EVX2

Summary

EVX2 (even-skipped homeobox 2, HGNC:3507) is a protein-coding gene on chromosome 2q31.1, encoding Homeobox even-skipped homolog protein 2 (Q03828).

This gene is located at the 5’ end of the HOXD gene cluster on chromosome 2. The encoded protein is a homeobox transcription factor that is related to the protein encoded by the Drosophila even-skipped (eve) gene, a member of the pair-rule class of segmentation genes. A 117 kb microdeletion at the 5’ end of the HOXD gene cluster, which includes this gene and the HOXD9-HOXD13 genes, causes synpolydactyly, a dominantly inherited disease resulting in limb malformation.

Source: NCBI Gene 344191 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 106 total — 1 pathogenic, 1 likely-pathogenic
• Dosage sensitivity (ClinGen): haploinsufficiency no evidence, triplosensitivity no evidence
• MANE Select transcript: NM_001080458

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3507
Approved symbol	EVX2
Name	even-skipped homeobox 2
Location	2q31.1
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000174279
Ensembl biotype	protein_coding
OMIM	142991
Entrez	344191

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000308618

RefSeq mRNA: 1 — MANE Select: NM_001080458 NM_001080458

CCDS: CCDS33333

Canonical transcript exons

ENST00000308618 — 3 exons

Exon	Start	End
ENSE00001195181	176077472	176080838
ENSE00001195185	176082178	176082449
ENSE00001272644	176083350	176083962

Expression profiles

Bgee: expression breadth broad, 25 present calls, max score 88.56.

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	88.56	gold quality
calcaneal tendon	UBERON:0003701	76.36	gold quality
ectocervix	UBERON:0012249	60.31	gold quality
vagina	UBERON:0000996	57.42	gold quality
left testis	UBERON:0004533	56.19	gold quality
right testis	UBERON:0004534	56.04	gold quality
uterine cervix	UBERON:0000002	55.71	gold quality
muscle layer of sigmoid colon	UBERON:0035805	55.60	gold quality
testis	UBERON:0000473	55.55	gold quality
endocervix	UBERON:0000458	54.62	gold quality
prostate gland	UBERON:0002367	51.13	gold quality
colonic epithelium	UBERON:0000397	49.02	gold quality
rectum	UBERON:0001052	46.13	gold quality
urinary bladder	UBERON:0001255	39.65	gold quality
sural nerve	UBERON:0015488	39.63	gold quality
stromal cell of endometrium	CL:0002255	38.76	gold quality
bone marrow cell	CL:0002092	38.08	gold quality
colon	UBERON:0001155	37.82	gold quality
ventricular zone	UBERON:0003053	36.48	gold quality
cortical plate	UBERON:0005343	36.47	gold quality
ganglionic eminence	UBERON:0004023	35.49	gold quality
skeletal muscle tissue	UBERON:0001134	34.72	gold quality
mucosa of transverse colon	UBERON:0004991	33.76	gold quality
intestine	UBERON:0000160	33.56	gold quality
bone marrow	UBERON:0002371	32.72	gold quality
monocyte	CL:0000576	32.66	gold quality
leukocyte	CL:0000738	32.20	gold quality
hindlimb stylopod muscle	UBERON:0004252	32.15	gold quality
muscle tissue	UBERON:0002385	32.04	gold quality
muscle of leg	UBERON:0001383	30.80	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.81

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

2 targets.

Target	Regulation
BMP4
HMGB1

JASPAR motifs

Motif	Name	Family
MA0888.1	EVX2	HOX
MA0888.2	EVX2	HOX

JASPAR matrix evidence (PMIDs): PMID:18585359

Upstream regulators (CollecTRI, top): EZH2

Functional genomics

ClinGen dosage: haploinsufficiency 0 (no evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 2)

• 117-kb microdeletion removing HOXD9-HOXD13 and EVX2 causes synpolydactyly (PMID:11778160)
• Amplifications of EVX2 and HOXD9-HOXD13 on 2q31 in mature cystic teratomas of the ovary identified by array comparative genomic hybridization may explain teratoma characteristics in chondrogenesis and osteogenesis. (PMID:38907278)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	evx2	ENSDARG00000059255
mus_musculus	Evx2	ENSMUSG00000001815
rattus_norvegicus	Evx2	ENSRNOG00000001589

Paralogs (50): ARX (ENSG00000004848), PAX6 (ENSG00000007372), PAX7 (ENSG00000009709), ALX4 (ENSG00000052850), GSC2 (ENSG00000063515), PITX1 (ENSG00000069011), PAX2 (ENSG00000075891), RHOXF1 (ENSG00000101883), CRX (ENSG00000105392), EVX1 (ENSG00000106038), 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), PROP1 (ENSG00000175325), ISX (ENSG00000175329), ALX1 (ENSG00000180318), MIXL1 (ENSG00000185155), SHOX (ENSG00000185960)

Protein

Protein identifiers

Homeobox even-skipped homolog protein 2 — Q03828 (reviewed: Q03828)

Alternative names: EVX-2

All UniProt accessions (1): Q03828

UniProt curated annotations — full annotation on UniProt →

Subcellular location. Nucleus.

Similarity. Belongs to the even-skipped homeobox family.

RefSeq proteins (1): NP_001073927* (*=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 (7 total): compositionally biased region 3, region of interest 2, chain 1, DNA-binding region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q03828-F1	56.44	0.14

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 37 (showing top): MISSIAGLIA_REGULATED_BY_METHYLATION_UP, DAWSON_METHYLATED_IN_LYMPHOMA_TCL1, GOBP_APPENDAGE_DEVELOPMENT, RIZ_ERYTHROID_DIFFERENTIATION_APOBEC2, GOMF_SEQUENCE_SPECIFIC_DNA_BINDING, MIKKELSEN_MCV6_HCP_WITH_H3K27ME3, MIKKELSEN_IPS_WITH_HCP_H3K27ME3, MIKKELSEN_NPC_HCP_WITH_H3K27ME3, GOBP_APPENDAGE_MORPHOGENESIS, DELACROIX_RARG_BOUND_MEF, DELACROIX_RAR_TARGETS_UP, GOMF_TRANSCRIPTION_REGULATOR_ACTIVITY, CBX7_TARGET_GENES, HSD17B8_TARGET_GENES, ZNF596_TARGET_GENES

GO Biological Process (3): regulation of transcription by RNA polymerase II (GO:0006357), limb morphogenesis (GO:0035108), 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), sequence-specific double-stranded DNA binding (GO:1990837), DNA binding (GO:0003677), protein binding (GO:0005515)

GO Cellular Component (2): chromatin (GO:0000785), nucleus (GO:0005634)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
RNA polymerase II transcription regulatory region sequence-specific DNA binding	2
regulation of DNA-templated transcription	1
transcription by RNA polymerase II	1
appendage morphogenesis	1
limb development	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
regulation of transcription by RNA polymerase II	1
double-stranded DNA binding	1
sequence-specific DNA binding	1
nucleic acid binding	1
binding	1
chromosome	1
cellular anatomical structure	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

584 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
EVX2	LNPK	Q9C0E8	880
EVX2	MTX2	O75431	837
EVX2	HOXD11	P31277	608
EVX2	HOXD10	P28358	601
EVX2	HOXD12	P35452	583
EVX2	SPOP	O43791	549
EVX2	SHH	Q15465	532
EVX2	LHX1	P48742	521
EVX2	HOXD13	P35453	496
EVX2	RAB2A	P08886	493
EVX2	HOXD9	P28356	475
EVX2	ISL1	P20663	466
EVX2	ALDH1A2	O94788	448
EVX2	GRIN1	P35437	411
EVX2	MTX1	Q13505	406

IntAct

29 interactions, top by confidence:

A	B	Type	Score
EVX2	KRTAP19-5	psi-mi:“MI:0915”(physical association)	0.560
EVX2	DMAC2L	psi-mi:“MI:0915”(physical association)	0.560
BPIFB3	EVX2	psi-mi:“MI:0915”(physical association)	0.560
EVX2	LASP1	psi-mi:“MI:0915”(physical association)	0.560
EVX2	CNFN	psi-mi:“MI:0915”(physical association)	0.560
EVX2	ITIH6	psi-mi:“MI:0915”(physical association)	0.560
EVX2	KRTAP19-7	psi-mi:“MI:0915”(physical association)	0.560
EVX2	ZMYND12	psi-mi:“MI:0915”(physical association)	0.560
EVX2	KRTAP6-1	psi-mi:“MI:0915”(physical association)	0.560
	EVX2	psi-mi:“MI:0915”(physical association)	0.370
EVX2	CNFN	psi-mi:“MI:0915”(physical association)	0.000
EVX2	DMAC2L	psi-mi:“MI:0915”(physical association)	0.000
EVX2	BPIFB3	psi-mi:“MI:0915”(physical association)	0.000
EVX2	LASP1	psi-mi:“MI:0915”(physical association)	0.000
EVX2	ITIH6	psi-mi:“MI:0915”(physical association)	0.000
EVX2	ZMYND12	psi-mi:“MI:0915”(physical association)	0.000
EVX2	KRTAP6-1	psi-mi:“MI:0915”(physical association)	0.000
EVX2	KRTAP19-7	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (10): EVX2 (Two-hybrid), EVX2 (Two-hybrid), EVX2 (Two-hybrid), EVX2 (Two-hybrid), EVX2 (Two-hybrid), KRTAP6-1 (Two-hybrid), BPIFB3 (Two-hybrid), KRTAP19-5 (Two-hybrid), KRTAP19-7 (Two-hybrid), EVX2 (Affinity Capture-MS)

ESM2 similar proteins: A0JPN1, A2A9A2, A6NHT5, A6YP92, A7MB54, E9PZZ1, M0R6D8, O02786, O08934, O35085, O35762, O42115, O60902, P09065, P13297, P23683, P28360, P42581, P49640, P49749, P50223, P70390, P78413, P78415, P81067, P97830, Q03828, Q14549, Q14774, Q1XID0, Q2NKI2, Q2VL76, Q2VL77, Q2VL78, Q2VL79, Q2VL80, Q2VL82, Q2VL83, Q2VL84, Q2VL85

Diamond homologs: A1L2P5, A1YF08, A1YG01, A1YG85, A1YGA4, A2D4R4, A2D649, A2T6H5, A2T6Z0, A2T756, A2T779, A2T7J2, A2T7T2, A8DT10, A9L937, B0VXK3, F1Q4R9, M0R6D8, O42365, O42367, O42368, O42370, O43364, O43365, O93353, P02831, P06602, P09022, P09026, P09027, P09070, P09631, P09638, P0C1T1, P10181, P14651, P14652, P14653, P14837, P17138

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	1
Uncertain significance	97
Likely benign	6
Benign	1

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
148781	GRCh38/hg38 2q31.1(chr2:176075289-176156257)x1	Pathogenic
3239637	NC_000002.12:g.176073523_176079120del	Likely pathogenic

SpliceAI

295 predictions. Top by Δscore:

Variant	Effect	Δscore
2:176082172:TGATA:T	donor_loss	1.0000
2:176082173:GATAC:G	donor_loss	1.0000
2:176082174:ATACC:A	donor_loss	1.0000
2:176082177:C:CA	donor_loss	1.0000
2:176080834:CACAC:C	acceptor_gain	0.9900
2:176080836:CAC:C	acceptor_gain	0.9900
2:176080839:C:CA	acceptor_loss	0.9900
2:176082448:CC:C	acceptor_gain	0.9900
2:176082449:CC:C	acceptor_gain	0.9900
2:176082450:C:CC	acceptor_gain	0.9900
2:176082454:C:CT	acceptor_gain	0.9900
2:176083345:GTTAC:G	donor_loss	0.9900
2:176083346:TTACC:T	donor_loss	0.9900
2:176083347:TACC:T	donor_loss	0.9900
2:176083348:A:C	donor_loss	0.9900
2:176082445:GTACC:G	acceptor_gain	0.9800
2:176082446:TACC:T	acceptor_gain	0.9800
2:176082447:ACC:A	acceptor_gain	0.9800
2:176082448:CCC:C	acceptor_gain	0.9800
2:176082451:T:A	acceptor_loss	0.9800
2:176082455:A:T	acceptor_gain	0.9800
2:176082458:C:CT	acceptor_gain	0.9800
2:176083344:GGTTA:G	donor_loss	0.9800
2:176083364:T:TA	donor_gain	0.9800
2:176080839:C:CC	acceptor_gain	0.9700
2:176082176:A:AC	donor_gain	0.9700
2:176082177:C:CC	donor_gain	0.9700
2:176080835:ACAC:A	acceptor_gain	0.9600
2:176080836:CACC:C	acceptor_gain	0.9600
2:176082447:ACCCT:A	acceptor_gain	0.9600

AlphaMissense

3029 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:176080782:C:A	W252C	1.000
2:176080782:C:G	W252C	1.000
2:176080784:A:G	W252R	1.000
2:176080784:A:T	W252R	1.000
2:176080801:T:G	Q246P	1.000
2:176080806:C:A	K244N	1.000
2:176080806:C:G	K244N	1.000
2:176080807:T:A	K244M	1.000
2:176080807:T:G	K244T	1.000
2:176080808:T:C	K244E	1.000
2:176080808:T:G	K244Q	1.000
2:176080810:T:A	D243V	1.000
2:176080810:T:C	D243G	1.000
2:176080810:T:G	D243A	1.000
2:176080812:C:A	K242N	1.000
2:176080812:C:G	K242N	1.000
2:176080813:T:A	K242M	1.000
2:176080813:T:G	K242T	1.000
2:176080814:T:C	K242E	1.000
2:176080814:T:G	K242Q	1.000
2:176080815:C:A	M241I	1.000
2:176080815:C:G	M241I	1.000
2:176080815:C:T	M241I	1.000
2:176080816:A:C	M241R	1.000
2:176080816:A:G	M241T	1.000
2:176080816:A:T	M241K	1.000
2:176080819:C:G	R240P	1.000
2:176080819:C:T	R240H	1.000
2:176080820:G:A	R240C	1.000
2:176080820:G:C	R240G	1.000

dbSNP variants (sampled 300 via entrez): RS1000025466 (2:176079771 G>A,T), RS1000035439 (2:176080070 G>A), RS1001032356 (2:176078168 A>G), RS1001043959 (2:176078530 A>G), RS1001240068 (2:176085202 T>G), RS1002481431 (2:176084654 C>T), RS1002778136 (2:176084893 C>G), RS1003825930 (2:176084537 C>T), RS1003939813 (2:176077199 G>C), RS1004839287 (2:176083014 G>A,C,T), RS1005842914 (2:176081603 A>G), RS1006066014 (2:176081842 G>A), RS1007233926 (2:176079911 G>A,C), RS1007453298 (2:176080695 G>C), RS1007669396 (2:176081711 C>G)

Disease associations

OMIM: gene MIM:142991 | disease phenotypes: MIM:186000

GenCC curated gene-disease

Mondo (1): synpolydactyly type 1 (MONDO:0008513)

Orphanet (1): Synpolydactyly type 1 (Orphanet:295195)

HPO phenotypes

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

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST001588_10	Periodontal microbiota	4.000000e-06
GCST006661_148	Male-pattern baldness	3.000000e-18
GCST009391_1326	Metabolite levels	3.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0010361	lysophosphatidylcholine 18:2 measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

6 total (human), top 6 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression	1
Arsenic	affects methylation	1
Benzo(a)pyrene	increases methylation	1
Aflatoxin B1	decreases methylation	1
Asbestos, Crocidolite	decreases methylation	1
Asbestos, Amosite	decreases methylation	1

Clinical trials (associated diseases)

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