EPHX4

Summary

EPHX4 (epoxide hydrolase 4, HGNC:23758) is a protein-coding gene on chromosome 1p22.1, encoding Epoxide hydrolase 4 (Q8IUS5).

Predicted to enable hydrolase activity. Predicted to be located in membrane.

Source: NCBI Gene 253152 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 57 total
• MANE Select transcript: NM_173567

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:23758
Approved symbol	EPHX4
Name	epoxide hydrolase 4
Location	1p22.1
Locus type	gene with protein product
Status	Approved
Aliases	EPHXRP, FLJ90341, EH4
Ensembl gene	ENSG00000172031
Ensembl biotype	protein_coding
OMIM	617401
Entrez	253152

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 2 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000370383, ENST00000480758, ENST00000947706

RefSeq mRNA: 1 — MANE Select: NM_173567 NM_173567

CCDS: CCDS736

Canonical transcript exons

ENST00000370383 — 7 exons

Exon	Start	End
ENSE00001124568	92050317	92050420
ENSE00001124578	92045532	92045660
ENSE00001124583	92042823	92042980
ENSE00001124588	92032505	92032590
ENSE00001207085	92052510	92052658
ENSE00001246410	92063055	92063538
ENSE00001452558	92029985	92030310

Expression profiles

Bgee: expression breadth ubiquitous, 159 present calls, max score 89.17.

FANTOM5 (CAGE): breadth broad, TPM avg 2.0123 / max 42.7918, expressed in 671 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
4024	1.3753	511
4022	0.3597	198
4023	0.2773	163

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	89.17	gold quality
middle temporal gyrus	UBERON:0002771	88.03	gold quality
Brodmann (1909) area 23	UBERON:0013554	87.76	gold quality
Brodmann (1909) area 9	UBERON:0013540	85.48	gold quality
primary visual cortex	UBERON:0002436	85.17	gold quality
prefrontal cortex	UBERON:0000451	84.75	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	84.52	gold quality
endothelial cell	CL:0000115	84.40	gold quality
right frontal lobe	UBERON:0002810	82.58	gold quality
frontal cortex	UBERON:0001870	82.12	gold quality
neocortex	UBERON:0001950	81.47	gold quality
anterior cingulate cortex	UBERON:0009835	81.17	gold quality
caudate nucleus	UBERON:0001873	80.30	gold quality
nucleus accumbens	UBERON:0001882	80.28	gold quality
putamen	UBERON:0001874	80.14	gold quality
occipital lobe	UBERON:0002021	80.00	gold quality
cerebral cortex	UBERON:0000956	78.36	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	78.13	gold quality
superior frontal gyrus	UBERON:0002661	76.92	gold quality
forebrain	UBERON:0001890	74.84	gold quality
Brodmann (1909) area 46	UBERON:0006483	73.85	gold quality
brain	UBERON:0000955	72.31	gold quality
postcentral gyrus	UBERON:0002581	72.06	gold quality
amygdala	UBERON:0001876	71.56	gold quality
temporal lobe	UBERON:0001871	70.79	gold quality
parietal lobe	UBERON:0001872	70.64	gold quality
entorhinal cortex	UBERON:0002728	69.28	silver quality
mucosa of stomach	UBERON:0001199	67.51	gold quality
lower esophagus muscularis layer	UBERON:0035833	66.94	gold quality
lower esophagus	UBERON:0013473	66.90	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)

37 targeting EPHX4, 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-548AW	99.99	72.57	3559
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-493-5P	99.96	72.47	2382
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-3910	99.95	71.13	2227
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192
HSA-MIR-6835-3P	99.93	70.49	2904
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057
HSA-LET-7A-2-3P	99.87	70.53	1921
HSA-LET-7G-3P	99.85	70.43	1929
HSA-MIR-576-5P	99.84	70.46	2582
HSA-MIR-205-5P	99.81	70.05	1557
HSA-MIR-7856-5P	99.75	69.99	2901
HSA-MIR-3714	99.71	70.74	2671
HSA-MIR-1303	99.65	69.77	1662
HSA-MIR-6513-3P	99.59	69.77	1102
HSA-MIR-4328	99.57	71.06	4094
HSA-MIR-4477B	99.23	70.49	1733
HSA-MIR-376A-3P	99.06	69.17	1128
HSA-MIR-376B-3P	99.06	69.17	1128
HSA-MIR-6737-3P	98.95	68.56	1577
HSA-MIR-7157-3P	98.95	68.70	1582
HSA-MIR-3145-3P	98.85	69.07	2031

Literature-anchored findings (GeneRIF, showing 3)

• The identification of two human epoxide hydrolases: EH3 and EH4. (PMID:22798687)
• Relative Importance of Soluble and Microsomal Epoxide Hydrolases for the Hydrolysis of Epoxy-Fatty Acids in Human Tissues. (PMID:34066758)
• Comprehensive analysis of the immune implication of EPHX4 gene in laryngeal squamous cell carcinoma. (PMID:38663041)

Cross-species orthologs

16 orthologs

Organism	Symbol	Gene ID
danio_rerio	ephx4	ENSDARG00000099515
mus_musculus	Ephx4	ENSMUSG00000033805
rattus_norvegicus	Ephx4	ENSRNOG00000023389
drosophila_melanogaster	CG5704	FBGN0026570
drosophila_melanogaster	CG5707	FBGN0026593
drosophila_melanogaster	CG15879	FBGN0035309
drosophila_melanogaster	CG15820	FBGN0035312
drosophila_melanogaster	CG11309	FBGN0037070
drosophila_melanogaster	CG7632	FBGN0037071
caenorhabditis_elegans	C31H5.1	WBGENE00007854
caenorhabditis_elegans		WBGENE00017335
caenorhabditis_elegans		WBGENE00018077
caenorhabditis_elegans		WBGENE00019525
caenorhabditis_elegans		WBGENE00022258
caenorhabditis_elegans		WBGENE00022259
caenorhabditis_elegans		WBGENE00022260

Paralogs (12): ABHD5 (ENSG00000011198), ABHD4 (ENSG00000100439), EPHX3 (ENSG00000105131), ABHD11 (ENSG00000106077), MEST (ENSG00000106484), ABHD14B (ENSG00000114779), EPHX2 (ENSG00000120915), ABHD8 (ENSG00000127220), BPHL (ENSG00000137274), ABHD6 (ENSG00000163686), SERHL2 (ENSG00000183569), ABHD14A (ENSG00000248487)

Protein

Protein identifiers

Epoxide hydrolase 4 — Q8IUS5 (reviewed: Q8IUS5)

Alternative names: Abhydrolase domain-containing protein 7, Epoxide hydrolase-related protein

All UniProt accessions (1): Q8IUS5

UniProt curated annotations — full annotation on UniProt →

Subcellular location. Membrane.

Similarity. Belongs to the AB hydrolase superfamily. Epoxide hydrolase family.

RefSeq proteins (1): NP_775838* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000073	AB_hydrolase_1	Domain
IPR000639	Epox_hydrolase-like	Family
IPR029058	AB_hydrolase_fold	Homologous_superfamily

Pfam: PF00561

UniProt features (8 total): active site 3, chain 1, transmembrane region 1, domain 1, sequence variant 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8IUS5-F1	92.95	0.85

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 (3): 169 (nucleophile); 281 (proton donor); 336 (proton acceptor)

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 67 (showing top): AP1_01, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, AP1_Q4_01, BILD_E2F3_ONCOGENIC_SIGNATURE, TGANTCA_AP1_C, RYTTCCTG_ETS2_B, chr1p22, MEF2_Q6_01, TGCCTTA_MIR124A, CTAWWWATA_RSRFC4_Q2, E4BP4_01, STAT5A_02, GOMF_HYDROLASE_ACTIVITY_ACTING_ON_ETHER_BONDS, GOMF_EPOXIDE_HYDROLASE_ACTIVITY, E2F3_UP.V1_UP

GO Biological Process (0):

GO Molecular Function (4): epoxide hydrolase activity (GO:0004301), hydrolase activity (GO:0016787), catalytic activity (GO:0003824), protein binding (GO:0005515)

GO Cellular Component (1): membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
ether hydrolase activity	1
catalytic activity	1
molecular_function	1
binding	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1142 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
EPHX4	EPHX1	P07099	568
EPHX4	TVP23A	A6NH52	489
EPHX4	ABHD16B	Q9H3Z7	465
EPHX4	ABHD15	Q6UXT9	462
EPHX4	ABHD13	Q7L211	441
EPHX4	COP1	Q8NHY2	439
EPHX4	NEXMIF	Q5QGS0	438
EPHX4	ABHD1	Q96SE0	422
EPHX4	ABHD12B	Q7Z5M8	422
EPHX4	ABHD18	Q0P651	406
EPHX4	ABHD14A	Q9BUJ0	398
EPHX4	ABHD16A	O95870	391
EPHX4	GSC	P56915	388
EPHX4	FBXL17	Q9UF56	386
EPHX4	CACNA1I	Q9P0X4	380

IntAct

24 interactions, top by confidence:

A	B	Type	Score
EPHX4	TMEM14B	psi-mi:“MI:0915”(physical association)	0.560
ARMC6	SLC27A2	psi-mi:“MI:0914”(association)	0.530
PBXIP1	KCNN4	psi-mi:“MI:0914”(association)	0.530
TTYH1	TMEM223	psi-mi:“MI:0914”(association)	0.350
TSPAN15	TMEM223	psi-mi:“MI:0914”(association)	0.350
CGRRF1	TMEM131L	psi-mi:“MI:0914”(association)	0.350
TMEM59	GPR89A	psi-mi:“MI:0914”(association)	0.350
CD3D	CLGN	psi-mi:“MI:0914”(association)	0.350
EPHX4	SERPINB7	psi-mi:“MI:0914”(association)	0.350
GPR182	SLC12A8	psi-mi:“MI:0914”(association)	0.350
PCDHB3	ESYT2	psi-mi:“MI:0914”(association)	0.350
HLA-C	TMEM131L	psi-mi:“MI:0914”(association)	0.350
GPR45	VWA8	psi-mi:“MI:0914”(association)	0.350
HS2ST1	DENND11	psi-mi:“MI:0914”(association)	0.350
MFSD4A	UBXN8	psi-mi:“MI:0914”(association)	0.350
PCDHA12	RPL23	psi-mi:“MI:0914”(association)	0.350
TMEM59	GOLIM4	psi-mi:“MI:0914”(association)	0.350
EPHX4	CCN2	psi-mi:“MI:0914”(association)	0.350
SLC30A3	WWP2	psi-mi:“MI:0914”(association)	0.350
SLC39A7	ESYT2	psi-mi:“MI:0914”(association)	0.350
SLC39A8	CEBPZOS	psi-mi:“MI:0914”(association)	0.350
EPHX4	TMEM14B	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (30): EPHX4 (Affinity Capture-MS), EPHX4 (Two-hybrid), KLK7 (Affinity Capture-MS), RBM6 (Affinity Capture-MS), SERPINA12 (Affinity Capture-MS), SBSN (Affinity Capture-MS), CDSN (Affinity Capture-MS), SERPINB7 (Affinity Capture-MS), RNASE7 (Affinity Capture-MS), EPHX4 (Affinity Capture-MS), EPHX4 (Affinity Capture-MS), EPHX4 (Affinity Capture-MS), EPHX4 (Affinity Capture-MS), EPHX4 (Affinity Capture-MS), EPHX4 (Affinity Capture-MS)

ESM2 similar proteins: A2A7Z8, A7LB60, P08910, P0DKC5, P0DKC6, P22760, P70683, P83006, Q05AK6, Q0P5B7, Q13093, Q14032, Q1LZ86, Q28017, Q32LS6, Q4R2Y9, Q4V8A1, Q502J0, Q5EA42, Q5PPS7, Q5VUY0, Q5VUY2, Q5XI64, Q5ZJL8, Q5ZKL5, Q60963, Q63276, Q6DHN0, Q6GLL2, Q6IE26, Q6P093, Q7L211, Q7M370, Q7SY73, Q7Z5M8, Q802V6, Q80UX8, Q8BM81, Q8IUS5, Q8R2Y0

Diamond homologs: A0A109QYD3, B2JQW2, B9JLT6, J9U5U9, O05235, O07015, P0DXI6, P0DXI7, P0DXI8, Q10J20, Q10QA5, Q48MQ7, Q5X590, Q6IE26, Q8IUS5, Q9SQR3, Q9SZU7, A0A126P745, A1A9R4, A1JMX1, A4VQH7, A4W922, A6T799, A7MB28, A7MFY0, A7ZKB4, A7ZYW4, A8GCT3, A8IAD8, A9W3H8, B0SW62, B1IV88, B1LIZ6, B1M5I5, B1X9D0, B1ZB18, B5XXN3, B5YU51, B6I985, B7KWT4

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	49
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1104 predictions. Top by Δscore:

Variant	Effect	Δscore
1:92030306:TCAAG:T	donor_loss	1.0000
1:92030308:AAG:A	donor_loss	1.0000
1:92030309:AGGT:A	donor_loss	1.0000
1:92030310:GGTG:G	donor_loss	1.0000
1:92030311:G:A	donor_loss	1.0000
1:92030312:T:A	donor_loss	1.0000
1:92032500:TTCA:T	acceptor_loss	1.0000
1:92032503:A:AG	acceptor_gain	1.0000
1:92032503:A:T	acceptor_loss	1.0000
1:92032503:AG:A	acceptor_gain	1.0000
1:92032504:G:GA	acceptor_gain	1.0000
1:92032504:GG:G	acceptor_gain	1.0000
1:92032588:CTGGT:C	donor_loss	1.0000
1:92032589:TGGT:T	donor_loss	1.0000
1:92032590:GGTA:G	donor_loss	1.0000
1:92032591:G:GG	donor_gain	1.0000
1:92032591:GTA:G	donor_loss	1.0000
1:92032592:T:A	donor_loss	1.0000
1:92042817:CTGCA:C	acceptor_loss	1.0000
1:92042818:TGCAG:T	acceptor_loss	1.0000
1:92042819:GCA:G	acceptor_loss	1.0000
1:92042820:CAGGT:C	acceptor_loss	1.0000
1:92042821:A:T	acceptor_loss	1.0000
1:92042822:G:C	acceptor_loss	1.0000
1:92042962:G:GT	donor_gain	1.0000
1:92052506:TTAG:T	acceptor_loss	1.0000
1:92052509:G:GC	acceptor_loss	1.0000
1:92052654:TTCAG:T	donor_gain	1.0000
1:92052655:TCAGG:T	donor_loss	1.0000
1:92052656:CAG:C	donor_gain	1.0000

AlphaMissense

2373 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:92052646:G:C	R282P	0.998
1:92032530:T:A	V86D	0.997
1:92042830:T:A	W109R	0.997
1:92042830:T:C	W109R	0.997
1:92045567:G:T	G171W	0.997
1:92045582:T:A	W176R	0.997
1:92045582:T:C	W176R	0.997
1:92063096:T:C	L300P	0.996
1:92042876:C:A	A124E	0.995
1:92042889:A:C	R128S	0.995
1:92042889:A:T	R128S	0.995
1:92045567:G:A	G171R	0.995
1:92045567:G:C	G171R	0.995
1:92042890:G:C	G129R	0.994
1:92045556:G:A	G167D	0.994
1:92045571:G:A	G172D	0.994
1:92030284:G:C	G69R	0.993
1:92032577:T:C	F102L	0.993
1:92032579:T:A	F102L	0.993
1:92032579:T:G	F102L	0.993
1:92032589:T:A	W106R	0.993
1:92032589:T:C	W106R	0.993
1:92042834:G:C	R110P	0.993
1:92042843:T:C	L113P	0.993
1:92042873:T:A	V123E	0.993
1:92042891:G:A	G129D	0.993
1:92045568:G:A	G171E	0.993
1:92045622:T:C	L189P	0.993
1:92063099:T:C	L301P	0.993
1:92042888:G:C	R128T	0.992

dbSNP variants (sampled 300 via entrez): RS1000105920 (1:92053365 A>G), RS1000287522 (1:92028788 G>A), RS1000368206 (1:92055891 G>A), RS1000457239 (1:92034749 C>G), RS1000568671 (1:92041519 C>T), RS1000578601 (1:92063759 G>C), RS1000697517 (1:92049582 A>G), RS1000702371 (1:92055343 G>A), RS1000811014 (1:92057103 G>A), RS1000878436 (1:92043260 C>G,T), RS1000921705 (1:92054842 T>C), RS1000978477 (1:92049805 A>G), RS1001003540 (1:92036705 A>G,T), RS1001156959 (1:92057363 A>G), RS1001157064 (1:92053930 G>A)

Disease associations

OMIM: gene MIM:617401 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST011105_2	Metamizole-induced agranulocytosis or neutropenia	3.000000e-07

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

19 total (human), top 19 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, increases expression	3
(+)-JQ1 compound	decreases expression	2
terbufos	increases methylation	1
methylparaben	decreases expression	1
zinc chromate	increases expression, increases abundance	1
S-(1,2-dichlorovinyl)cysteine	affects cotreatment, decreases expression, affects response to substance, increases expression	1
di-n-butylphosphoric acid	affects expression	1
chromium hexavalent ion	increases abundance, increases expression	1
2,3,5-trichloro-6-phenyl-(1,4)benzoquinone	increases expression	1
Sunitinib	decreases expression	1
Allergens	increases expression	1
Benzo(a)pyrene	decreases methylation	1
Fonofos	increases methylation	1
Lipopolysaccharides	affects response to substance, increases expression, affects cotreatment, decreases expression	1
Parathion	increases methylation	1
Thiram	decreases expression	1
Tobacco Smoke Pollution	increases expression	1
Vanadates	decreases expression	1
Thapsigargin	increases expression	1

Clinical trials (associated diseases)

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