glial cell proliferation	1
positive regulation of gliogenesis	1
regulation of glial cell proliferation	1
intracellular signaling cassette	1

Protein interactions and networks

STRING

0 interactions, top by confidence (×1000):

IntAct

0 interactions, top by confidence:

ESM2 similar proteins: A0JNN8, A4IFR0, A5PK62, A6NC62, A6NNL5, A8MTW9, B3H4Y2, C0HM02, C1BJQ3, C9JXX5, D2HJ50, L7N648, O09800, O19098, P03165, P0C171, P0C172, P0C689, P0DW50, P12912, P45440, Q08648, Q0VG49, Q4R1S1, Q4R1S9, Q5BKU9, Q5BLP8, Q5R7Q6, Q64902, Q69027, Q69607, Q6NNL9, Q6PDA7, Q84VK7, Q86SI9, Q8CF31, Q8JMY3, Q8K1M5, Q8MJV4, Q8NG41

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	136
Likely benign	2
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

2728 predictions. Top by Δscore:

Variant	Effect	Δscore
14:61322460:GTTGG:G	donor_gain	1.0000
14:61322465:G:GG	donor_gain	1.0000
14:61391219:TTGTA:T	acceptor_loss	1.0000
14:61391220:TGTAG:T	acceptor_loss	1.0000
14:61391221:GTAG:G	acceptor_loss	1.0000
14:61391222:TAGG:T	acceptor_loss	1.0000
14:61391223:A:AG	acceptor_gain	1.0000
14:61391223:AGGT:A	acceptor_gain	1.0000
14:61391223:AGGTG:A	acceptor_gain	1.0000
14:61391224:G:A	acceptor_loss	1.0000
14:61391224:G:GG	acceptor_gain	1.0000
14:61391224:GGT:G	acceptor_gain	1.0000
14:61391224:GGTG:G	acceptor_gain	1.0000
14:61391224:GGTGG:G	acceptor_gain	1.0000
14:61391287:AGGTA:A	donor_loss	1.0000
14:61391288:GGTA:G	donor_loss	1.0000
14:61391289:GT:G	donor_loss	1.0000
14:61391290:T:G	donor_loss	1.0000
14:61443102:A:AG	acceptor_gain	1.0000
14:61443103:A:G	acceptor_gain	1.0000
14:61443104:T:G	acceptor_gain	1.0000
14:61443107:ATAG:A	acceptor_loss	1.0000
14:61443108:T:G	acceptor_gain	1.0000
14:61443109:A:AG	acceptor_gain	1.0000
14:61443109:A:AT	acceptor_loss	1.0000
14:61443110:G:A	acceptor_loss	1.0000
14:61443110:G:GG	acceptor_gain	1.0000
14:61443110:GC:G	acceptor_gain	1.0000
14:61443110:GCT:G	acceptor_gain	1.0000
14:61443110:GCTA:G	acceptor_gain	1.0000

AlphaMissense

4553 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
14:61443197:C:G	H172D	1.000
14:61443204:T:C	F174S	1.000
14:61443236:T:A	C185S	1.000
14:61443236:T:C	C185R	1.000
14:61443237:G:A	C185Y	1.000
14:61443237:G:C	C185S	1.000
14:61443238:C:G	C185W	1.000
14:61443245:T:C	C188R	1.000
14:61443246:G:A	C188Y	1.000
14:61443247:C:G	C188W	1.000
14:61445720:T:A	C203S	1.000
14:61445720:T:C	C203R	1.000
14:61445721:G:C	C203S	1.000
14:61445722:C:G	C203W	1.000
14:61449166:T:C	C206R	1.000
14:61449167:G:A	C206Y	1.000
14:61449168:C:G	C206W	1.000
14:61449179:T:A	V210D	1.000
14:61449190:T:A	C214S	1.000
14:61449190:T:C	C214R	1.000
14:61449191:G:A	C214Y	1.000
14:61449191:G:C	C214S	1.000
14:61449191:G:T	C214F	1.000
14:61449192:C:G	C214W	1.000
14:61449214:T:C	C222R	1.000
14:61449216:T:G	C222W	1.000
14:61450875:C:G	H246D	1.000
14:61450914:T:A	C259S	1.000
14:61450914:T:C	C259R	1.000
14:61450915:G:A	C259Y	1.000

dbSNP variants (sampled 300 via entrez): RS1000008466 (14:61336923 G>T), RS1000012142 (14:61246006 G>C), RS1000014371 (14:61486386 G>T), RS1000015382 (14:61279928 GCCCC>G,GCC,GCCC,GCCCCC), RS1000020111 (14:61437582 C>A,G), RS1000020518 (14:61514848 G>A), RS1000033470 (14:61232003 C>A,T), RS1000037171 (14:61241233 G>A), RS1000051788 (14:61514633 C>T), RS1000054314 (14:61412218 C>G), RS1000061767 (14:61529683 C>T), RS1000063910 (14:61194040 T>G), RS1000065138 (14:61335539 A>C,G), RS1000067102 (14:61208825 C>G,T), RS1000074672 (14:61405920 A>G)

Disease associations

OMIM: gene MIM:605437 | disease phenotypes:

GenCC curated gene-disease

Mondo (1): ischemic stroke (MONDO:1060198)

Orphanet (0):

HPO phenotypes

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

GWAS associations

11 associations (top):

Study	Trait	p-value
GCST001454_12	Rheumatoid arthritis	4.000000e-07
GCST001957_4	Obesity (early onset extreme)	3.000000e-10
GCST002060_5	Word reading	3.000000e-06
GCST002062_5	Reading and spelling	6.000000e-06
GCST002318_90	Rheumatoid arthritis	2.000000e-09
GCST002318_91	Rheumatoid arthritis	4.000000e-09
GCST005011_9	Yeast infection	3.000000e-10
GCST006959_109	Rheumatoid arthritis	1.000000e-07
GCST006959_11	Rheumatoid arthritis	1.000000e-07
GCST008163_615	Height	9.000000e-06
GCST010043_67	Asthma	2.000000e-08

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0005300	word reading
EFO:0005301	reading and spelling ability
EFO:0008412	susceptibility to vaginal yeast infection measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

65 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression	8
bisphenol A	decreases expression, decreases methylation, affects cotreatment, increases methylation	3
trichostatin A	affects cotreatment, increases expression	3
mercuric bromide	increases expression, affects cotreatment	2
entinostat	increases expression, affects cotreatment	2
bisphenol S	affects cotreatment, decreases methylation, increases expression	2
Vorinostat	affects cotreatment, increases expression	2
Panobinostat	affects cotreatment, increases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Tunicamycin	decreases expression	2
Thapsigargin	decreases expression	2
p-Chloromercuribenzoic Acid	affects cotreatment, increases expression	2
aristolochic acid I	increases expression	1
FR900359	affects phosphorylation	1
mivebresib	decreases expression	1
triphenyl phosphate	affects expression	1
propionaldehyde	increases expression	1
sodium arsenite	increases abundance, increases expression	1
cobaltous chloride	decreases expression	1
benzo(e)pyrene	decreases methylation	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
aflatoxin B2	decreases methylation	1
coumarin	decreases phosphorylation	1
1-nitropyrene	increases expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
CGP 52608	affects binding, increases reaction	1
2-palmitoylglycerol	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
beta-hydroxy simvastatin acid	decreases expression	1
abrine	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00077805	PHASE4	COMPLETED	PREVAIL: PREvention of VTE After Acute Ischemic Stroke With LMWH Enoxaparin ( - VTE: Venous Thromboembolism - LMWH: Low Molecular Weight Heparin)
NCT00328640	PHASE4	COMPLETED	Quality Improvement in Stroke Prevention (QUISP)
NCT00697151	PHASE4	COMPLETED	Patent Foramen Ovale in Cryptogenic Stroke Study
NCT00747279	PHASE4	UNKNOWN	Comparison of Two Strategies for Glycemic Control in Acute Ischemic Stroke
NCT00754429	PHASE4	COMPLETED	The Effect of Losartan Versus Amlodipine-based Therapy in Ischemic Stroke (0954-338)(COMPLETED)
NCT00868283	PHASE4	COMPLETED	The Safety and Efficacy of Cerebrolysin in Patients With Acute Ischemic Stroke
NCT00874601	PHASE4	UNKNOWN	Valsartan Efficacy on Modest Blood Pressure Reduction in Acute Ischemic Stroke
NCT00931788	PHASE4	COMPLETED	Preventing Recurrent Vascular Events in Patients With Stroke or Transient Ischemic Attack
NCT00966316	PHASE4	COMPLETED	Establishment and Evaluation to the Effects of a Clinical Pathway for Acute Ischemic Stroke
NCT01088672	PHASE4	COMPLETED	Thrombectomy REvascularization of Large Vessel Occlusions in Acute Ischemic Stroke (TREVO)
NCT01097967	PHASE4	UNKNOWN	Sleep Disordered Breathing in Transient Ischemic Attack (TIA)/Ischemic Stroke and Continuous Positive Airway Pressure (CPAP) Treatment Efficacy
NCT01109836	PHASE4	COMPLETED	Austrian Polyintervention Study to Prevent Cognitive Decline After Ischemic Stroke
NCT01188824	PHASE4	COMPLETED	The Safety and Efficacy of Cilostazol in Ischemic Stroke Patients With Peripheral Arterial Disease (SPAD Study)
NCT01429350	PHASE4	COMPLETED	Assess the Penumbra System in the Treatment of Acute Stroke
NCT01463878	PHASE4	TERMINATED	Enteral Nutrition and Glycemic Variability Neurological Intensive Care Unit Study
NCT01758536	PHASE4	UNKNOWN	Efficacy Study of Huatuo Zaizao Pills in Improving of Neural Function in Acute Ischemic Stroke
NCT01762163	PHASE4	COMPLETED	Efficacy and Safety of Qizhitongluo Capsule in the Recovery Phase of Ischemic Stroke
NCT01862978	PHASE4	UNKNOWN	Safety and Efficacy of Heparin and Nadroparin in the Acute Phase of Ischemic Stroke
NCT01863277	PHASE4	UNKNOWN	Safety Study of Melatonin in Stroke Patients
NCT01919671	PHASE4	COMPLETED	Tongxinluo Capsule in Ischemic Stroke Patients（TISS)
NCT01958957	PHASE4	COMPLETED	A Safety Study of Ginkgolides Meglumine Injection in the Treatment of Ischemic Stroke.
NCT02046031	PHASE4	COMPLETED	Preliminary Study of Pharmacokinetics of Ginkgolides Meglumine Injection.
NCT02122718	PHASE4	COMPLETED	XILO-FIST, the Effect of Allopurinol on the Brain Heart and Blood Pressure After Stroke
NCT02225834	PHASE4	COMPLETED	Atorvastatin in Acute Stroke Treatment
NCT02334969	PHASE4	COMPLETED	Curative Efficacy of Secondary Prevention for Patients With Ischemic Stroke Through Syndrome Differentiation of TCM
NCT02403349	PHASE4	UNKNOWN	Comparison of Peripheral and Cerebral Arterial Flow in Acute Ischemic Stroke: Fimasartan vs. Valsartan vs. Atenolol
NCT02549846	PHASE4	COMPLETED	AdminiStration of Statin On Acute Ischemic stRoke patienT Trial
NCT02581371	PHASE4	UNKNOWN	Comprehensive Reparative Therapy in Ischemic Stroke COMplex Repair in Ischemic Stroke-Arm
NCT02728180	PHASE4	UNKNOWN	Xingnaojing for Moderate-to-severe Acute Ischemic Stroke (XMAS)
NCT02983214	PHASE4	COMPLETED	Diabetic Artery Obstruction: is it Possible to Reduce Ischemic Events With Cilostazol?
NCT03062319	PHASE4	TERMINATED	Optimal Antithrombotic Therapy in Ischemic Stroke Patients with Non-Valvular Atrial Fibrillation and Atherothrombosis
NCT03116269	PHASE4	COMPLETED	The Effect of Cilostazol Compared to Aspirin on Endothelial Function in Acute Cerebral Ischemia Patients
NCT03385538	PHASE4	COMPLETED	Clopidogrel Response and CYP2C19 Genotype in Ischemic Stroke Patients
NCT03413202	PHASE4	COMPLETED	Effectiveness of Butylphthalide on Dynamic Cerebral Autoregulation in Patients With Acute Ischemic Stroke.
NCT03431909	PHASE4	COMPLETED	Evaluation Of HUK in Acute Stroke Patients: MRS and CTP
NCT03494530	PHASE4	COMPLETED	Lixiana Acute Stroke Evaluation Registry
NCT03529149	PHASE4	UNKNOWN	TCD Monitoring Technology Guides the Precise Control of Blood Pressure After EVT
NCT03686163	PHASE4	COMPLETED	Effects of Intranasal Nerve Growth Factor for Acute Ischemic Stroke
NCT03871517	PHASE4	COMPLETED	INdobufen Versus aSpirin in acUte Ischemic stRokE,INSURE
NCT04150835	PHASE4	UNKNOWN	Xingnaojing for Mild-to-severe Acute Ischemic Stroke