EVX1

Summary

EVX1 (even-skipped homeobox 1, HGNC:3506) is a protein-coding gene on chromosome 7p15.2, encoding Homeobox even-skipped homolog protein 1 (P49640). May play a role in the specification of neuronal cell types.

This gene encodes a member of the even-skipped homeobox family characterized by the presence of a homeodomain closely related to the Drosophila even-skipped (eve) segmentation gene of the pair-rule class. The encoded protein may play an important role as a transcriptional repressor during embryogenesis.

Source: NCBI Gene 2128 — RefSeq curated summary.

At a glance

• GWAS associations: 31
• Clinical variants (ClinVar): 76 total — 1 pathogenic
• MANE Select transcript: NM_001989

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3506
Approved symbol	EVX1
Name	even-skipped homeobox 1
Location	7p15.2
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000106038
Ensembl biotype	protein_coding
OMIM	142996
Entrez	2128

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 3 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000222761, ENST00000496902, ENST00000518886, ENST00000580535

RefSeq mRNA: 3 — MANE Select: NM_001989 NM_001304519, NM_001304520, NM_001989

CCDS: CCDS5413

Canonical transcript exons

ENST00000496902 — 3 exons

Exon	Start	End
ENSE00000832103	27242802	27243457
ENSE00001891220	27245886	27247830
ENSE00003630409	27245048	27245304

Expression profiles

Bgee: expression breadth ubiquitous, 144 present calls, max score 95.68.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.0872 / max 11.6626, expressed in 39 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
77819	0.0585	27
77818	0.0286	13

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
type B pancreatic cell	CL:0000169	95.68	silver quality
olfactory bulb	UBERON:0002264	95.66	silver quality
cervix squamous epithelium	UBERON:0006922	93.34	silver quality
vena cava	UBERON:0004087	92.71	gold quality
cardia of stomach	UBERON:0001162	92.20	silver quality
body of tongue	UBERON:0011876	91.64	gold quality
renal medulla	UBERON:0000362	91.30	gold quality
male germ cell	CL:0000015	91.22	silver quality
sperm	CL:0000019	90.71	silver quality
tongue	UBERON:0001723	90.67	silver quality
subthalamic nucleus	UBERON:0001906	90.56	silver quality
ventral tegmental area	UBERON:0002691	90.55	silver quality
inferior vagus X ganglion	UBERON:0005363	90.49	silver quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	90.43	gold quality
dorsal plus ventral thalamus	UBERON:0001897	90.14	silver quality
pylorus	UBERON:0001166	90.11	gold quality
tongue squamous epithelium	UBERON:0006919	90.05	silver quality
nipple	UBERON:0002030	89.80	silver quality
pericardium	UBERON:0002407	89.75	gold quality
lateral nuclear group of thalamus	UBERON:0002736	89.56	silver quality
superior surface of tongue	UBERON:0007371	89.52	silver quality
lateral globus pallidus	UBERON:0002476	89.35	silver quality
triceps brachii	UBERON:0001509	89.25	gold quality
substantia nigra pars reticulata	UBERON:0001966	89.22	silver quality
trachea	UBERON:0003126	89.13	silver quality
cervix epithelium	UBERON:0004801	88.99	silver quality
substantia nigra pars compacta	UBERON:0001965	88.79	silver quality
pons	UBERON:0000988	88.77	silver quality
pharyngeal mucosa	UBERON:0000355	88.76	silver quality
trigeminal ganglion	UBERON:0001675	88.64	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	1.95

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

4 targets.

Target	Regulation
GSC	Repression
INHBA
SLU7
TNC	Activation

JASPAR motifs

Motif	Name	Family
MA0887.1	EVX1	HOX
MA0887.2	EVX1	HOX
MA1960.1	MGA::EVX1	TBX6-related factors::HOX
MA1960.2	MGA::EVX1	TBX6-related factors::HOX

JASPAR matrix evidence (PMIDs): PMID:18585359, PMID:24218641

Upstream regulators (CollecTRI, top): GSC

miRNA regulators (miRDB)

62 targeting EVX1, 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-574-5P	100.00	66.01	989
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-6783-3P	99.89	67.92	2059
HSA-MIR-1343-3P	99.89	66.78	1815
HSA-MIR-137-3P	99.87	74.74	2401
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-204-5P	99.79	71.62	2439
HSA-MIR-211-5P	99.79	71.65	2440
HSA-MIR-4766-5P	99.75	69.23	2662
HSA-MIR-1825	99.72	68.11	1089
HSA-MIR-4755-5P	99.71	70.34	2716
HSA-MIR-5006-3P	99.71	70.26	2728
HSA-MIR-6892-3P	99.68	66.40	1178
HSA-MIR-466	99.67	70.85	2863
HSA-MIR-4310	99.59	68.84	2527
HSA-MIR-6716-5P	99.56	68.62	1244
HSA-MIR-4672	99.50	71.58	2893
HSA-MIR-4441	99.49	66.56	3216
HSA-MIR-3915	99.45	68.49	1905
HSA-MIR-4735-5P	99.43	68.49	1780
HSA-MIR-208A-5P	99.42	70.83	1913
HSA-MIR-208B-5P	99.42	70.83	1952
HSA-MIR-4312	99.34	67.30	511
HSA-MIR-3064-5P	99.26	66.13	1497

Literature-anchored findings (GeneRIF, showing 2)

• Even-skipped homeobox 1 controls human embryonic stem cell differentiation by directly repressing Goosecoid expression. (PMID:22178155)
• Low EVX1 expression is Correlated with Aggressiveness of Esophageal Squamous Cell Carcinoma. (PMID:26552663)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	EVX1	ENSDARG00000100087
mus_musculus	Evx1	ENSMUSG00000005503
rattus_norvegicus	Evx1	ENSRNOG00000046734

Paralogs (50): ARX (ENSG00000004848), PAX6 (ENSG00000007372), PAX7 (ENSG00000009709), ALX4 (ENSG00000052850), GSC2 (ENSG00000063515), PITX1 (ENSG00000069011), PAX2 (ENSG00000075891), RHOXF1 (ENSG00000101883), CRX (ENSG00000105392), PAX4 (ENSG00000106331), NOBOX (ENSG00000106410), PITX3 (ENSG00000107859), PHOX2B (ENSG00000109132), OTX1 (ENSG00000115507), PRRX1 (ENSG00000116132), VSX2 (ENSG00000119614), ESX1 (ENSG00000123576), PAX8 (ENSG00000125618), PAX1 (ENSG00000125813), RHOXF2 (ENSG00000131721), GSC (ENSG00000133937), RAX (ENSG00000134438), PAX3 (ENSG00000135903), ALX3 (ENSG00000156150), HESX1 (ENSG00000163666), PITX2 (ENSG00000164093), UNCX (ENSG00000164853), PHOX2A (ENSG00000165462), OTX2 (ENSG00000165588), DRGX (ENSG00000165606), PRRX2 (ENSG00000167157), SHOX2 (ENSG00000168779), OTP (ENSG00000171540), RAX2 (ENSG00000173976), EVX2 (ENSG00000174279), PROP1 (ENSG00000175325), ISX (ENSG00000175329), ALX1 (ENSG00000180318), MIXL1 (ENSG00000185155), SHOX (ENSG00000185960)

Protein

Protein identifiers

Homeobox even-skipped homolog protein 1 — P49640 (reviewed: P49640)

Alternative names: EVX-1

All UniProt accessions (3): P49640, F8W9J5, J3QQJ1

UniProt curated annotations — full annotation on UniProt →

Function. May play a role in the specification of neuronal cell types.

Subcellular location. Nucleus.

Similarity. Belongs to the even-skipped homeobox family.

Isoforms (2)

UniProt ID	Names	Canonical?
P49640-1	1	yes
P49640-2	2

RefSeq proteins (3): NP_001291448, NP_001291449, NP_001980* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001356	HD	Domain
IPR009057	Homeodomain-like_sf	Homologous_superfamily
IPR017970	Homeobox_CS	Conserved_site
IPR020479	HD_metazoa	Domain
IPR052002	Even-skipped_HD	Family

Pfam: PF00046

UniProt features (6 total): region of interest 2, chain 1, DNA-binding region 1, compositionally biased region 1, splice variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P49640-F1	57.95	0.16

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 115 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_MCMV_INFECTION_UP, RNGTGGGC_UNKNOWN, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, BENPORATH_ES_WITH_H3K27ME3, GRUETZMANN_PANCREATIC_CANCER_DN, PAX4_01, ENK_UV_RESPONSE_KERATINOCYTE_UP, GOBP_NEUROGENESIS, RIZKI_TUMOR_INVASIVENESS_3D_DN, GGGTGGRR_PAX4_03, FOXD3_01, CREB_Q4, GOBP_NEURON_MIGRATION, CREB_Q2_01, LYF1_01

GO Biological Process (7): regulation of transcription by RNA polymerase II (GO:0006357), embryo development ending in birth or egg hatching (GO:0009792), ventral spinal cord interneuron specification (GO:0021521), positive regulation of transcription by RNA polymerase II (GO:0045944), spinal cord interneuron axon guidance (GO:0097377), interneuron migration (GO:1904936), regulation of DNA-templated transcription (GO:0006355)

GO Molecular Function (5): RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), DNA-binding transcription factor activity (GO:0003700), sequence-specific double-stranded DNA binding (GO:1990837), DNA binding (GO:0003677)

GO Cellular Component (5): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), axon (GO:0030424), neuronal cell body (GO:0043025)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regulation of DNA-templated transcription	2
transcription by RNA polymerase II	2
regulation of transcription by RNA polymerase II	2
RNA polymerase II transcription regulatory region sequence-specific DNA binding	2
cellular anatomical structure	2
embryo development	1
neuron fate specification	1
cell fate specification involved in pattern specification	1
ventral spinal cord interneuron fate commitment	1
positive regulation of DNA-templated transcription	1
interneuron axon guidance	1
neuron migration	1
DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
cis-regulatory region sequence-specific DNA binding	1
chromatin	1
DNA-binding transcription factor activity	1
transcription cis-regulatory region binding	1
transcription regulator activity	1
double-stranded DNA binding	1
sequence-specific DNA binding	1
nucleic acid binding	1
chromosome	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
neuron projection	1
somatodendritic compartment	1
cell body	1

Protein interactions and networks

STRING

944 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
EVX1	ISL1	P20663	747
EVX1	LHX1	P48742	746
EVX1	SPOP	O43791	685
EVX1	ISL2	Q96A47	626
EVX1	RAB2A	P08886	564
EVX1	ZNF180	Q9UJW8	533
EVX1	LHX3	Q9UBR4	509
EVX1	GRIN1	P35437	497
EVX1	PAX2	Q02962	491
EVX1	FOXA2	Q9Y261	475
EVX1	OLIG2	Q13516	433
EVX1	GRIN3A	Q8TCU5	423
EVX1	HIBADH	P31937	416
EVX1	CHRD	Q9H2X0	414
EVX1	GRIN3B	O60391	413
EVX1	TBX6	O95947	413

IntAct

0 interactions, top by confidence:

BioGRID (1): EVX1 (Affinity Capture-MS)

ESM2 similar proteins: A0A1W2PQ73, A1YF16, A1YG93, A2RU54, A5PKG8, O02786, O14813, O15353, O35602, O43638, O57601, P13297, P19419, P28360, P35548, P41969, P42580, P43687, P49640, P50223, P50548, P52946, P52950, P63156, P63157, P70459, P78413, Q03358, Q14549, Q2VL78, Q2VL79, Q2VL82, Q2VL83, Q2VL84, Q2VL85, Q2VL86, Q2VL87, Q2VL88, Q5NSW5, Q61575

Diamond homologs: A1YGA4, A2RU54, A2T7T2, A6NCS4, A6NHT5, A8XJD0, G5EE18, M0R6D8, O08686, O35767, O42173, O42230, O43711, O43763, O55144, O57601, O88181, O93366, O93367, O93590, O95231, P15142, P18488, P20269, P22544, P22807, P22809, P23683, P31264, P31314, P42581, P42582, P42583, P43345, P43687, P43688, P48031, P49640, P50219, P50221

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
EVX1	“down-regulates quantity by repression”	GSC	“transcriptional regulation”
GSC	“down-regulates quantity by repression”	EVX1	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	73
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
58544	GRCh38/hg38 7p15.2(chr7:27154807-27422335)x1	Pathogenic

SpliceAI

452 predictions. Top by Δscore:

Variant	Effect	Δscore
7:27245301:CAAG:C	donor_loss	1.0000
7:27245303:AGG:A	donor_loss	1.0000
7:27245306:T:A	donor_loss	1.0000
7:27245881:CCCA:C	acceptor_loss	1.0000
7:27245884:A:AG	acceptor_gain	1.0000
7:27245884:AG:A	acceptor_gain	1.0000
7:27245884:AGGT:A	acceptor_gain	1.0000
7:27245885:G:GA	acceptor_gain	1.0000
7:27245885:GG:G	acceptor_gain	1.0000
7:27245885:GGT:G	acceptor_gain	1.0000
7:27245885:GGTG:G	acceptor_gain	1.0000
7:27245885:GGTGT:G	acceptor_gain	1.0000
7:27245019:C:G	acceptor_gain	0.9900
7:27245020:A:AG	acceptor_gain	0.9900
7:27245021:C:G	acceptor_gain	0.9900
7:27245303:AG:A	donor_gain	0.9900
7:27245304:GG:G	donor_gain	0.9900
7:27245305:G:GG	donor_gain	0.9900
7:27245020:AC:A	acceptor_gain	0.9800
7:27245300:TCAAG:T	donor_gain	0.9800
7:27245018:A:AG	acceptor_gain	0.9700
7:27245018:ACAC:A	acceptor_gain	0.9700
7:27245021:C:CA	acceptor_gain	0.9700
7:27245046:AG:A	acceptor_gain	0.9700
7:27245047:GG:G	acceptor_gain	0.9700
7:27245305:GTAT:G	donor_gain	0.9700
7:27243529:G:GT	donor_gain	0.9600
7:27245301:CAAGG:C	donor_gain	0.9600
7:27245302:AAG:A	donor_gain	0.9600
7:27245302:AAGG:A	donor_gain	0.9600

AlphaMissense

2590 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:27245179:C:A	R187S	1.000
7:27245179:C:G	R187G	1.000
7:27245179:C:T	R187C	1.000
7:27245183:C:T	T188I	1.000
7:27245186:C:A	A189D	1.000
7:27245188:T:A	F190I	1.000
7:27245188:T:C	F190L	1.000
7:27245188:T:G	F190V	1.000
7:27245189:T:C	F190S	1.000
7:27245189:T:G	F190C	1.000
7:27245190:C:A	F190L	1.000
7:27245190:C:G	F190L	1.000
7:27245192:C:T	T191I	1.000
7:27245201:A:C	Q194P	1.000
7:27245201:A:G	Q194R	1.000
7:27245202:G:C	Q194H	1.000
7:27245202:G:T	Q194H	1.000
7:27245204:T:G	I195S	1.000
7:27245213:T:A	L198Q	1.000
7:27245213:T:C	L198P	1.000
7:27245213:T:G	L198R	1.000
7:27245215:G:A	E199K	1.000
7:27245216:A:C	E199A	1.000
7:27245216:A:T	E199V	1.000
7:27245217:G:C	E199D	1.000
7:27245217:G:T	E199D	1.000
7:27245221:G:A	E201K	1.000
7:27245224:T:A	F202I	1.000
7:27245224:T:C	F202L	1.000
7:27245224:T:G	F202V	1.000

dbSNP variants (sampled 300 via entrez): RS1000968982 (7:27243853 G>A), RS1000998666 (7:27243567 G>A,C), RS1001682756 (7:27247092 C>G,T), RS1001962185 (7:27242565 C>T), RS1002920580 (7:27246580 A>C,G), RS1002972974 (7:27241496 A>C), RS1003004198 (7:27241191 G>A,C), RS1003235518 (7:27243783 C>A), RS1003299923 (7:27246342 T>C), RS1003667529 (7:27245664 C>A,T), RS1003718445 (7:27243426 C>A), RS1004663944 (7:27240840 C>T), RS1004982588 (7:27244676 A>G), RS1005064453 (7:27245808 C>G,T), RS1005320398 (7:27244826 A>C)

Disease associations

OMIM: gene MIM:142996 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

31 associations (top):

Study	Trait	p-value
GCST000675_7	Heart failure	7.000000e-06
GCST002143_1	Blood pressure	2.000000e-09
GCST002143_5	Blood pressure	2.000000e-12
GCST002831_8	Lead levels in blood	4.000000e-06
GCST004384_5	Hypertension	9.000000e-09
GCST004385_8	Systolic blood pressure	5.000000e-10
GCST004386_13	Diastolic blood pressure	2.000000e-11
GCST004386_7	Diastolic blood pressure	2.000000e-06
GCST004388_29	Blood pressure traits (multi-trait analysis)	7.000000e-07
GCST004388_30	Blood pressure traits (multi-trait analysis)	1.000000e-06
GCST004388_4	Blood pressure traits (multi-trait analysis)	2.000000e-11
GCST004388_5	Blood pressure traits (multi-trait analysis)	2.000000e-09
GCST006166_4	Diastolic blood pressure x alcohol consumption interaction (2df test)	4.000000e-19
GCST006166_61	Diastolic blood pressure x alcohol consumption interaction (2df test)	5.000000e-11
GCST006167_21	Mean arterial pressure x alcohol consumption interaction (2df test)	2.000000e-08
GCST006167_5	Mean arterial pressure x alcohol consumption interaction (2df test)	4.000000e-17
GCST006167_78	Mean arterial pressure x alcohol consumption interaction (2df test)	1.000000e-09
GCST006169_17	Diastolic blood pressure x alcohol consumption (light vs heavy) interaction (2df test)	4.000000e-11
GCST006169_36	Diastolic blood pressure x alcohol consumption (light vs heavy) interaction (2df test)	4.000000e-08
GCST006170_2	Systolic blood pressure x alcohol consumption (light vs heavy) interaction (2df test)	3.000000e-09
GCST006170_38	Systolic blood pressure x alcohol consumption (light vs heavy) interaction (2df test)	8.000000e-13
GCST006172_1	Mean arterial pressure x alcohol consumption (light vs heavy) interaction (2df test)	1.000000e-13
GCST006172_22	Mean arterial pressure x alcohol consumption (light vs heavy) interaction (2df test)	2.000000e-09
GCST006364_3	Hepatitis B surface antigen seroclearance in chronic hepatitis B infection	3.000000e-06
GCST006434_8	Systolic blood pressure x alcohol consumption interaction (2df test)	9.000000e-23
GCST006979_338	Heel bone mineral density	5.000000e-18
GCST007094_63	Diastolic blood pressure	5.000000e-09
GCST007096_76	Pulse pressure	3.000000e-06
GCST007098_83	Diastolic blood pressure	3.000000e-06
GCST007098_84	Diastolic blood pressure	9.000000e-06

EFO canonical traits (7, from GWAS)

EFO ID	Trait name
EFO:0006336	diastolic blood pressure
EFO:0006335	systolic blood pressure
EFO:0005763	pulse pressure measurement
EFO:0004329	alcohol drinking
EFO:0006340	mean arterial pressure
EFO:0009345	Hepatitis B virus surface antigen seropositivity
EFO:0009270	heel bone mineral density

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

16 total (human), top 16 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
tamibarotene	decreases expression	1
abrine	increases expression	1
bisphenol S	decreases methylation	1
Resveratrol	affects cotreatment, decreases expression	1
Air Pollutants	increases abundance, increases expression	1
Arsenic	affects methylation	1
Benzo(a)pyrene	affects methylation	1
Folic Acid	decreases expression	1
Gold	increases expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Tretinoin	decreases expression	1
Aflatoxin B1	decreases methylation	1
Asbestos, Crocidolite	decreases methylation	1
Asbestos, Amosite	decreases methylation	1
Antirheumatic Agents	decreases expression	1
Particulate Matter	increases abundance, increases expression	1

Cellosaurus cell lines

3 cell lines: 3 embryonic stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_A1P6	SEES3-1V human EVX1, clone1	Embryonic stem cell	Male
CVCL_A1P7	SEES3-1V human EVX1, clone2	Embryonic stem cell	Male
CVCL_A1P8	SEES3-1V human EVX1, clone3	Embryonic stem cell	Male

Clinical trials (associated diseases)

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