VSX2

Summary

VSX2 (visual system homeobox 2, HGNC:1975) is a protein-coding gene on chromosome 14q24.3, encoding Visual system homeobox 2 (P58304). Acts as a transcriptional regulator through binding to DNA at the consensus sequence 5’-[TC]TAATT[AG][AG]-3’ upstream of gene promoters.

This gene encodes a homeobox protein originally described as a retina-specific transcription factor. Mutations in this gene are associated with microphthalmia, cataracts and iris abnormalities.

Source: NCBI Gene 338917 — RefSeq curated summary.

At a glance

• Gene–disease (curated): microphthalmia, isolated, with coloboma 3 (Definitive, GenCC) — +4 more curated relationships
• GWAS associations: 3
• Clinical variants (ClinVar): 539 total — 33 pathogenic, 19 likely-pathogenic
• Phenotypes (HPO): 7
• Transcription factor: yes — 32 downstream targets (CollecTRI)
• MANE Select transcript: NM_182894

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1975
Approved symbol	VSX2
Name	visual system homeobox 2
Location	14q24.3
Locus type	gene with protein product
Status	Approved
Aliases	RET1
Ensembl gene	ENSG00000119614
Ensembl biotype	protein_coding
OMIM	142993
Entrez	338917

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000261980

RefSeq mRNA: 1 — MANE Select: NM_182894 NM_182894

CCDS: CCDS9827

Canonical transcript exons

ENST00000261980 — 5 exons

Exon	Start	End
ENSE00000808105	74239449	74239931
ENSE00000808106	74241182	74241266
ENSE00000808107	74245165	74245288
ENSE00000808109	74260594	74262738
ENSE00001626136	74259602	74259782

Expression profiles

Bgee: expression breadth broad, 11 present calls, max score 83.01.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.0869 / max 42.2643, expressed in 14 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
140571	0.0869	14

Top tissues by expression

119 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	83.01	silver quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	77.57	gold quality
cortical plate	UBERON:0005343	46.76	gold quality
lymph node	UBERON:0000029	44.22	silver quality
ganglionic eminence	UBERON:0004023	43.90	gold quality
sural nerve	UBERON:0015488	40.86	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	40.23	gold quality
hindlimb stylopod muscle	UBERON:0004252	38.62	gold quality
bone marrow cell	CL:0002092	38.10	gold quality
colonic epithelium	UBERON:0000397	37.20	gold quality
tonsil	UBERON:0002372	36.75	gold quality
ventricular zone	UBERON:0003053	36.48	gold quality
primary visual cortex	UBERON:0002436	36.25	gold quality
vermiform appendix	UBERON:0001154	35.12	gold quality
bone marrow	UBERON:0002371	34.95	gold quality
skeletal muscle tissue	UBERON:0001134	34.89	gold quality
mucosa of transverse colon	UBERON:0004991	34.69	gold quality
substantia nigra	UBERON:0002038	34.57	gold quality
Brodmann (1909) area 9	UBERON:0013540	33.77	gold quality
muscle tissue	UBERON:0002385	33.26	gold quality
subcutaneous adipose tissue	UBERON:0002190	32.97	gold quality
calcaneal tendon	UBERON:0003701	32.71	gold quality
superior frontal gyrus	UBERON:0002661	32.54	gold quality
hypothalamus	UBERON:0001898	32.48	silver quality
cerebellum	UBERON:0002037	32.48	gold quality
cerebellar hemisphere	UBERON:0002245	32.48	gold quality
liver	UBERON:0002107	32.45	gold quality
duodenum	UBERON:0002114	32.39	gold quality
cerebellar cortex	UBERON:0002129	32.33	gold quality
amygdala	UBERON:0001876	32.17	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-7316	yes	36.55
E-ANND-3	no	1.63

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

32 targets.

Target	Regulation
ACHE
AHR
AR
BAD
CARM1
CES1
CHGB
CREBBP
F12
FMO3
GUSB
HLA-DQB1
HLA-DRB1
HPSE
HTT
IGHG1
MAPK8
MAPK9
NES	Repression
NXNL1
PCK1
PDGFB
POLL
RB1
SAG
SCN5A
SMARCA4
SP3
TP53
TPM1

JASPAR motifs

Motif	Name	Family
MA0726.1	VSX2	Paired-related HD factors
MA0726.2	VSX2	Paired-related HD factors

JASPAR matrix evidence (PMIDs): PMID:18585360

Upstream regulators (CollecTRI, top): LHX3, NEUROG1, NEUROG3, PRDM1, VSX2

miRNA regulators (miRDB)

91 targeting VSX2, 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-3185	99.99	68.12	1959
HSA-MIR-23B-5P	99.98	66.07	587
HSA-MIR-493-5P	99.96	72.47	2382
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-4487	99.96	64.58	1252
HSA-MIR-23A-5P	99.94	65.39	468
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-12119	99.87	68.35	1653
HSA-MIR-3941	99.86	70.54	2735
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-6715A-3P	99.83	68.05	1473
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-4659A-3P	99.80	72.62	4248
HSA-MIR-4659B-3P	99.80	72.62	4248
HSA-MIR-4694-3P	99.79	69.53	2640
HSA-MIR-92A-2-5P	99.75	67.01	2164
HSA-MIR-6745	99.74	65.33	1321
HSA-MIR-12129	99.72	67.45	1311
HSA-MIR-4699-3P	99.71	70.15	3142
HSA-MIR-378G	99.71	64.90	1106
HSA-MIR-518A-5P	99.70	69.01	2209
HSA-MIR-527	99.70	69.01	2209
HSA-MIR-4530	99.69	66.47	1509
HSA-MIR-6766-5P	99.68	67.70	2325
HSA-MIR-10394-5P	99.65	66.83	1852
HSA-MIR-1205	99.65	66.76	1826
HSA-MIR-587	99.64	70.86	2611
HSA-MIR-4310	99.59	68.84	2527

Literature-anchored findings (GeneRIF, showing 20)

• CHX10 and VSX1 may control retinal bipolar cell specification or differentiation by repressing genes required for the development of other cell types (PMID:15647262)
• CHX10 may target specific motifs to inhibit rod photoreceptor gene expression in bipolar cells (PMID:16236706)
• CHX10 defects in microphthalmia/anophthalmia patiients of midle-eastern origin are because od shared ancestry and consanguinity. (PMID:17661825)
• These results support the role of SOX2 in ocular development. Loss of SOX2 function results in severe eye malformation. CHX10 was not implicated with microphthalmia/anophthalmia in our patient cohort. (PMID:18385794)
• Mutations in the transgenic Chx10 homeobox gene cause reduced proliferation of retinal progenitor cells during development; lack of Chx10 leads to maintenance of a dormant neural progenitor population in the adult central neural retina. (PMID:18514541)
• These results do not support a significant role for CHX10 or MFRP mutations in primary angle closure glaucoma. (PMID:18648522)
• Data support the hypothesis that exogenous pDNA binds to cytoplasmic shuttle proteins NM23-H2 and Chx10, and is then translocated to the nucleus using the minimal import machinery (PMID:19638341)
• CHX10 regulates RdCVF promoter activity in the inner retina. (PMID:19843539)
• study identified 3 recessive VSX2 mutations associated with isolated congenital anophthalmia or severe microphthalmia; also identified a novel inner retinal dystrophy in 2 carrier parents suggesting a semidominant effect for this particular VSX2 mutation (PMID:20414678)
• major differentiation factors of the NK-cell lineage, including HOXA9, HOXA10 and ID2, were (de)regulated via PRC2 which therefore contributes to T-cell leukemogenesis. (PMID:20565746)
• Mutations in VSX2 represent an important cause of autosomal recessive microphthalmia in consanguineous pedigrees. (PMID:21976963)
• The phenotype of this girl is unique and suggests a normal regulatory role for VSX2 in iris, zonule, and cone-rod development. (PMID:24001013)
• The role of visual system homeobox 2 (VSX2), using human induced pluripotent stem cells derived from a patient with microphthalmia caused by an R200Q mutation in the VSX2 homeodomain region, is reported. (PMID:24532057)
• marker for neurogenic potential in cultured retinal progenitor cells (PMID:26292211)
• Regulation of WNT signaling by VSX2 during optic vesicle patterning in human induced pluripotent stem cells has been described. (PMID:27301076)
• In conclusion, targeted sequencing for SOX2 and VSX2 identified the etiology in two patients (7.4%) and this is the first report of SOX2 mutation from Egypt. (PMID:28121235)
• These findings expand the clinical and molecular spectrum of RET variants in Hirschsprung disease and reveal a high frequency of RET DNVs in the Chinese population. (PMID:31666091)
• Functional analysis of the Vsx2 super-enhancer uncovers distinct cis-regulatory circuits controlling Vsx2 expression during retinogenesis. (PMID:35831950)
• Association of Missense Variants in VSX2 With a Peculiar Form of Congenital Stationary Night Blindness Affecting All Bipolar Cells. (PMID:36264558)
• Evolutionary conservation of VSX2 super-enhancer modules in retinal development. (PMID:38994775)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	vsx2	ENSDARG00000005574
mus_musculus	Vsx2	ENSMUSG00000021239
rattus_norvegicus	Vsx2	ENSRNOG00000011918

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), 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

Visual system homeobox 2 — P58304 (reviewed: P58304)

Alternative names: Ceh-10 homeodomain-containing homolog, Homeobox protein CHX10

All UniProt accessions (1): P58304

UniProt curated annotations — full annotation on UniProt →

Function. Acts as a transcriptional regulator through binding to DNA at the consensus sequence 5’-[TC]TAATT[AG][AG]-3’ upstream of gene promoters. Plays a significant role in the specification and morphogenesis of the sensory retina. May play a role in specification of V2a interneurons during spinal cord development. Mediates differentiation of V2a interneurons by repression of motor neuron gene transcription, via competitively binding to response elements that are activated by the ISL1-LHX3 complex, such as VSX1. Acts as a positive transcriptional regulator of NXNL1; regulation is significantly increased in synergy with VSX1. Acts as a negative transcriptional regulator of MITF. Represses SAG transcription by competitive inhibition of ISL1-LHX3 response elements. Binds to the photoreceptor conserved element-1 (PCE-1) in the promoter of rod photoreceptor arrestin SAG and acts as a transcriptional repressor. Involved in the development of retinal ganglion cells (RGCs) which leads to release of SHH by RGCs, promoting Hedgehog signaling and subsequent proliferation of retinal progenitor cells. Participates in the development of the cells of the inner nuclear layer, by promoting postnatal differentiation of bipolar cells with a comparable inhibition of rod cell differentiation. May play a role in the maintenance of neural retina identity during development by regulation of canonical Wnt genes and CTNNB1 localization, suggesting a role in the regulation of canonical Wnt signaling.

Subunit / interactions. Interacts with MITF.

Subcellular location. Nucleus.

Tissue specificity. Abundantly expressed in retinal neuroblasts during eye development and in the inner nuclear layer of the adult retina. Within this layer, expression is stronger in the outer margin where bipolar cells predominate.

Disease relevance. Microphthalmia, isolated, 2 (MCOP2) [MIM:610093] A disorder of eye formation, ranging from small size of a single eye to complete bilateral absence of ocular tissues. Ocular abnormalities like opacities of the cornea and lens, scaring of the retina and choroid, and other abnormalities may also be present. The disease is caused by variants affecting the gene represented in this entry. Microphthalmia with cataracts and iris abnormalities (MCOPCTI) [MIM:610092] A disorder of eye formation, ranging from small size of a single eye to complete bilateral absence of ocular tissues. Ocular abnormalities like opacities of the cornea and lens, scaring of the retina and choroid, cataract and other abnormalities like cataract may also be present. The disease is caused by variants affecting the gene represented in this entry. Microphthalmia/Coloboma 3 (MCOPCB3) [MIM:610092] A disorder of eye formation, ranging from small size of a single eye to complete bilateral absence of ocular tissues. Ocular abnormalities like opacities of the cornea and lens, scaring of the retina and choroid, and other abnormalities may also be present. Ocular colobomas are a set of malformations resulting from abnormal morphogenesis of the optic cup and stalk, and the fusion of the fetal fissure (optic fissure). The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the paired homeobox family.

RefSeq proteins (1): NP_878314* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001356	HD	Domain
IPR003654	OAR_dom	Domain
IPR009057	Homeodomain-like_sf	Homologous_superfamily
IPR017970	Homeobox_CS	Conserved_site
IPR023339	CVC	Domain
IPR052294	VSX_homeobox_regulators	Family

Pfam: PF00046, PF03826

UniProt features (16 total): sequence variant 6, region of interest 4, chain 1, domain 1, mutagenesis site 1, DNA-binding region 1, short sequence motif 1, compositionally biased region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P58304-F1	61.65	0.19

Functional residue map

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

Mutagenesis-validated functional residues (1):

Position	Phenotype
198	loss of sag repressor activity. loss of competitive inhibition of isl1-lhx3 binding to common response elements.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 127 (showing top): BENPORATH_ES_WITH_H3K27ME3, LFA1_Q6, GCANCTGNY_MYOD_Q6, AREB6_03, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, GOBP_NEUROGENESIS, GOBP_NEURAL_RETINA_DEVELOPMENT, SHEPARD_BMYB_MORPHOLINO_DN, COUP_01, NFKB_Q6, NFKB_C, GOBP_ANIMAL_ORGAN_MORPHOGENESIS, chr14q24, GOBP_SENSORY_PERCEPTION_OF_LIGHT_STIMULUS

GO Biological Process (14): negative regulation of transcription by RNA polymerase II (GO:0000122), regulation of transcription by RNA polymerase II (GO:0006357), neuroblast proliferation (GO:0007405), negative regulation of neuroblast proliferation (GO:0007406), visual perception (GO:0007601), positive regulation of cell population proliferation (GO:0008284), central nervous system neuron differentiation (GO:0021953), cell fate commitment (GO:0045165), positive regulation of transcription by RNA polymerase II (GO:0045944), retinal bipolar neuron differentiation (GO:0060040), regulation of DNA-templated transcription (GO:0006355), cell population proliferation (GO:0008283), camera-type eye development (GO:0043010), retina morphogenesis in camera-type eye (GO:0060042)

GO Molecular Function (6): RNA polymerase II transcription regulatory region sequence-specific DNA binding (GO:0000977), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), DNA-binding transcription repressor activity, RNA polymerase II-specific (GO:0001227), 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
regulation of transcription by RNA polymerase II	3
transcription by RNA polymerase II	3
RNA polymerase II transcription regulatory region sequence-specific DNA binding	2
cellular anatomical structure	2
negative regulation of DNA-templated transcription	1
regulation of DNA-templated transcription	1
generation of neurons	1
neural precursor cell proliferation	1
neuroblast proliferation	1
negative regulation of neurogenesis	1
regulation of neuroblast proliferation	1
negative regulation of neural precursor cell proliferation	1
sensory perception of light stimulus	1
cell population proliferation	1
regulation of cell population proliferation	1
positive regulation of cellular process	1
central nervous system development	1
neuron differentiation	1
cell differentiation	1
cellular developmental process	1
positive regulation of DNA-templated transcription	1
neural retina development	1
retina morphogenesis in camera-type eye	1
glutamatergic neuron differentiation	1
DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
cellular process	1
eye development	1
anatomical structure morphogenesis	1
camera-type eye morphogenesis	1
retina development in camera-type eye	1
transcription cis-regulatory region binding	1
chromatin	1
DNA-binding transcription factor activity	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
double-stranded DNA binding	1
sequence-specific DNA binding	1

Protein interactions and networks

STRING

1356 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
VSX2	SIX3	O95343	858
VSX2	NXNL1	Q96CM4	813
VSX2	ATOH7	Q8N100	800
VSX2	RHO	P08100	792
VSX2	MFRP	Q9BY79	787
VSX2	RCVRN	P35243	782
VSX2	POU4F2	Q12837	769
VSX2	GDF3	Q9NR23	748
VSX2	POU4F1	Q01851	727
VSX2	ISL1	P20663	709
VSX2	SIX6	O95475	701
VSX2	FOXN4	Q96NZ1	689
VSX2	RLBP1	P12271	683
VSX2	PDE6B	P35913	662
VSX2	SHH	Q15465	657

IntAct

96 interactions, top by confidence:

A	B	Type	Score
VSX2	APBB2	psi-mi:“MI:0915”(physical association)	0.560
VSX2	DNM2	psi-mi:“MI:0915”(physical association)	0.560
DR1	VSX2	psi-mi:“MI:0915”(physical association)	0.560
VSX2		psi-mi:“MI:0915”(physical association)	0.560
ELAVL4	VSX2	psi-mi:“MI:0915”(physical association)	0.560
VSX2	GFAP	psi-mi:“MI:0915”(physical association)	0.560
GRN	VSX2	psi-mi:“MI:0915”(physical association)	0.560
GTF2B	VSX2	psi-mi:“MI:0915”(physical association)	0.560
VSX2	HSPB1	psi-mi:“MI:0915”(physical association)	0.560
VSX2	NDUFV2	psi-mi:“MI:0915”(physical association)	0.560
VSX2	NEFL	psi-mi:“MI:0915”(physical association)	0.560
NF2	VSX2	psi-mi:“MI:0915”(physical association)	0.560
NOS3	VSX2	psi-mi:“MI:0915”(physical association)	0.560
VSX2	PMP22	psi-mi:“MI:0915”(physical association)	0.560
VSX2	PRPS1	psi-mi:“MI:0915”(physical association)	0.560
VSX2	TTR	psi-mi:“MI:0915”(physical association)	0.560
VSX2	WFS1	psi-mi:“MI:0915”(physical association)	0.560
DNALI1	VSX2	psi-mi:“MI:0915”(physical association)	0.560
BAG6	VSX2	psi-mi:“MI:0915”(physical association)	0.560
KLF11	VSX2	psi-mi:“MI:0915”(physical association)	0.560
VSX2	GTF3C3	psi-mi:“MI:0915”(physical association)	0.560
NUP58	VSX2	psi-mi:“MI:0915”(physical association)	0.560
VSX2	KIF1B	psi-mi:“MI:0915”(physical association)	0.560
VSX2	RNF11	psi-mi:“MI:0915”(physical association)	0.560
DDIT4	VSX2	psi-mi:“MI:0915”(physical association)	0.560
LRIF1	VSX2	psi-mi:“MI:0915”(physical association)	0.560
VSX2	JPH3	psi-mi:“MI:0915”(physical association)	0.560
VSX2	TARDBP	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (32): VSX2 (Two-hybrid), WDR20 (Affinity Capture-MS), CHMP1A (Affinity Capture-MS), WDR48 (Affinity Capture-MS), CSNK2A2 (Affinity Capture-MS), CSNK2A1 (Affinity Capture-MS), USP20 (Affinity Capture-MS), USP33 (Affinity Capture-MS), USP12 (Affinity Capture-MS), AHCYL2 (Affinity Capture-MS), C18orf25 (Affinity Capture-MS), ZNF703 (Affinity Capture-MS), USP20 (Affinity Capture-MS), USP12 (Affinity Capture-MS), WDR20 (Affinity Capture-MS)

ESM2 similar proteins: A1A546, A1YEY5, A1YF16, A1YFI3, A1YG57, A1YG93, A2RU54, A2T733, A2T764, A2T7P4, A5YC49, A6NJ46, A6NNA5, O09113, O35137, O35160, O42115, O42201, O42358, O42567, O75364, P20263, P23410, P28362, P29454, P35548, P53545, P56915, P58304, P70368, P81062, P97436, Q01703, Q02591, Q03356, Q03358, Q04281, Q0P5C3, Q3UHX8, Q5TIS6

Diamond homologs: A0A1W2PPK0, A0A1W2PPM1, A1A546, A1YEY5, A1YFI3, A1YG57, A1YGA2, A2T733, A2T777, A2T7P4, A6NFQ7, G5EC89, L8E946, O14813, O15499, O35690, O42250, O42356, O42357, O42477, O70137, O73917, O75360, O95076, O97670, P0DMV5, P26367, P26630, P29454, P41935, P47237, P47238, P53544, P53545, P53546, P54366, P55813, P55864, P56915, P56916

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
NEUROG3	“down-regulates quantity by repression”	VSX2	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	33
Likely pathogenic	19
Uncertain significance	144
Likely benign	267
Benign	37

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1374787	NM_182894.3(VSX2):c.84del (p.Arg28fs)	Pathogenic
1387187	NM_182894.3(VSX2):c.224del (p.Gly75fs)	Pathogenic
1387606	NM_182894.3(VSX2):c.371-1G>A	Pathogenic
1406550	NM_182894.3(VSX2):c.598C>T (p.Arg200Ter)	Pathogenic
1412831	NM_182894.3(VSX2):c.50_51insAT (p.Ala18fs)	Pathogenic
1419627	NM_182894.3(VSX2):c.179dup (p.His60fs)	Pathogenic
1451168	NM_182894.3(VSX2):c.608G>A (p.Trp203Ter)	Pathogenic
1453132	NM_182894.3(VSX2):c.59del (p.Ser20fs)	Pathogenic
1457945	NC_000014.8:g.(?74707875)(74712001_?)del	Pathogenic
14860	NM_182894.3(VSX2):c.599G>A (p.Arg200Gln)	Pathogenic
14863	NG_013092.1:g.(7926_9509)_(12624_14744)del	Pathogenic
1984660	NM_182894.3(VSX2):c.513del (p.Tyr172fs)	Pathogenic
2017212	NM_182894.3(VSX2):c.264C>G (p.Tyr88Ter)	Pathogenic
2022813	NM_182894.3(VSX2):c.15del (p.Glu7fs)	Pathogenic
2032657	NM_182894.3(VSX2):c.419del (p.Ala139_Leu140insTer)	Pathogenic
2112771	NM_182894.3(VSX2):c.667G>C (p.Gly223Arg)	Pathogenic
221962	NM_182894.3(VSX2):c.71dup (p.Ala25fs)	Pathogenic
2427598	NC_000014.8:g.(?74726295)(74727632_?)del	Pathogenic
2758164	NM_182894.3(VSX2):c.166dup (p.Leu56fs)	Pathogenic
2764044	NM_182894.3(VSX2):c.634del (p.Arg212fs)	Pathogenic
2813462	NM_182894.3(VSX2):c.4del (p.Thr2fs)	Pathogenic
2843544	NM_182894.3(VSX2):c.248_249del (p.Gly83fs)	Pathogenic
2979108	NM_182894.3(VSX2):c.438del (p.Lys147fs)	Pathogenic
3000990	NM_182894.3(VSX2):c.249dup (p.Leu84fs)	Pathogenic
3244000	NC_000014.8:g.(?74706265)(74727622_?)del	Pathogenic
3244001	NC_000014.8:g.(?74707865)(74707989_?)del	Pathogenic
3244002	NC_000014.8:g.(?74703158)(74706277_?)del	Pathogenic
4081830	NM_182894.3(VSX2):c.316C>T (p.Gln106Ter)	Pathogenic
4817010	NM_182894.3(VSX2):c.371-2A>C	Pathogenic
560530	NM_182894.3(VSX2):c.609G>A (p.Trp203Ter)	Pathogenic

SpliceAI

899 predictions. Top by Δscore:

Variant	Effect	Δscore
14:74241262:CACAG:C	donor_loss	1.0000
14:74241263:ACAG:A	donor_loss	1.0000
14:74241264:CAGG:C	donor_loss	1.0000
14:74241265:AGGTG:A	donor_loss	1.0000
14:74241266:GGTGA:G	donor_loss	1.0000
14:74241268:T:A	donor_loss	1.0000
14:74245285:ACAG:A	donor_loss	1.0000
14:74245286:CAGG:C	donor_loss	1.0000
14:74245289:G:GA	donor_loss	1.0000
14:74245290:T:A	donor_loss	1.0000
14:74259600:A:AG	acceptor_gain	1.0000
14:74259600:AG:A	acceptor_gain	1.0000
14:74259601:G:A	acceptor_loss	1.0000
14:74259601:G:GG	acceptor_gain	1.0000
14:74259601:GG:G	acceptor_gain	1.0000
14:74259601:GGT:G	acceptor_gain	1.0000
14:74259601:GGTC:G	acceptor_gain	1.0000
14:74259601:GGTCT:G	acceptor_gain	1.0000
14:74259746:G:GT	donor_gain	1.0000
14:74259780:TGG:T	donor_gain	1.0000
14:74259781:GG:G	donor_gain	1.0000
14:74259781:GGG:G	donor_gain	1.0000
14:74259782:GG:G	donor_gain	1.0000
14:74259783:G:GG	donor_gain	1.0000
14:74259783:GTA:G	donor_loss	1.0000
14:74259784:T:G	donor_loss	1.0000
14:74260588:TTCTA:T	acceptor_loss	1.0000
14:74260589:TCTA:T	acceptor_loss	1.0000
14:74260590:CTA:C	acceptor_loss	1.0000
14:74260591:TAGG:T	acceptor_loss	1.0000

AlphaMissense

2347 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
14:74239655:T:C	F32L	1.000
14:74239656:T:C	F32S	1.000
14:74239657:C:A	F32L	1.000
14:74239657:C:G	F32L	1.000
14:74239662:T:A	I34N	1.000
14:74239662:T:C	I34T	1.000
14:74239671:T:C	I37T	1.000
14:74241262:C:G	H151D	1.000
14:74241265:A:G	R152G	1.000
14:74241265:A:T	R152W	1.000
14:74241266:G:C	R152T	1.000
14:74241266:G:T	R152M	1.000
14:74245165:G:C	R152S	1.000
14:74245165:G:T	R152S	1.000
14:74245167:C:A	T153K	1.000
14:74245167:C:T	T153I	1.000
14:74245170:T:A	I154N	1.000
14:74245172:T:A	F155I	1.000
14:74245172:T:C	F155L	1.000
14:74245172:T:G	F155V	1.000
14:74245173:T:C	F155S	1.000
14:74245173:T:G	F155C	1.000
14:74245174:T:A	F155L	1.000
14:74245174:T:G	F155L	1.000
14:74245176:C:T	T156I	1.000
14:74245184:C:A	Q159K	1.000
14:74245185:A:G	Q159R	1.000
14:74245186:G:C	Q159H	1.000
14:74245186:G:T	Q159H	1.000
14:74245188:T:A	L160Q	1.000

dbSNP variants (sampled 300 via entrez): RS1000091496 (14:74262512 A>G), RS1000108432 (14:74248027 C>A,T), RS1000256046 (14:74251280 T>A), RS1000420471 (14:74246146 G>T), RS1000458139 (14:74262172 G>A), RS1000477311 (14:74258627 A>G), RS1000530609 (14:74258098 T>C), RS1000687374 (14:74252944 G>C), RS1000691668 (14:74254277 G>A,T), RS1000699404 (14:74246965 G>A), RS1000751850 (14:74247224 A>G), RS1000752978 (14:74251502 T>C), RS1000758341 (14:74258434 C>A,G), RS1000997114 (14:74252669 A>G), RS1001398626 (14:74243386 T>A,C)

Disease associations

OMIM: gene MIM:142993 | disease phenotypes: MIM:610093, MIM:610092, MIM:268000

GenCC curated gene-disease

Disease	Classification	Inheritance
microphthalmia, isolated, with coloboma 3	Definitive	Autosomal recessive
isolated microphthalmia 2	Definitive	Autosomal recessive
microphthalmia	Strong	Autosomal recessive
isolated anophthalmia-microphthalmia syndrome	Supportive	Autosomal dominant
microphthalmia, isolated, with coloboma	Supportive	Autosomal dominant

Mondo (6): isolated microphthalmia 2 (MONDO:0012409), microphthalmia (MONDO:0021129), microphthalmia, isolated, with coloboma 3 (MONDO:0012408), retinitis pigmentosa (MONDO:0019200), isolated anophthalmia-microphthalmia syndrome (MONDO:0016764), microphthalmia, isolated, with coloboma (MONDO:0000170)

Orphanet (4): Isolated microphthalmia-anophthalmia-coloboma (Orphanet:2542), Colobomatous microphthalmia (Orphanet:98938), Microphthalmia-anophthalmia-coloboma (Orphanet:98555), Retinitis pigmentosa (Orphanet:791)

HPO phenotypes

7 total (7 of 7 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000518	Cataract
HP:0000568	Microphthalmia
HP:0000612	Iris coloboma
HP:0001249	Intellectual disability
HP:0003577	Congenital onset
HP:0007759	Opacification of the corneal stroma

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST003958_8	Inflammatory bowel disease	8.000000e-06
GCST010002_156	Refractive error	7.000000e-25
GCST011837_10	Cervical high-risk human papilloma virus infection	3.000000e-06

MeSH disease descriptors (5)

Descriptor	Name	Tree numbers
D008850	Microphthalmos	C11.250.566; C16.131.384.666
D012174	Retinitis Pigmentosa	C11.270.684; C11.768.585.658.500; C16.320.290.684
C537463	Microphthalmia associated with colobomatous cyst (supp.)
C566446	Microphthalmia, Isolated 2 (supp.)
C566447	Microphthalmia, Isolated, with Coloboma 3 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

11 total (human), top 11 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	increases expression	1
arsenite	increases methylation	1
mono-(2-ethylhexyl)phthalate	decreases expression	1
sodium arsenite	increases expression	1
CGP 52608	increases reaction, affects binding	1
theaflavin-3,3’-digallate	affects expression	1
Atrazine	increases expression	1
Benzo(a)pyrene	affects methylation, decreases methylation	1
Diazinon	increases methylation	1
Asbestos, Crocidolite	decreases methylation	1
Asbestos, Amosite	decreases methylation	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00717080	PHASE4	COMPLETED	The Role of Capsular Tension Ring (CTR) in Anterior Capsular Contraction
NCT00000114	PHASE3	COMPLETED	Randomized Trial of Vitamin A and Vitamin E Supplementation for Retinitis Pigmentosa
NCT00000116	PHASE3	COMPLETED	Randomized Trial of DHA for Retinitis Pigmentosa Patients Receiving Vitamin A
NCT00346333	PHASE3	COMPLETED	Clinical Trial of Lutein for Patients With Retinitis Pigmentosa Receiving Vitamin A
NCT01786395	PHASE3	TERMINATED	Phase III Efficacy and Safety Clinical Study of UF-021 for Treatment of Retinitis Pigmentosa
NCT04224207	PHASE3	COMPLETED	Management of Retinitis Pigmentosa by Mesenchymal Stem Cells by Wharton’s Jelly Derived Mesenchymal Stem Cells
NCT04636853	PHASE3	COMPLETED	CB-PRP in Retinitis Pigmentosa and Dry Age-related Macular Degeneration
NCT05537220	PHASE3	ACTIVE_NOT_RECRUITING	Oral N-acetylcysteine for Retinitis Pigmentosa
NCT05800301	PHASE3	COMPLETED	Management of Retinitis Pigmentosa Via Combination of Wharton’s Jelly-derived Mesenchymal Stem Cells and Magnovision
NCT05926583	PHASE3	ACTIVE_NOT_RECRUITING	A Study of AAV5-hRKp.RPGR for the Treatment of Japanese Participants With X-linked Retinitis Pigmentosa
NCT06388200	PHASE3	ACTIVE_NOT_RECRUITING	A Phase 3 Study Of OCU400 Gene Therapy for the Treatment Of Retinitis Pigmentosa
NCT07082855	PHASE3	NOT_YET_RECRUITING	A Multicenter, Randomized, Double-Blind, Controlled Clinical Study of Minocycline for the Treatment of Retinitis Pigmentosa
NCT07290530	PHASE3	NOT_YET_RECRUITING	24-Month Trial of NPI-001 for the Preservation of Photoreceptors in Retinitis Pigmentosa Associated With Usher Syndrome
NCT00100230	PHASE2	COMPLETED	DHA and X-Linked Retinitis Pigmentosa
NCT00447980	PHASE2	COMPLETED	A Study of Encapsulated Cell Technology (ECT) Implant for Participants With Early Stage Retinitis Pigmentosa
NCT00447993	PHASE2	COMPLETED	A Study of Encapsulated Cell Technology (ECT) Implant for Patients With Late Stage Retinitis Pigmentosa
NCT01233609	PHASE2	COMPLETED	Trial of Oral Valproic Acid for Retinitis Pigmentosa
NCT01399515	PHASE2	COMPLETED	Efficacy and Safety of Oral Valproic Acid for Retinitis Pigmentosa
NCT01530659	PHASE2	COMPLETED	Retinal Imaging in CNTF -Releasing Encapsulated Cell Implant Treated Patients for Early-stage Retinitis Pigmentosa
NCT01560715	PHASE2	COMPLETED	Autologous Bone Marrow-Derived Stem Cells Transplantation For Retinitis Pigmentosa
NCT02609165	PHASE2	COMPLETED	Nerve Growth Factor Eye Drops Treatment in Patients With Retinitis Pigmentosa and Cystoid Macular Edema
NCT02661711	PHASE2	COMPLETED	Aflibercept for Macular Oedema With Underlying Retinitis Pigmentosa (AMOUR) Study
NCT02804360	PHASE2	UNKNOWN	Intravitreal Dexamethasone Implant in Retinitis Pigmentosa-related Macular Edema- a Retrospective Study
NCT02837640	PHASE2	UNKNOWN	Studying a Potential Protective Effect of L-Dopa on Retinitis Pigmentosa
NCT03073733	PHASE2	COMPLETED	Safety and Efficacy of Intravitreal Injection of Human Retinal Progenitor Cells in Adults With Retinitis Pigmentosa
NCT04068207	PHASE2	COMPLETED	Minocycline Treatment in Retinitis Pigmentosa
NCT04356716	PHASE2	COMPLETED	Sildenafil for Treatment of Choroidal Ischemia
NCT04604899	PHASE2	COMPLETED	Safety of Repeat Intravitreal Injection of Human Retinal Progenitor Cells (jCell) in Adult Subjects With Retinitis Pigmentosa
NCT04763369	PHASE2	UNKNOWN	Investigation of Therapeutic Efficacy and Safety of UMSCs for the Management of Retinitis Pigmentosa (RP)
NCT04864496	PHASE2	UNKNOWN	Effects of Treatment With N- Acetylcysteine on Visual Outcomes in Patients With Retinitis Pigmentosa
NCT04945772	PHASE2	COMPLETED	Efficacy and Safety of MCO-010 Optogenetic Therapy in Adults With Retinitis Pigmentosa [RESTORE]
NCT05085964	PHASE2	TERMINATED	An Open-Label Extension Study to Evaluate Safety & Tolerability of QR-421a in Subjects With Retinitis Pigmentosa
NCT05392179	PHASE2	COMPLETED	A Study in Subjects With Retinitis Pigmentosa
NCT06627179	PHASE2	RECRUITING	Study to Evaluate Ultevursen in Subjects With Retinitis Pigmentosa (RP) Due to Mutations in Exon 13 of the USH2A Gene
NCT06628947	PHASE2	RECRUITING	A Phase II Study of Intravitreal KIO-301 in Patients With Late-stage Retinitis Pigmentosa
NCT06912633	PHASE2	RECRUITING	Safety of a Single, Intravitreal Injection of 6.0M jCell (Famzeretcel) in Retinitis Pigmentosa (RP)
NCT00063765	PHASE1	COMPLETED	Evaluation of Safety of Ciliary Neurotrophic Factor Implants in the Eye
NCT00065455	PHASE1	COMPLETED	Investigating the Effect of Vitamin A Supplementation on Retinitis Pigmentosa
NCT00458575	PHASE1	TERMINATED	A Study to Evaluate the Safety of CNTO 2476 in Patients With Advanced Retinitis Pigmentosa
NCT01068561	PHASE1	COMPLETED	Autologous Bone Marrow-Derived Stem Cells Transplantation For Retinitis Pigmentosa