NDP

Summary

NDP (norrin cystine knot growth factor NDP, HGNC:7678) is a protein-coding gene on chromosome Xp11.3, encoding Norrin (Q00604). Activates the canonical Wnt signaling pathway through FZD4 and LRP5 coreceptor. It is haploinsufficient (ClinGen: sufficient evidence).

This gene encodes a secreted protein with a cystein-knot motif that activates the Wnt/beta-catenin pathway. The protein forms disulfide-linked oligomers in the extracellular matrix. Mutations in this gene result in Norrie disease and X-linked exudative vitreoretinopathy.

Source: NCBI Gene 4693 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Norrie disease (Definitive, ClinGen) — +3 more curated relationships
• GWAS associations: 8
• Clinical variants (ClinVar): 204 total — 46 pathogenic, 27 likely-pathogenic
• Phenotypes (HPO): 126
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_000266

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7678
Approved symbol	NDP
Name	norrin cystine knot growth factor NDP
Location	Xp11.3
Locus type	gene with protein product
Status	Approved
Aliases	norrin
Ensembl gene	ENSG00000124479
Ensembl biotype	protein_coding
OMIM	300658
Entrez	4693

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 4 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000470584, ENST00000642620, ENST00000647044, ENST00000868527, ENST00000868528

RefSeq mRNA: 1 — MANE Select: NM_000266 NM_000266

CCDS: CCDS14262

Canonical transcript exons

ENST00000642620 — 3 exons

Exon	Start	End
ENSE00001476115	43948776	43950026
ENSE00001476118	43958472	43958852
ENSE00003820935	43973304	43973390

Expression profiles

Bgee: expression breadth ubiquitous, 197 present calls, max score 95.09.

FANTOM5 (CAGE): breadth broad, TPM avg 1.7802 / max 97.1436, expressed in 270 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
198990	0.7213	176
198989	0.5795	114
198993	0.2173	103
198992	0.1840	98
198991	0.0707	38
198994	0.0073	2

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cranial nerve II	UBERON:0000941	95.09	gold quality
decidua	UBERON:0002450	94.89	gold quality
caudate nucleus	UBERON:0001873	89.25	gold quality
putamen	UBERON:0001874	88.93	gold quality
amygdala	UBERON:0001876	88.63	gold quality
nucleus accumbens	UBERON:0001882	88.51	gold quality
Brodmann (1909) area 9	UBERON:0013540	87.57	gold quality
right frontal lobe	UBERON:0002810	87.35	gold quality
medial globus pallidus	UBERON:0002477	87.28	gold quality
globus pallidus	UBERON:0001875	87.06	gold quality
lateral globus pallidus	UBERON:0002476	86.24	gold quality
cerebellar hemisphere	UBERON:0002245	86.09	gold quality
ventricular zone	UBERON:0003053	85.99	gold quality
cerebellar cortex	UBERON:0002129	85.98	gold quality
right hemisphere of cerebellum	UBERON:0014890	85.59	gold quality
prefrontal cortex	UBERON:0000451	85.46	gold quality
ganglionic eminence	UBERON:0004023	85.38	gold quality
cerebellum	UBERON:0002037	85.33	gold quality
temporal lobe	UBERON:0001871	85.32	gold quality
cingulate cortex	UBERON:0003027	85.15	gold quality
telencephalon	UBERON:0001893	85.14	gold quality
anterior cingulate cortex	UBERON:0009835	84.92	gold quality
left ovary	UBERON:0002119	84.78	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	84.77	gold quality
endothelial cell	CL:0000115	84.56	silver quality
endometrium	UBERON:0001295	84.36	gold quality
frontal cortex	UBERON:0001870	84.35	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	84.29	gold quality
neocortex	UBERON:0001950	84.25	gold quality
Ammon’s horn	UBERON:0001954	84.24	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	2.94

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

61 targeting NDP, 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-7110-3P	100.00	73.18	2486
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-15A-5P	99.90	72.80	2787
HSA-MIR-15B-5P	99.90	72.78	2798
HSA-MIR-16-5P	99.90	72.80	2780
HSA-MIR-195-5P	99.90	72.81	2805
HSA-MIR-6838-5P	99.89	71.94	2690
HSA-MIR-424-5P	99.89	71.90	2641
HSA-MIR-182-5P	99.87	74.03	2589
HSA-MIR-3681-5P	99.82	66.88	387
HSA-MIR-6817-3P	99.79	68.35	2126
HSA-MIR-3156-3P	99.76	66.72	939
HSA-MIR-2681-5P	99.75	67.64	1655
HSA-MIR-6849-5P	99.64	66.00	352
HSA-MIR-4524A-5P	99.57	71.73	1193
HSA-MIR-4524B-5P	99.57	71.68	1195
HSA-MIR-7159-5P	99.53	72.12	2472
HSA-MIR-3123	99.47	67.15	2693
HSA-MIR-4728-3P	99.47	68.94	981
HSA-MIR-520A-5P	99.35	66.72	1632
HSA-MIR-525-5P	99.35	66.85	1615
HSA-MIR-4427	99.34	70.33	1854
HSA-MIR-130A-5P	99.33	70.26	2623
HSA-MIR-888-5P	99.30	70.15	1855
HSA-MIR-3064-5P	99.26	66.13	1497
HSA-MIR-3085-3P	99.26	66.16	1490
HSA-MIR-6504-5P	99.26	65.95	1487
HSA-MIR-7974	99.24	65.48	1137

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• de novo mutations in the 5’ regulatory region in retinopathy of prematurity (PMID:11748312)
• Data show a strong association between the AA genotype of the C597A Norrie disease gene polymorphism and progression of retinopathy of prematurity. (PMID:12145535)
• No Norrie Disease (ND) gene mutations were detected. (PMID:12546446)
• DNA sequencing demonstrated a novel missense mutation (703G>T) that significantly alters predicted protein structure. (PMID:15609522)
• Here we report two novel mutations in the NDP gene in Mexican patients and propose that GeneScan is a viable mean of establishing ND carrier status. (PMID:15799735)
• NDP polymorphisms may play a role in the pathogenesis of retinopathy of prematurity, but do not appear to be a major causative factor. (PMID:16052165)
• We discuss Wnts and a novel Frizzled ligand, Norrin, in physiological and pathological angiogenesis. (PMID:16714476)
• We found genetic testing of NDP to be helpful in confirming the diagnosis of X-linked FEVR (familial exudative vitreoretinopathy) in male patients, especially when limited family history was available. (PMID:17050281)
• Norrin binds to the Frizzled4 cysteine-rich domain (CRD) and does not detectably bind to 14 other mammalian Frizzled and secreted Frizzled-related protein CRDs. (PMID:17158104)
• Patients exhibiting severe retinal dysgenesis should be suspected of carrying a mutation that disrupts the cysteine-knot motif in the NDP gene. (PMID:17296899)
• These observations indicate that mutations of the NDP gene can cause ND(Norrie disease) and 6% of FEVR(familial exudative vitreoretinopathy) cases in the Japanese population. (PMID:17325173)
• A novel missense mutation at position c.134T > A resulting in amino acid change at codon V45E in Norrie disease with neurological disorder and infantile spasms. (PMID:17334993)
• Norrin mutants demonstrated variable effects on signal transduction, and no apparent correlation with clinical phenotypes was observed. (PMID:17955262)
• correlation of ophthalmic examination with carrier status for asymptomatic females from a family known to harbor a severe ND gene mutation (C95F) (PMID:18387409)
• We report a novel mutation in the NDP gene in a patient whose presentation demonstrates the phenotypic heterogeneity of NDP-related disorders. (PMID:19373682)
• Norrin is a potent factor that induces angiogenesis in microvascular and endothelial cells following oxygen-induced retinal vessel loss. (PMID:20053900)
• family harboring a single base-pair deletion, c.268delC, in the NDP gene causing a severe Norrie disese phenotype in the male proband and peripheral retinal vascular abnormalities with dragged maculae similar (PMID:20227630)
• Studies report 21 novel variants for FZD4, LRP5, and NDP. (PMID:20340138)
• Norrin has pronounced neuroprotective properties on retinal neurons. The effects of Norrin involve activation of Wnt/beta-catenin signaling and subsequent induction of neurotrophic growth factors in Muller cells. (PMID:20427659)
• A novel Norrin missense mutation, p.Arg41Thr, was identified in two apparently unrelated families with Norrie disease (PMID:20491809)
• In cases of dysplastic retinas with bilateral multiple unclear pseudotumourous lesions, cytology seems to be a useful tool to differentiate in a very short term patients with Norrie’s syndrome from those with retinoblastoma or lymphoma. (PMID:21159148)
• Mutation screening of the NDP gene identified a novel nonsense mutation, c.343C>T. (PMID:21179243)
• Norrin has a neuroprotective role for retinal neurons independent from its role on the growth of retinal capillaries. (PMID:22183393)
• NDP mutations are common cause of Norrie disease but might be rare cause for familial exudative vitreoretinopathy (FEVR) in Chinese. (PMID:22563645)
• Report of a missense mutation, p.Arg41Ser, in NDP causing Norrie disease in an Indian family. (PMID:22674248)
• Multi-functional norrin is a ligand for the LGR4 receptor. (PMID:23444378)
• Norrin induces the formation of a ternary complex with Fz4 and Lrp5/6 by binding to their respective extracellular domains (PMID:24186977)
• a novel c.277T>C missense mutation causing the substitution of a hydrophobic cysteine to a hydrophilic arginine [p.(Cys93Arg)]in patients with Norrie disease. (PMID:24801666)
• Norrin may play a role in the regulation of angiogenesis. (PMID:25005225)
• Norrie disease was diagnosed in three patients from a Japanese family by clinical examination and was confirmed by genetic analysis. (PMID:25023092)
• hemizygous pathogenic variant in NDP, c.293 C>T, p.(Pro98Leu) was identified in two brothers with isolated bilateral microphthalmia and sclerocornea. (PMID:26130484)
• These structural, biophysical and cellular data, map Fz4 and putative Lrp5/6 binding sites to distinct patches on Norrin, and reveal a GAG binding site spanning Norrin and Fz4 cysteine-rich domain. (PMID:26158506)
• Genetic evaluation of a case of bilateral leukocoria and asymmetric microphthalmia revealed a previously undescribed mutation in the Norrie disease protein gene. (PMID:26459204)
• we reported a novel missense NDP mutation of a familial case of Norrie Disease in a Chinese family. (PMID:26547627)
• First study to demonstrate the involvement of NDP among patients with Indian familial exudative vitreoretinopathy (FEVR) that further expands its mutation spectrum. (PMID:27217716)
• The mutation c.310A>C (p.Lys104Gln) in exon 3 of NDP is associated with familial exudative vitreoretinopathy in the studied family (PMID:27720678)
• Among the detected mutations, LRP5 accounted for the largest proportion with a mean mutation rate of 16.1% (5/31, 16.1%), followed by NDP (3/31, 9.7%), FZD4 (2/31, 6.5%), TSPAN12 (1/31, 3.2%), and KIF11 (1/31, 3.2%). All the novel changes were predicted to be pathogenic by a series of bioinformatics analyses. (PMID:28494495)
• The patient with whole NDP gene deletion did not exhibit any apparent extraocular defects (like mental retardation or sensorineural hearing loss) during his first decade of life, and this is considered to be a notable finding. Our study also provides evidence emphasizing the need for genetic testing which could eliminate ambiguities in clinical diagnosis and detect carrier status, thereby aiding the patient and family mem (PMID:28602015)
• NDP is a potent trigger of FZD4 ubiquitination and induces internalization of the NDP receptor complex into the endo-lysosomal compartment. of ubiquitinated cargo transport through the multivesicular body (MVB) pathway using a dominant negative ESCRT (endosomal sorting complexes required for transport) component VPS4 EQ strongly impairs NDP/FZD4 signalling in vitro. (PMID:28675177)
• A novel mutation was found in the NDP gene in the affected males of the family. As the mutation was absent in the normal male members of the family, it should be the genetic cause of the disease. (PMID:28922694)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Ndp	ENSMUSG00000040138
rattus_norvegicus	Ndp	ENSRNOG00000002960

Protein

Protein identifiers

Norrin — Q00604 (reviewed: Q00604)

Alternative names: Norrie disease protein, X-linked exudative vitreoretinopathy 2 protein

All UniProt accessions (1): Q00604

UniProt curated annotations — full annotation on UniProt →

Function. Activates the canonical Wnt signaling pathway through FZD4 and LRP5 coreceptor. Plays a central role in retinal vascularization by acting as a ligand for FZD4 that signals via stabilizing beta-catenin (CTNNB1) and activating LEF/TCF-mediated transcriptional programs. Acts in concert with TSPAN12 to activate FZD4 independently of the Wnt-dependent activation of FZD4, suggesting the existence of a Wnt-independent signaling that also promote accumulation the beta-catenin (CTNNB1). May be involved in a pathway that regulates neural cell differentiation and proliferation. Possible role in neuroectodermal cell-cell interaction.

Subunit / interactions. Homodimer; disulfide-linked. Component of a complex, at least composed of TSPAN12, FZD4, LRP5/6 and norrin (NDP). Binds FZD4 with high affinity. Interacts with LRP6 (via Beta-propellers 1 and 2).

Subcellular location. Secreted.

Tissue specificity. Expressed in the outer nuclear, inner nuclear and ganglion cell layers of the retina, and in fetal and adult brain.

Disease relevance. Norrie disease (ND) [MIM:310600] Recessive disorder characterized by very early childhood blindness due to degenerative and proliferative changes of the neuroretina. Approximately 50% of patients show some form of progressive mental disorder, often with psychotic features, and about one-third of patients develop sensorineural deafness in the second decade. In addition, some patients have more complex phenotypes, including growth failure and seizure. The disease is caused by variants affecting the gene represented in this entry. Vitreoretinopathy, exudative 2 (EVR2) [MIM:305390] An X-linked form of exudative vitreoretinopathy, a disorder of the retinal vasculature characterized by an abrupt cessation of growth of peripheral capillaries, leading to an avascular peripheral retina. This may lead to compensatory retinal neovascularization, which is thought to be induced by hypoxia from the initial avascular insult. New vessels are prone to leakage and rupture causing exudates and bleeding, followed by scarring, retinal detachment and blindness. Clinical features can be highly variable, even within the same family. Patients with mild forms of the disease are asymptomatic, and their only disease related abnormality is an arc of avascular retina in the extreme temporal periphery. The disease is caused by variants affecting the gene represented in this entry.

RefSeq proteins (1): NP_000257* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003064	Norrie_dis	Family
IPR006207	Cys_knot_C	Domain
IPR006208	Glyco_hormone_CN	Domain
IPR029034	Cystine-knot_cytokine	Homologous_superfamily

Pfam: PF00007

UniProt features (83 total): sequence variant 63, strand 8, disulfide bond 7, signal peptide 1, chain 1, domain 1, mutagenesis site 1, turn 1

Structure

Experimental structures (PDB)

12 structures.

PDB	Method	Resolution (Å)
5BQ8	X-RAY DIFFRACTION	2
5BQB	X-RAY DIFFRACTION	2.3
5BQE	X-RAY DIFFRACTION	2.3
5BPU	X-RAY DIFFRACTION	2.4
4MY2	X-RAY DIFFRACTION	2.4
5BQC	X-RAY DIFFRACTION	3
9UOK	ELECTRON MICROSCOPY	3.05
8WVY	ELECTRON MICROSCOPY	3.29
8WVX	ELECTRON MICROSCOPY	3.32
9KHH	ELECTRON MICROSCOPY	3.65
9MAN	ELECTRON MICROSCOPY	3.78
5CL1	X-RAY DIFFRACTION	3.8

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q00604-F1	83.92	0.65

Antibody-complex structures (SAbDab): 2 — 9KHH, 9UOK

Functional residue map

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

Disulfide bonds (7): 39–96, 55–110, 65–126, 69–128, 93, 95, 131

Mutagenesis-validated functional residues (1):

Position	Phenotype
95	impairs oligomerization.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 546 (showing top): GSE45365_HEALTHY_VS_MCMV_INFECTION_CD8_TCELL_IFNAR_KO_UP, GOBP_MYELOID_CELL_DIFFERENTIATION, GSE45365_NK_CELL_VS_CD8A_DC_DN, GOBP_DENDRITE_DEVELOPMENT, AP1_01, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_LYSOSOMAL_TRANSPORT, GOBP_BEHAVIOR, GOBP_VACUOLE_ORGANIZATION, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, GOBP_INFLAMMATORY_RESPONSE, GOBP_ALPHA_AMINO_ACID_METABOLIC_PROCESS, GOBP_RETINAL_GANGLION_CELL_AXON_GUIDANCE, GOBP_DENDRITIC_SPINE_DEVELOPMENT, GOBP_PROTEIN_TARGETING

GO Biological Process (58): mitotic cell cycle (GO:0000278), re-entry into mitotic cell cycle (GO:0000320), action potential (GO:0001508), angiogenesis (GO:0001525), blood vessel remodeling (GO:0001974), lens development in camera-type eye (GO:0002088), retinal pigment epithelium development (GO:0003406), tricarboxylic acid cycle (GO:0006099), transcription by RNA polymerase II (GO:0006366), glycine metabolic process (GO:0006544), L-serine metabolic process (GO:0006563), protein targeting to lysosome (GO:0006622), glutathione metabolic process (GO:0006749), inflammatory response (GO:0006954), vacuole organization (GO:0007033), transforming growth factor beta receptor signaling pathway (GO:0007179), smoothened signaling pathway (GO:0007224), nervous system development (GO:0007399), visual perception (GO:0007601), retina layer formation (GO:0010842), microglia differentiation (GO:0014004), protein ubiquitination (GO:0016567), optic nerve development (GO:0021554), retinal ganglion cell axon guidance (GO:0031290), extracellular matrix-cell signaling (GO:0035426), exploration behavior (GO:0035640), endothelial cell differentiation (GO:0045446), positive regulation of DNA-templated transcription (GO:0045893), positive regulation of transcription by RNA polymerase II (GO:0045944), decidualization (GO:0046697), response to axon injury (GO:0048678), neuron apoptotic process (GO:0051402), positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction (GO:0051897), canonical Wnt signaling pathway (GO:0060070), retinal rod cell differentiation (GO:0060221), establishment of blood-brain barrier (GO:0060856), dendritic spine development (GO:0060996), retinal blood vessel morphogenesis (GO:0061304), microglial cell proliferation (GO:0061518), ubiquitin-dependent endocytosis (GO:0070086)

GO Molecular Function (4): frizzled binding (GO:0005109), cytokine activity (GO:0005125), protein homodimerization activity (GO:0042803), protein binding (GO:0005515)

GO Cellular Component (3): obsolete extracellular space (GO:0005615), cell surface (GO:0009986), extracellular region (GO:0005576)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
anatomical structure formation involved in morphogenesis	2
proteinogenic amino acid metabolic process	2
cellular anatomical structure	2
cell cycle	1
mitotic nuclear division	1
cell cycle process	1
regulation of membrane potential	1
blood vessel morphogenesis	1
tissue remodeling	1
camera-type eye development	1
anatomical structure development	1
retina development in camera-type eye	1
epithelium development	1
aerobic respiration	1
primary metabolic process	1
DNA-templated transcription	1
L-amino acid metabolic process	1
protein targeting to vacuole	1
lysosomal transport	1
protein localization to lysosome	1
modified amino acid metabolic process	1
sulfur compound metabolic process	1
defense response	1
organelle organization	1
cellular response to transforming growth factor beta stimulus	1
transforming growth factor beta receptor superfamily signaling pathway	1
cell surface receptor signaling pathway	1
system development	1
sensory perception of light stimulus	1
neural retina development	1
retina morphogenesis in camera-type eye	1
G protein-coupled receptor binding	1
receptor ligand activity	1
identical protein binding	1
protein dimerization activity	1
binding	1

Protein interactions and networks

STRING

1343 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NDP	LRP5	O75197	999
NDP	FZD4	Q9ULV1	999
NDP	TSPAN12	O95859	997
NDP	LGR4	Q9BXB1	947
NDP	LRP6	O75581	886
NDP	ADGRA2	Q96PE1	763
NDP	FZD1	Q9UP38	757
NDP	CTNNB1	P35222	737
NDP	ZNF408	Q9H9D4	724
NDP	FZD7	O75084	694
NDP	FZD9	O00144	686
NDP	FZD2	Q14332	680
NDP	NDUFB2	O95178	647
NDP	DVL2	O14641	642
NDP	SOST	Q9BQB4	619

IntAct

9 interactions, top by confidence:

A	B	Type	Score
NDP	FZD4	psi-mi:“MI:0915”(physical association)	0.530
NDP	NDP	psi-mi:“MI:0407”(direct interaction)	0.440
PPP1CA	NDP	psi-mi:“MI:0915”(physical association)	0.370
NDP	LRP5	psi-mi:“MI:0914”(association)	0.350
NDP	TSPAN12	psi-mi:“MI:0914”(association)	0.350
NDP	PLXNA2	psi-mi:“MI:0914”(association)	0.350
NDP	MYCBP2	psi-mi:“MI:0914”(association)	0.350

BioGRID (109): NDP (Affinity Capture-RNA), COL6A2 (Affinity Capture-MS), TMEM67 (Affinity Capture-MS), MRC2 (Affinity Capture-MS), CACNA2D2 (Affinity Capture-MS), SORL1 (Affinity Capture-MS), VWDE (Affinity Capture-MS), ATRN (Affinity Capture-MS), TRIP6 (Affinity Capture-MS), TRPC4AP (Affinity Capture-MS), PLXNA2 (Affinity Capture-MS), LRP1B (Affinity Capture-MS), CACNA2D1 (Affinity Capture-MS), KDM5C (Affinity Capture-MS), BCHE (Affinity Capture-MS)

ESM2 similar proteins: A2VB89, A7X3V0, A8E7N9, A9XE49, B0VXV3, C0K3N4, C5J895, E1ZVK1, G5EBY8, H2CYP1, L0GB04, P09534, P0DQC7, P0DQE0, P0DQG2, P0DQG5, P0DQG8, P0DRJ1, P17219, P42579, P48250, P48744, P49764, P54631, P67860, P67861, P67964, P67965, P85315, P85316, P86785, P92172, Q00604, Q06ZW0, Q11070, Q22687, Q2KI78, Q330K6, Q4FCM6, Q566B1

Diamond homologs: P48744, Q00604, Q2KI78, Q60HE4

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
TSPAN12	up-regulates	NDP

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	46
Likely pathogenic	27
Uncertain significance	65
Likely benign	39
Benign	12

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
10683	NM_000266.4(NDP):c.287G>A (p.Cys96Tyr)	Pathogenic
10686	NM_000266.4(NDP):c.384C>A (p.Cys128Ter)	Pathogenic
10687	NM_000266.4(NDP):c.1A>G (p.Met1Val)	Pathogenic
10689	NM_000266.4(NDP):c.38T>G (p.Leu13Arg)	Pathogenic
10690	NM_000266.4(NDP):c.181C>T (p.Leu61Phe)	Pathogenic
10691	NM_000266.4(NDP):c.125A>G (p.His42Arg)	Pathogenic
10693	NM_000266.4(NDP):c.313G>A (p.Ala105Thr)	Pathogenic
10695	NM_000266.4(NDP):c.362G>T (p.Arg121Leu)	Pathogenic
10696	NM_000266.4(NDP):c.288C>G (p.Cys96Trp)	Pathogenic
10698	NM_000266.4(NDP):c.218C>A (p.Ser73Ter)	Pathogenic
10699	NM_000266.4(NDP):c.302C>T (p.Ser101Phe)	Pathogenic
1072592	NM_000266.4(NDP):c.196G>T (p.Glu66Ter)	Pathogenic
1213861	NM_000266.4(NDP):c.58G>T (p.Gly20Ter)	Pathogenic
1408371	NM_000266.4(NDP):c.65_66del (p.Thr22fs)	Pathogenic
1459580	NM_000266.4(NDP):c.288C>A (p.Cys96Ter)	Pathogenic
1511645	NM_000266.4(NDP):c.196G>A (p.Glu66Lys)	Pathogenic
167326	NM_000266.4(NDP):c.220C>T (p.Arg74Cys)	Pathogenic
1805040	NM_000266.4(NDP):c.223_224dup (p.Glu76fs)	Pathogenic
2013719	NM_000266.4(NDP):c.339dup (p.Met114fs)	Pathogenic
2021859	NM_000266.4(NDP):c.174+1G>A	Pathogenic
2030965	NM_000266.4(NDP):c.269_273dup (p.Ser92fs)	Pathogenic
2138556	NM_000266.4(NDP):c.335G>A (p.Gly112Glu)	Pathogenic
2693748	NM_000266.4(NDP):c.310A>T (p.Lys104Ter)	Pathogenic
2737212	NM_000266.4(NDP):c.343C>T (p.Arg115Ter)	Pathogenic
2737213	NM_000266.4(NDP):c.333del (p.Gly113fs)	Pathogenic
2737214	NM_000266.4(NDP):c.295C>T (p.Gln99Ter)	Pathogenic
2737216	NM_000266.4(NDP):c.65del (p.Thr22fs)	Pathogenic
285135	NM_000266.4(NDP):c.325C>T (p.Arg109Ter)	Pathogenic
3237510	NM_000266.4(NDP):c.199G>T (p.Gly67Trp)	Pathogenic
3248708	NM_000266.4(NDP):c.162G>C (p.Lys54Asn)	Pathogenic

SpliceAI

548 predictions. Top by Δscore:

Variant	Effect	Δscore
X:43950023:CCAT:C	acceptor_gain	0.9900
X:43950024:CAT:C	acceptor_gain	0.9900
X:43950024:CATC:C	acceptor_gain	0.9900
X:43950026:TCTGG:T	acceptor_loss	0.9900
X:43950027:C:CC	acceptor_gain	0.9900
X:43971435:C:A	donor_gain	0.9900
X:43973299:CTTA:C	donor_loss	0.9900
X:43973300:TTA:T	donor_loss	0.9900
X:43973301:TAC:T	donor_loss	0.9900
X:43950022:ACCAT:A	acceptor_gain	0.9800
X:43950023:CCATC:C	acceptor_gain	0.9800
X:43958599:A:T	acceptor_gain	0.9800
X:43958850:CAG:C	acceptor_gain	0.9800
X:43973298:GCTTA:G	donor_loss	0.9800
X:43950025:AT:A	acceptor_gain	0.9700
X:43958719:T:TA	donor_gain	0.9700
X:43958853:C:CC	acceptor_gain	0.9700
X:43959745:C:CT	acceptor_gain	0.9700
X:43973302:A:AC	donor_gain	0.9400
X:43973303:C:CC	donor_gain	0.9400
X:43958598:C:CT	acceptor_gain	0.9200
X:43958848:CACAG:C	acceptor_gain	0.9200
X:43961795:A:C	donor_gain	0.9100
X:43972886:G:A	donor_gain	0.8800
X:43950025:A:T	acceptor_gain	0.8400
X:43973370:T:TA	donor_gain	0.8400
X:43950024:CATCT:C	acceptor_gain	0.8300
X:43950025:ATCT:A	acceptor_gain	0.8300
X:43951333:TGA:T	donor_gain	0.8100
X:43958851:AG:A	acceptor_gain	0.8000

AlphaMissense

862 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:43949823:A:C	C126W	0.999
X:43949824:C:T	C126Y	0.999
X:43949848:G:T	A118D	0.999
X:43949871:G:C	C110W	0.999
X:43949878:A:G	L108P	0.999
X:43949889:C:A	K104N	0.999
X:43949889:C:G	K104N	0.999
X:43949935:A:C	F89C	0.999
X:43949958:G:C	F81L	0.999
X:43949958:G:T	F81L	0.999
X:43949959:A:C	F81C	0.999
X:43949960:A:G	F81L	0.999
X:43950006:G:C	C65W	0.999
X:43950007:C:G	C65S	0.999
X:43950008:A:T	C65S	0.999
X:43958481:A:C	C55W	0.999
X:43949825:A:G	C126R	0.998
X:43949839:C:G	R121P	0.998
X:43949843:A:C	Y120D	0.998
X:43949872:C:G	C110S	0.998
X:43949872:C:T	C110Y	0.998
X:43949873:A:G	C110R	0.998
X:43949873:A:T	C110S	0.998
X:43949891:T:C	K104E	0.998
X:43949893:A:G	L103P	0.998
X:43949913:G:C	C96W	0.998
X:43949914:C:G	C96S	0.998
X:43949914:C:T	C96Y	0.998
X:43949915:A:G	C96R	0.998
X:43949915:A:T	C96S	0.998

dbSNP variants (sampled 300 via entrez): RS1000037980 (X:43966720 G>A,T), RS1000279 (X:43967453 A>G), RS1000356936 (X:43966420 T>C), RS1000379261 (X:43974896 G>A), RS1000389509 (X:43966059 A>G,T), RS1000625021 (X:43954640 C>T), RS1000678307 (X:43964512 CT>C,CTT), RS1000693326 (X:43956376 A>T), RS1000860385 (X:43960076 C>T), RS1000881678 (X:43973271 A>G), RS1000976020 (X:43955133 C>A,T), RS1001068352 (X:43952865 A>G), RS1001329740 (X:43950748 T>C), RS1001355248 (X:43972838 C>T), RS1001403326 (X:43951055 G>A)

Disease associations

OMIM: gene MIM:300658 | disease phenotypes: MIM:310600, MIM:305390, MIM:300216, MIM:133780, MIM:221900, MIM:180050, MIM:312530

GenCC curated gene-disease

Disease	Classification	Inheritance
Norrie disease	Definitive	X-linked
exudative vitreoretinopathy 2, X-linked	Definitive	X-linked
exudative vitreoretinopathy	Supportive	Autosomal dominant
persistent hyperplastic primary vitreous	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
Norrie disease	Definitive	XL

Mondo (10): Norrie disease (MONDO:0010691), exudative vitreoretinopathy 2, X-linked (MONDO:0010588), inherited retinal dystrophy (MONDO:0019118), Coats disease (MONDO:0010269), exudative vitreoretinopathy (MONDO:0019516), pathologic nystagmus (MONDO:0004843), persistent hyperplastic primary vitreous (MONDO:0019631), retinal disorder (MONDO:0005283), retinal detachment (MONDO:0008375), hearing loss disorder (MONDO:0005365)

Orphanet (5): Norrie disease (Orphanet:649), Familial exudative vitreoretinopathy (Orphanet:891), OBSOLETE: Inherited retinal disorder (Orphanet:71862), Coats disease (Orphanet:190), Persistent hyperplastic primary vitreous (Orphanet:91495)

HPO phenotypes

126 total (30 of 126 shown, HPO-id order):

HPO	Term
HP:0000028	Cryptorchidism
HP:0000233	Thin vermilion border
HP:0000252	Microcephaly
HP:0000272	Malar flattening
HP:0000365	Hearing impairment
HP:0000375	Abnormal cochlea morphology
HP:0000400	Macrotia
HP:0000407	Sensorineural hearing impairment
HP:0000411	Protruding ear
HP:0000446	Narrow nasal bridge
HP:0000482	Microcornea
HP:0000486	Strabismus
HP:0000490	Deeply set eye
HP:0000501	Glaucoma
HP:0000518	Cataract
HP:0000519	Developmental cataract
HP:0000532	Abnormal chorioretinal morphology
HP:0000533	Chorioretinal atrophy
HP:0000541	Retinal detachment
HP:0000545	Myopia
HP:0000555	Leukocoria
HP:0000557	Buphthalmos
HP:0000568	Microphthalmia
HP:0000593	Abnormal anterior chamber morphology
HP:0000594	Shallow anterior chamber
HP:0000601	Hypotelorism
HP:0000615	Abnormal pupil morphology
HP:0000618	Blindness
HP:0000639	Nystagmus
HP:0000646	Amblyopia

GWAS associations

8 associations (top):

Study	Trait	p-value
GCST006010_21	Mean arterial pressure	4.000000e-08
GCST006288_417	Heel bone mineral density	1.000000e-11
GCST006288_697	Heel bone mineral density	4.000000e-15
GCST006288_94	Heel bone mineral density	5.000000e-07
GCST006979_839	Heel bone mineral density	7.000000e-46
GCST006979_840	Heel bone mineral density	9.000000e-13
GCST90011766_22	Glaucoma (primary open-angle)	4.000000e-08
GCST90011770_88	Glaucoma (primary open-angle)	6.000000e-20

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0006340	mean arterial pressure
EFO:0009270	heel bone mineral density

MeSH disease descriptors (9)

Descriptor	Name	Tree numbers
D034381	Hearing Loss	C09.218.458.341; C10.597.751.418.341; C23.888.592.763.393.341
D009759	Nystagmus, Pathologic	C10.292.562.675; C11.590.400
D054514	Persistent Hyperplastic Primary Vitreous	C11.250.616; C16.131.384.725
D012163	Retinal Detachment	C11.768.648
D012164	Retinal Diseases	C11.768
D058499	Retinal Dystrophies	C11.768.585.658
D058456	Retinal Telangiectasis	C11.768.748; C14.907.823.502
C564428	Exudative Vitreoretinopathy, Familial, X-Linked Recessive (supp.)
C537849	Norrie disease (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

34 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases expression, decreases methylation	4
mercuric bromide	decreases expression, affects cotreatment	2
entinostat	decreases expression, affects cotreatment	2
belinostat	affects cotreatment, decreases expression	2
Panobinostat	affects cotreatment, decreases expression	2
Estradiol	affects cotreatment, increases expression	2
Phenylmercuric Acetate	decreases expression, affects cotreatment	2
Progesterone	affects cotreatment, increases expression	2
Aflatoxin B1	decreases expression, decreases methylation	2
p-Chloromercuribenzoic Acid	affects cotreatment, decreases expression	2
methylmercuric chloride	decreases expression	1
pirinixic acid	affects binding, increases activity, increases expression	1
geraniol	decreases expression	1
trichostatin A	decreases expression	1
caffeic acid	increases expression	1
4-methoxycinnamate methyl ester	increases expression	1
pentabromodiphenyl ether	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
quinocetone	increases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
dorsomorphin	decreases expression, affects cotreatment	1
archazolid B	decreases expression	1
(+)-JQ1 compound	decreases expression	1
NSC668394	decreases expression	1
Temozolomide	decreases expression	1
Arsenic Trioxide	decreases expression	1
Air Pollutants	decreases expression, increases abundance	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Drugs, Chinese Herbal	increases expression	1
Nickel	decreases expression	1

Cellosaurus cell lines

1 cell lines: 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_5M58	GM12318	Transformed cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT06520410	PHASE4	RECRUITING	Safety and Efficacy of 18 mm Short Vitrectomy Probe for Pediatric Vitreoretinal Surgeries
NCT01955135	PHASE4	COMPLETED	Anesthesia for Retinopathy of Prematurity
NCT00634972	PHASE4	TERMINATED	Efficient Study of ACULAR in Inhibiting Proliferative Retinopathy in Prematurity
NCT01001429	PHASE4	COMPLETED	Dexmedetomidine Versus Propofol in Vitreoretinal Surgery
NCT01326585	PHASE4	WITHDRAWN	Study Trial of Dexamethasone Use for Alleviation of Symptoms After Scleral Buckle Eye Surgery
NCT01417572	PHASE4	UNKNOWN	Adjunctive Local Application of Lidocaine During Scleral Buckling Under General Anesthesia
NCT01995045	PHASE4	COMPLETED	Postoperative Pain Control Following Vitreoretinal Surgery
NCT02068625	PHASE4	TERMINATED	Rasagiline (Azilect) - Neuroprotection for Macula-off Retinal Detachment
NCT04346095	PHASE4	UNKNOWN	Oral Sedation in Vitreoretinal Surgery
NCT04464629	PHASE4	TERMINATED	Assessing the Efficacy and Safety of DEXTENZA in Pseudo Phakic Patients Undergoing Gas Bubble Repair and Laser Following Retinal Detachment
NCT04701593	PHASE4	COMPLETED	Using Triamcinolone Acetonide to Reduce Pain After Scleral Buckle Surgery
NCT06587945	PHASE4	RECRUITING	Nicotinamide Riboside Oral Supplementation in Macula Off Retinal Detachment
NCT00205881	PHASE4	COMPLETED	Bilateral Benefit in Adult Users of the HiRes 90K Bionic Ear System
NCT00331539	PHASE4	UNKNOWN	Relationship Between Auto NRT and Behavioural T & C Levels With the Nucleus Freedom Cochlear Implant
NCT00424307	PHASE4	UNKNOWN	Bilateral Cochlear Implant Benefit in Young Children
NCT00765635	PHASE4	COMPLETED	Chlorobutanol, Potassium Carbonate, and Irrigation in Cerumen Removal
NCT03321006	PHASE4	COMPLETED	Treating Hearing Loss to Improve Mood and Cognition in Older Adults
NCT04224207	PHASE3	COMPLETED	Management of Retinitis Pigmentosa by Mesenchymal Stem Cells by Wharton’s Jelly Derived Mesenchymal Stem Cells
NCT07082855	PHASE3	NOT_YET_RECRUITING	A Multicenter, Randomized, Double-Blind, Controlled Clinical Study of Minocycline for the Treatment of Retinitis Pigmentosa
NCT03940690	PHASE3	TERMINATED	Interest of Intravitreal Injections of Anti-VEGF as Initial and Adjuvant Treatment in Coats Disease
NCT00000140	PHASE3	COMPLETED	The Silicone Study
NCT00000154	PHASE3	COMPLETED	Diabetic Retinopathy Vitrectomy Study (DRVS)
NCT00120445	PHASE3	COMPLETED	Comparison of Air and Expansile Gas in Pneumatic Retinopexy
NCT00404209	PHASE3	TERMINATED	Pressurized PPV 23GA Vitrectomy in Complicated Diabetic Tractional Retinal Detachment
NCT06294847	PHASE3	RECRUITING	Ursodeoxycholic Acid (UDCA) as a Neuroprotective Adjuvant Treatment to Rhegmatogenous Retinal Detachment Surgery
NCT01499901	PHASE3	WITHDRAWN	Comparison of the Bilateral Sequential and Simultaneous Cochlear Implantation in the Deaf Children
NCT02561091	PHASE3	COMPLETED	AM-111 in the Treatment of Acute Inner Ear Hearing Loss
NCT03331627	PHASE3	COMPLETED	Safety and Efficacy of STR001-IT and STR001-ER in Patients With SSHL
NCT05532657	PHASE3	ACTIVE_NOT_RECRUITING	ACHIEVE Brain Health Follow-Up Study
NCT05107921	PHASE2	UNKNOWN	Bromfenac Sodium Hydrate Eye Drops in Familial Exudative Vitreoretinopathy
NCT03763227	PHASE2	COMPLETED	Intravitreal Ranibizumab (Lucentis®) in the Treatment of Non-leaking Macular Cysts in Retinal Dystrophy
NCT04068207	PHASE2	COMPLETED	Minocycline Treatment in Retinitis Pigmentosa
NCT04945772	PHASE2	COMPLETED	Efficacy and Safety of MCO-010 Optogenetic Therapy in Adults With Retinitis Pigmentosa [RESTORE]
NCT01373476	PHASE2	COMPLETED	Multicentre, Randomized, Controlled Trial of Qideng Mingmu Capsule in The Treatment of Diabetic Retinopathy
NCT01793090	PHASE2	COMPLETED	EPI-743 in Cobalamin C Defect: Effects on Visual and Neurological Impairment
NCT00083967	PHASE2	TERMINATED	Study of Denufosol (INS37217) in Subjects With Rhegmatogenous Retinal Detachment
NCT00690768	PHASE2	COMPLETED	Pars Plana Vitrectomy (PPV) Versus Preoperative Intravitreal Bevacizumab Plus PPV to Treat Diabetic Tractional Retinal Detachment (IBETRA)
NCT01201161	PHASE2	COMPLETED	Ranibizumab for Diabetic Traction Retinal Detachment
NCT01297816	PHASE2	UNKNOWN	Evaluation of Neuroprotective Effect of Minocycline
NCT02192970	PHASE2	COMPLETED	Bevacizumab Against Recurrent Retinal Detachment