VAX2

Summary

VAX2 (ventral anterior homeobox 2, HGNC:12661) is a protein-coding gene on chromosome 2p13.3, encoding Ventral anterior homeobox 2 (Q9UIW0). Transcription factor that may function in dorsoventral specification of the forebrain.

This gene encodes a homeobox protein and is almost exclusively expressed in the ventral portion of the retina during development. In mouse studies, this gene was found to be required for the correct formation of the optic fissure and other aspects of retinal development.

Source: NCBI Gene 25806 — RefSeq curated summary.

At a glance

• GWAS associations: 7
• Clinical variants (ClinVar): 85 total
• MANE Select transcript: NM_012476

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12661
Approved symbol	VAX2
Name	ventral anterior homeobox 2
Location	2p13.3
Locus type	gene with protein product
Status	Approved
Aliases	DRES93
Ensembl gene	ENSG00000116035
Ensembl biotype	protein_coding
OMIM	604295
Entrez	25806

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 2 nonsense_mediated_decay, 1 protein_coding

ENST00000234392, ENST00000432367, ENST00000646783

RefSeq mRNA: 1 — MANE Select: NM_012476 NM_012476

CCDS: CCDS1911

Canonical transcript exons

ENST00000234392 — 3 exons

Exon	Start	End
ENSE00000846550	70900576	70900868
ENSE00000846551	70932767	70933446
ENSE00002443742	70921098	70921285

Expression profiles

Bgee: expression breadth ubiquitous, 150 present calls, max score 87.48.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 2.8550 / max 37.8897, expressed in 918 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
20853	2.8550	918

Top tissues by expression

284 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	87.48	gold quality
cerebellar hemisphere	UBERON:0002245	79.21	gold quality
cerebellar cortex	UBERON:0002129	79.14	gold quality
right hemisphere of cerebellum	UBERON:0014890	78.71	gold quality
cerebellum	UBERON:0002037	77.99	gold quality
stromal cell of endometrium	CL:0002255	74.78	gold quality
pigmented layer of retina	UBERON:0001782	73.27	gold quality
retina	UBERON:0000966	73.26	gold quality
hindlimb stylopod muscle	UBERON:0004252	66.15	gold quality
omental fat pad	UBERON:0010414	65.73	gold quality
skin of leg	UBERON:0001511	65.70	gold quality
peritoneum	UBERON:0002358	65.66	gold quality
amygdala	UBERON:0001876	65.23	gold quality
adipose tissue of abdominal region	UBERON:0007808	64.40	gold quality
right uterine tube	UBERON:0001302	64.00	gold quality
body of uterus	UBERON:0009853	63.61	gold quality
body of pancreas	UBERON:0001150	63.51	gold quality
hypothalamus	UBERON:0001898	62.89	gold quality
endocervix	UBERON:0000458	62.86	gold quality
skin of abdomen	UBERON:0001416	62.69	gold quality
left coronary artery	UBERON:0001626	62.26	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	62.04	gold quality
zone of skin	UBERON:0000014	61.88	gold quality
upper leg skin	UBERON:0004262	61.63	silver quality
tibialis anterior	UBERON:0001385	61.45	silver quality
right coronary artery	UBERON:0001625	61.30	gold quality
cranial nerve II	UBERON:0000941	60.98	silver quality
coronary artery	UBERON:0001621	60.98	gold quality
minor salivary gland	UBERON:0001830	60.75	gold quality
apex of heart	UBERON:0002098	60.73	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-CURD-119	yes	18.28
E-ANND-3	no	1.12

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

4 targets.

Target	Regulation
ALDH1A3	Unknown
BMP4
PAX6	Repression
WNT2

JASPAR motifs

Motif	Name	Family
MA0723.1	VAX2	NK
MA0723.2	VAX2	NK
MA0723.3	VAX2	NK

JASPAR matrix evidence (PMIDs): PMID:18585360

miRNA regulators (miRDB)

25 targeting VAX2, 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-8485	100.00	77.57	4731
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-205-3P	99.92	69.92	3165
HSA-MIR-4302	99.89	67.94	1187
HSA-MIR-4271	99.88	68.32	2244
HSA-MIR-30A-3P	99.87	69.74	2928
HSA-MIR-30D-3P	99.87	69.92	2917
HSA-MIR-30E-3P	99.87	69.68	2942
HSA-MIR-204-5P	99.79	71.62	2439
HSA-MIR-211-5P	99.79	71.65	2440
HSA-MIR-623	99.76	68.16	1170
HSA-MIR-92A-2-5P	99.75	67.01	2164
HSA-MIR-12122	99.56	69.33	1672
HSA-MIR-6733-3P	99.54	67.80	1281
HSA-MIR-593-3P	99.22	67.28	1327
HSA-MIR-328-5P	99.08	64.65	1000
HSA-MIR-3922-5P	98.77	66.53	1059
HSA-MIR-6885-5P	98.71	64.33	902
HSA-MIR-1248	98.47	67.54	1314
HSA-MIR-5088-3P	98.29	66.63	1310
HSA-MIR-3921	97.81	67.45	1431
HSA-MIR-4653-5P	97.22	67.72	1429
HSA-MIR-597-5P	96.82	67.57	732
HSA-MIR-616-3P	96.82	66.99	784

Literature-anchored findings (GeneRIF, showing 3)

• A susceptibility locus was identified with lead single nucleotide polymorphism rs3771395 on chromosome 2p13.3 (meta-analysis, P = 1.97 x 10(-7)) in the VAX2 gene for astigmatism. (PMID:23322567)
• Although inappropriate promoter methylation was not invariantly associated with reduced transcript expression, a significant association was apparent for the ARHGEF4, PON3, STAT5a, and VAX2 gene transcripts (P<0.05). Herein, we present the first genome-wide DNA methylation analysis in a unique HG-NMIBC cohort, showing extensive and discrete methylation changes relative to normal bladder and low-intermediate-grade tumor (PMID:26929985)
• This study raises the interesting possibility for evaluating VAX2 as a candidate gene for cone dystrophy. (PMID:29947570)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	vax2	ENSDARG00000058702
mus_musculus	Vax2	ENSMUSG00000034777
rattus_norvegicus	Vax2	ENSRNOG00000013261
drosophila_melanogaster	E5	FBGN0008646
caenorhabditis_elegans	ceh-2	WBGENE00000429

Paralogs (3): EMX1 (ENSG00000135638), VAX1 (ENSG00000148704), EMX2 (ENSG00000170370)

Protein

Protein identifiers

Ventral anterior homeobox 2 — Q9UIW0 (reviewed: Q9UIW0)

All UniProt accessions (4): A0A2R8Y6H5, C9J5E3, Q9UIW0, F1T0K5

UniProt curated annotations — full annotation on UniProt →

Function. Transcription factor that may function in dorsoventral specification of the forebrain. Regulates the expression of Wnt signaling antagonists including the expression of a truncated TCF7L2 isoform that cannot bind CTNNB1 and acts therefore as a potent dominant-negative Wnt antagonist. Plays a crucial role in eye development and, in particular, in the specification of the ventral optic vesicle. May be a regulator of axial polarization in the retina.

Subcellular location. Nucleus.

Similarity. Belongs to the EMX homeobox family.

RefSeq proteins (1): NP_036608* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000047	HTH_motif	Conserved_site
IPR001356	HD	Domain
IPR009057	Homeodomain-like_sf	Homologous_superfamily
IPR017970	Homeobox_CS	Conserved_site
IPR020479	HD_metazoa	Domain
IPR050877	EMX-VAX-Noto_Homeobox_TFs	Family

Pfam: PF00046

UniProt features (8 total): region of interest 2, compositionally biased region 2, sequence variant 2, chain 1, DNA-binding region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UIW0-F1	70.91	0.34

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 111 (showing top): BENPORATH_ES_WITH_H3K27ME3, GOBP_AXIS_SPECIFICATION, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GOBP_NEUROGENESIS, GOBP_DORSAL_VENTRAL_PATTERN_FORMATION, GOBP_FOREBRAIN_DEVELOPMENT, GOBP_ECTODERM_DEVELOPMENT, GOBP_ANIMAL_ORGAN_MORPHOGENESIS, GOBP_EMBRYONIC_ORGAN_MORPHOGENESIS, GOBP_SENSORY_PERCEPTION_OF_LIGHT_STIMULUS, GOBP_HEAD_DEVELOPMENT, GOBP_SENSORY_PERCEPTION, GOBP_EMBRYO_DEVELOPMENT, GOBP_EMBRYONIC_EYE_MORPHOGENESIS, GOBP_SENSORY_ORGAN_DEVELOPMENT

GO Biological Process (15): regulation of transcription by RNA polymerase II (GO:0006357), ectoderm development (GO:0007398), axonogenesis (GO:0007409), central nervous system development (GO:0007417), brain development (GO:0007420), visual perception (GO:0007601), dorsal/ventral axis specification (GO:0009950), Wnt signaling pathway (GO:0016055), neuron differentiation (GO:0030182), forebrain development (GO:0030900), embryonic eye morphogenesis (GO:0048048), retina development in camera-type eye (GO:0060041), negative regulation of transcription by RNA polymerase II (GO:0000122), regulation of DNA-templated transcription (GO:0006355), camera-type eye development (GO:0043010)

GO Molecular Function (9): RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), RNA polymerase II intronic transcription regulatory region sequence-specific DNA binding (GO:0001162), DNA-binding transcription repressor activity, RNA polymerase II-specific (GO:0001227), DNA-binding transcription factor activity (GO:0003700), chromatin DNA binding (GO:0031490), sequence-specific double-stranded DNA binding (GO:1990837), DNA binding (GO:0003677), protein binding (GO:0005515)

GO Cellular Component (3): chromatin (GO:0000785), nucleus (GO:0005634), cytoplasm (GO:0005737)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
RNA polymerase II transcription regulatory region sequence-specific DNA binding	4
regulation of DNA-templated transcription	2
transcription by RNA polymerase II	2
anatomical structure development	2
regulation of transcription by RNA polymerase II	2
cellular anatomical structure	2
tissue development	1
cell morphogenesis involved in neuron differentiation	1
neuron projection morphogenesis	1
axon development	1
nervous system development	1
system development	1
central nervous system development	1
animal organ development	1
head development	1
sensory perception of light stimulus	1
axis specification	1
dorsal/ventral pattern formation	1
cell surface receptor signaling pathway	1
cell differentiation	1
generation of neurons	1
brain development	1
embryonic organ morphogenesis	1
eye morphogenesis	1
camera-type eye development	1
negative regulation of DNA-templated transcription	1
DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
eye development	1
cis-regulatory region sequence-specific DNA binding	1
chromatin	1
DNA-binding transcription factor activity	1
intronic transcription regulatory region sequence-specific DNA binding	1
negative regulation of transcription by RNA polymerase II	1
DNA-binding transcription factor activity, RNA polymerase II-specific	1
DNA-binding transcription repressor activity	1
transcription cis-regulatory region binding	1
transcription regulator activity	1
DNA binding	1

Protein interactions and networks

STRING

690 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
VAX2	PAX2	Q02962	674
VAX2	SIX3	O95343	616
VAX2	SIX6	O95475	592
VAX2	TBX5	Q99593	569
VAX2	ALDH1A3	P47895	440
VAX2	LHX2	P50458	431
VAX2	SHH	Q15465	419
VAX2	PHACTR4	Q8IZ21	417
VAX2	CRYBB1	P53674	383
VAX2	TPRN	Q4KMQ1	367
VAX2	PAX6	P26367	365
VAX2	BMP4	P12644	359
VAX2	ATP6V1B1	P15313	357
VAX2	FOXF1	Q12946	353
VAX2	ATOH7	Q8N100	348

IntAct

14 interactions, top by confidence:

A	B	Type	Score
UFSP1	VAX2	psi-mi:“MI:0915”(physical association)	0.560
PFDN5	VAX2	psi-mi:“MI:0915”(physical association)	0.560
POU6F2	VAX2	psi-mi:“MI:0915”(physical association)	0.560
VAX2	CHMP4A	psi-mi:“MI:0914”(association)	0.530
VAX2	GPX1	psi-mi:“MI:0915”(physical association)	0.400
IFNA7	VAX2	psi-mi:“MI:0915”(physical association)	0.370
VAX2	POU6F2	psi-mi:“MI:0915”(physical association)	0.000
VAX2	PFDN5	psi-mi:“MI:0915”(physical association)	0.000
VAX2	UFSP1	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (11): IMPDH1 (Affinity Capture-MS), CHMP3 (Affinity Capture-MS), CHMP3 (Affinity Capture-MS), CHMP4A (Affinity Capture-MS), VAX2 (Two-hybrid), PFDN5 (Two-hybrid), UFSP1 (Two-hybrid), VAX2 (Affinity Capture-MS), CHMP3 (Affinity Capture-MS), CHMP4A (Affinity Capture-MS), GPX1 (Affinity Capture-MS)

ESM2 similar proteins: A0A1W2PRP0, A6NCS4, A7Y7W2, O14512, O43638, O57601, O70220, O96004, P07812, P09023, P10085, P10284, P17483, P22091, P24899, P50548, P52954, P52955, P55318, P57100, P63156, P63157, P70447, P79772, P97832, Q02346, Q05917, Q0VCE2, Q12952, Q1XID0, Q28555, Q3I5G5, Q3Y598, Q60688, Q61660, Q63244, Q63250, Q64279, Q64305, Q64731

Diamond homologs: A2X7U1, A2X980, A2YR02, A2ZAI7, A3BPF2, A9ZPC9, G5EE18, O93528, P09075, P09076, P14150, P34326, P46607, P46897, Q00400, Q01IK0, Q04896, Q0J9X2, Q0WV12, Q2NKI2, Q336P2, Q5JMF3, Q5SQQ9, Q5ZAY0, Q651Z5, Q69T58, Q6EPF0, Q6H6S3, Q6YWR4, Q6ZAR0, Q707Y6, Q7XUJ5, Q7Y0V7, Q7Y0V9, Q801E0, Q801E1, Q8L7H4, Q8RWU4, Q93V99, Q94C37

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	75
Likely benign	5
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

4038 predictions. Top by Δscore:

Variant	Effect	Δscore
2:70921085:AT:A	acceptor_gain	1.0000
2:70921085:ATG:A	acceptor_gain	1.0000
2:70921086:T:TA	acceptor_gain	1.0000
2:70921087:G:A	acceptor_gain	1.0000
2:70921095:CAG:C	acceptor_loss	1.0000
2:70921096:A:AG	acceptor_gain	1.0000
2:70921096:AGATG:A	acceptor_loss	1.0000
2:70921097:G:GG	acceptor_gain	1.0000
2:70921284:AGGT:A	donor_loss	1.0000
2:70921286:G:C	donor_loss	1.0000
2:70921286:G:GG	donor_gain	1.0000
2:70921287:T:G	donor_loss	1.0000
2:70936069:GTCA:G	donor_gain	1.0000
2:70936073:G:GG	donor_gain	1.0000
2:70958040:T:A	acceptor_gain	1.0000
2:70958042:CCA:C	acceptor_loss	1.0000
2:70958043:CAG:C	acceptor_loss	1.0000
2:70958044:A:AC	acceptor_loss	1.0000
2:70958044:A:AG	acceptor_gain	1.0000
2:70958045:G:GA	acceptor_gain	1.0000
2:70958045:GTT:G	acceptor_gain	1.0000
2:70958141:TCAGG:T	donor_loss	1.0000
2:70958143:AGG:A	donor_loss	1.0000
2:70958145:GT:G	donor_loss	1.0000
2:70958330:CAGGT:C	acceptor_loss	1.0000
2:70958331:A:T	acceptor_loss	1.0000
2:70958332:G:A	acceptor_loss	1.0000
2:70958332:GGT:G	acceptor_gain	1.0000
2:70958417:G:GT	donor_gain	1.0000
2:70958422:GCTGG:G	donor_gain	1.0000

AlphaMissense

1827 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:70921175:T:C	F109L	1.000
2:70921176:T:C	F109S	1.000
2:70921176:T:G	F109C	1.000
2:70921177:C:A	F109L	1.000
2:70921177:C:G	F109L	1.000
2:70921200:T:C	L117P	1.000
2:70921211:T:C	F121L	1.000
2:70921213:C:A	F121L	1.000
2:70921213:C:G	F121L	1.000
2:70921227:A:G	Y126C	1.000
2:70932778:G:C	W149C	1.000
2:70932778:G:T	W149C	1.000
2:70932779:T:A	F150I	1.000
2:70932779:T:C	F150L	1.000
2:70932779:T:G	F150V	1.000
2:70932780:T:C	F150S	1.000
2:70932781:C:A	F150L	1.000
2:70932781:C:G	F150L	1.000
2:70932785:A:G	N152D	1.000
2:70932786:A:G	N152S	1.000
2:70932787:C:A	N152K	1.000
2:70932787:C:G	N152K	1.000
2:70921175:T:A	F109I	0.999
2:70921175:T:G	F109V	0.999
2:70921191:T:C	L114P	0.999
2:70921200:T:A	L117Q	0.999
2:70921211:T:A	F121I	0.999
2:70921212:T:C	F121S	0.999
2:70921212:T:G	F121C	0.999
2:70921226:T:C	Y126H	0.999

dbSNP variants (sampled 300 via entrez): RS1000261021 (2:70910318 G>T), RS1000364536 (2:70933830 C>A), RS1000417775 (2:70904751 G>A,T), RS1000470195 (2:70904933 G>C), RS1001000587 (2:70911877 A>G), RS1001087662 (2:70929110 G>C), RS1001172081 (2:70915062 A>G), RS1001341612 (2:70922717 G>C), RS1001429748 (2:70927769 G>A), RS1001667506 (2:70908894 C>A), RS1001863047 (2:70899773 C>T), RS1001925258 (2:70931780 G>A,T), RS1002035697 (2:70898881 C>G,T), RS1002314014 (2:70900011 G>A), RS1002377678 (2:70931616 G>T)

Disease associations

OMIM: gene MIM:604295 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (1): Microphthalmia-anophthalmia-coloboma (Orphanet:98555)

HPO phenotypes

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

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST001819_2	Corneal astigmatism	2.000000e-07
GCST002481_1	Acne (severe)	5.000000e-06
GCST003184_12	Atopic dermatitis	2.000000e-07
GCST003184_4	Atopic dermatitis	9.000000e-09
GCST003854_9	Gut microbiota (functional units)	2.000000e-08
GCST012020_38	Serum metabolite levels	1.000000e-11
GCST012490_407	Femur bone mineral density x serum urate levels interaction	2.000000e-08

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0007874	gut microbiome measurement
EFO:0004531	urate measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

15 total (human), top 15 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases abundance, increases expression	2
Arsenic	increases abundance, increases expression, affects methylation	2
pirinixic acid	affects binding, decreases expression, increases activity	1
bisphenol A	decreases methylation, affects cotreatment	1
ethyl-p-hydroxybenzoate	increases expression	1
coumarin	increases phosphorylation	1
Fulvestrant	affects cotreatment, decreases methylation	1
Benzo(a)pyrene	increases methylation	1
Cadmium	increases abundance, increases expression	1
Caffeine	increases phosphorylation	1
Cisplatin	decreases expression	1
Cyclosporine	decreases expression	1
Asbestos, Crocidolite	decreases methylation	1
Asbestos, Amosite	decreases methylation	1
Cadmium Chloride	increases expression, increases abundance	1

Cellosaurus cell lines

3 cell lines: 3 embryonic stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_A7T3	SEES3-1V human VAX2, clone1	Embryonic stem cell	Male
CVCL_A7T4	SEES3-1V human VAX2, clone2	Embryonic stem cell	Male
CVCL_A7T5	SEES3-1V human VAX2, clone3	Embryonic stem cell	Male

Clinical trials (associated diseases)

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