TENM3

Summary

TENM3 (teneurin transmembrane protein 3, HGNC:29944) is a protein-coding gene on chromosome 4q34.3-q35.1, encoding Teneurin-3 (Q9P273). Involved in neural development by regulating the establishment of proper connectivity within the nervous system.

This gene encodes a member of the teneurin transmembrane protein family. The encoded protein may be involved in the regulation of neuronal development including development of the visual pathway. Mutations in this gene have been associated with microphthalmia and developmental dysplasia of the hip.

Source: NCBI Gene 55714 — RefSeq curated summary.

At a glance

• Gene–disease (curated): microphthalmia, isolated, with coloboma 9 (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 17
• Clinical variants (ClinVar): 672 total — 5 pathogenic, 5 likely-pathogenic
• Phenotypes (HPO): 22
• MANE Select transcript: NM_001080477

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:29944
Approved symbol	TENM3
Name	teneurin transmembrane protein 3
Location	4q34.3-q35.1
Locus type	gene with protein product
Status	Approved
Aliases	Ten-M3, KIAA1455, TEN3
Ensembl gene	ENSG00000218336
Ensembl biotype	protein_coding
OMIM	610083
Entrez	55714

Gene structure

Transcript identifiers

Ensembl transcripts: 22 — 19 protein_coding, 2 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000502950, ENST00000507737, ENST00000510504, ENST00000511685, ENST00000512480, ENST00000513201, ENST00000851037, ENST00000851038, ENST00000851039, ENST00000851040, ENST00000851041, ENST00000851042, ENST00000851043, ENST00000851045, ENST00000851046, ENST00000851051, ENST00000851052, ENST00000851053, ENST00000851054, ENST00000851055, ENST00000851056, ENST00000851057

RefSeq mRNA: 17 — MANE Select: NM_001080477 NM_001080477, NM_001415960, NM_001415961, NM_001415962, NM_001415963, NM_001415964, NM_001415966, NM_001415967, NM_001415968, NM_001415969, NM_001415970, NM_001415971, NM_001415973, NM_001415974, NM_001415975, NM_001415976, NM_001415977

CCDS: CCDS47165

Canonical transcript exons

ENST00000511685 — 28 exons

Exon	Start	End
ENSE00002054072	182243402	182243476
ENSE00003617151	182323946	182324252
ENSE00003788879	182346651	182346929
ENSE00004283513	182738401	182738544
ENSE00004283514	182730878	182731139
ENSE00004283515	182680543	182680737
ENSE00004283516	182673005	182673219
ENSE00004283517	182730200	182730319
ENSE00004283518	182628651	182628889
ENSE00004283519	182789093	182789389
ENSE00004283520	182714087	182714233
ENSE00004283522	182680248	182680349
ENSE00004283523	182754385	182755259
ENSE00004283524	182773472	182773647
ENSE00004283525	182796637	182796767
ENSE00004283526	182774918	182775153
ENSE00004283527	182736808	182737075
ENSE00004283528	182792274	182793885
ENSE00004283529	182743170	182743419
ENSE00004283530	182688166	182688351
ENSE00004283531	182653771	182653893
ENSE00004283532	182679666	182679876
ENSE00004283533	182681814	182682014
ENSE00004283534	182753450	182753604
ENSE00004283535	182728965	182729181
ENSE00004283537	182600924	182601161
ENSE00004283558	182751800	182752032
ENSE00004283591	182799596	182803024

Expression profiles

Bgee: expression breadth ubiquitous, 189 present calls, max score 90.29.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 21.3101 / max 500.3729, expressed in 1312 samples.

FANTOM5 promoters (13 alternative TSS)

Promoter ID	TPM avg	Samples expressed
50766	14.0957	1258
50751	3.6221	928
50765	0.9132	399
50746	0.7826	440
50750	0.6289	363
50759	0.3303	53
50747	0.2793	117
50749	0.1678	73
50748	0.1623	58
50764	0.1353	48

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
sural nerve	UBERON:0015488	90.29	gold quality
adrenal tissue	UBERON:0018303	90.16	gold quality
stromal cell of endometrium	CL:0002255	89.67	gold quality
calcaneal tendon	UBERON:0003701	85.96	gold quality
cortical plate	UBERON:0005343	82.82	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	81.90	gold quality
islet of Langerhans	UBERON:0000006	81.46	gold quality
placenta	UBERON:0001987	80.70	gold quality
cartilage tissue	UBERON:0002418	80.65	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	79.53	gold quality
medial globus pallidus	UBERON:0002477	78.82	gold quality
entorhinal cortex	UBERON:0002728	77.31	gold quality
prefrontal cortex	UBERON:0000451	77.18	gold quality
Brodmann (1909) area 23	UBERON:0013554	76.98	gold quality
colonic epithelium	UBERON:0000397	75.86	gold quality
adrenal gland	UBERON:0002369	75.83	gold quality
left adrenal gland	UBERON:0001234	75.29	gold quality
middle temporal gyrus	UBERON:0002771	75.26	gold quality
right adrenal gland	UBERON:0001233	75.05	gold quality
right adrenal gland cortex	UBERON:0035827	74.60	gold quality
left adrenal gland cortex	UBERON:0035825	74.56	gold quality
adenohypophysis	UBERON:0002196	73.85	gold quality
tendon	UBERON:0000043	73.73	gold quality
tibial nerve	UBERON:0001323	73.47	gold quality
frontal cortex	UBERON:0001870	73.35	gold quality
globus pallidus	UBERON:0001875	73.26	gold quality
adrenal cortex	UBERON:0001235	72.93	gold quality
tibia	UBERON:0000979	72.65	gold quality
neocortex	UBERON:0001950	72.63	gold quality
nucleus accumbens	UBERON:0001882	72.47	gold quality

Single-cell (SCXA)

Detected in 10 experiment(s), a significant marker in 8.

Experiment	Marker?	Max mean expression
E-HCAD-35	yes	83.99
E-MTAB-3929	yes	66.57
E-HCAD-25	yes	47.13
E-CURD-119	yes	26.71
E-MTAB-5061	yes	12.41
E-ANND-3	yes	6.11
E-GEOD-81547	yes	5.88
E-GEOD-81608	yes	5.62
E-CURD-11	no	50.62
E-GEOD-83139	no	3.69

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

172 targeting TENM3, 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-4668-3P	100.00	68.74	2635
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-6748-5P	100.00	65.81	1057
HSA-MIR-3064-3P	100.00	70.09	1254
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-499A-5P	99.98	70.79	1323
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-4650-5P	99.98	64.69	999
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-548AT-5P	99.96	70.83	2666
HSA-MIR-1250-3P	99.96	70.04	4038

Literature-anchored findings (GeneRIF, showing 7)

• Null mutation in ODZ3 causes autosomal recessive microphthalmia in humans. (PMID:22766609)
• This report supports the association of TENM3 mutations with colobomatous microphthalmia and expands the phenotypic spectrum associated with mutations in this gene (PMID:27103084)
• TENM3 missense mutation was identified in a patient with eye abnormalities and intellectual disability. (PMID:29753094)
• novel A to C transversion at position 183721398 on chromosome four found to co-segregate with the affected phenotype of developmental dysplasia of the hip (PMID:30273960)
• Exome sequencing in patients with microphthalmia, anophthalmia, and coloboma (MAC) from a consanguineous population. (PMID:32799327)
• Ten-m/Odz3 regulates migration and differentiation of chondrogenic ATDC5 cells via RhoA-mediated actin reorganization. (PMID:32960451)
• Replicative verification of susceptibility genes previously identified from families with segregating developmental dysplasia of the hip. (PMID:34174923)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	TENM3	ENSDARG00000087599
mus_musculus	Tenm3	ENSMUSG00000031561
rattus_norvegicus	Tenm3	ENSRNOG00000012802
drosophila_melanogaster	Ten-m	FBGN0004449
drosophila_melanogaster	Ten-a	FBGN0267001
caenorhabditis_elegans		WBGENE00017892
caenorhabditis_elegans		WBGENE00018237

Paralogs (4): TENM1 (ENSG00000009694), NAGPA (ENSG00000103174), TENM2 (ENSG00000145934), TENM4 (ENSG00000149256)

Protein

Protein identifiers

Teneurin-3 — Q9P273 (reviewed: Q9P273)

Alternative names: Protein Odd Oz/ten-m homolog 3, Tenascin-M3, Teneurin transmembrane protein 3

All UniProt accessions (4): Q9P273, A0A140VJW8, D6RGC5, H0YAF0

UniProt curated annotations — full annotation on UniProt →

Function. Involved in neural development by regulating the establishment of proper connectivity within the nervous system. Acts in both pre- and postsynaptic neurons in the hippocampus to control the assembly of a precise topographic projection: required in both CA1 and subicular neurons for the precise targeting of proximal CA1 axons to distal subiculum, probably by promoting homophilic cell adhesion. Required for proper dendrite morphogenesis and axon targeting in the vertebrate visual system, thereby playing a key role in the development of the visual pathway. Regulates the formation in ipsilateral retinal mapping to both the dorsal lateral geniculate nucleus (dLGN) and the superior colliculus (SC). May also be involved in the differentiation of the fibroblast-like cells in the superficial layer of mandibular condylar cartilage into chondrocytes.

Subunit / interactions. Homodimer; disulfide-linked; to mediate homophilic cell adhesion. Heterodimer with either TENM1 or TENM2. May also form heterodimer with TENM4.

Subcellular location. Cell membrane. Cell projection. Axon.

Tissue specificity. Expressed in adult and fetal brain, slightly lower levels in testis and ovary, and intermediate levels in all other peripheral tissues examined. Not expressed in spleen or liver. Expression was high in brain, with highest levels in amygdala and caudate nucleus, followed by thalamus and subthalamic nucleus.

Disease relevance. Microphthalmia/Coloboma 9 (MCOPCB9) [MIM:615145] 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. Microphthalmia, syndromic, 15 (MCOPS15) [MIM:615145] A form of microphthalmia, a disorder of eye formation, ranging from small size of a single eye to complete bilateral absence of ocular tissues (anophthalmia). In many cases, microphthalmia/anophthalmia occurs in association with syndromes that include non-ocular abnormalities. MCOPS15 is characterized by microphthalmia and/or coloboma, with developmental delay in which speech appears to be more severely affected than motor abilities. Additional ocular anomalies that have been observed include ptosis, keyhole-shaped pupils, microcornea, sclerocornea, and anterior segment dysgenesis. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. EGF-like domains 2 and 5 which have an odd number of cysteines might enable the formation of intermolecular disulfide bonds. Cytoplasmic proline-rich regions could serve as docking domains for intracellular SH3-containing proteins.

Similarity. Belongs to the tenascin family. Teneurin subfamily.

RefSeq proteins (17): NP_001073946, NP_001402889, NP_001402890, NP_001402891, NP_001402892, NP_001402893, NP_001402895, NP_001402896, NP_001402897, NP_001402898, NP_001402899, NP_001402900, NP_001402902, NP_001402903, NP_001402904, NP_001402905, NP_001402906 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000742	EGF	Domain
IPR006530	YD	Repeat
IPR008969	CarboxyPept-like_regulatory	Homologous_superfamily
IPR009471	Ten_N	Domain
IPR011042	6-blade_b-propeller_TolB-like	Homologous_superfamily
IPR022385	Rhs_assc_core	Domain
IPR028916	Tox-GHH_dom	Domain
IPR036322	WD40_repeat_dom_sf	Homologous_superfamily
IPR051216	Teneurin	Family
IPR056820	TEN_TTR-like	Domain
IPR056822	TEN_NHL	Domain
IPR056823	TEN-like_YD-shell	Domain
IPR057627	FN-plug_TEN1-4	Domain
IPR057629	Teneurin1-4_GBD	Domain

Pfam: PF06484, PF15636, PF23093, PF23538, PF24329, PF25020, PF25021, PF25023, PF25024

UniProt features (91 total): repeat 28, disulfide bond 22, glycosylation site 17, domain 9, compositionally biased region 4, sequence variant 4, topological domain 2, region of interest 2, chain 1, transmembrane region 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9P273-F1	77.76	0.38

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 (22): 518–528, 522–533, 535–544, 553–564, 566–575, 582–593, 587–598, 600–609, 614–625, 619–630, 632–641, 652–665, 667–676, 681–691, 685–696, 698–707, 712–722, 716–727, 729–738, 743–753 …

Glycosylation sites (17): 345, 380, 419, 670, 860, 883, 1202, 1527, 1544, 1640, 1677, 1735, 1820, 1921, 2124, 2264, 2576

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 185 (showing top): TSENG_IRS1_TARGETS_UP, FISCHER_G1_S_CELL_CYCLE, chr4q34, GOBP_NEUROGENESIS, ACEVEDO_LIVER_CANCER_WITH_H3K27ME3_UP, GOBP_CELL_CELL_ADHESION, GOBP_ANIMAL_ORGAN_MORPHOGENESIS, GOBP_REGULATION_OF_CELL_PROJECTION_ORGANIZATION, LE_EGR2_TARGETS_UP, GOBP_REGULATION_OF_NEURON_PROJECTION_DEVELOPMENT, GOCC_NEURON_PROJECTION, GOBP_SENSORY_ORGAN_DEVELOPMENT, GOBP_CELL_PROJECTION_ORGANIZATION, GOBP_SENSORY_ORGAN_MORPHOGENESIS, GRYDER_PAX3FOXO1_ENHANCERS_IN_TADS

GO Biological Process (8): homophilic cell-cell adhesion (GO:0007156), signal transduction (GO:0007165), positive regulation of neuron projection development (GO:0010976), camera-type eye morphogenesis (GO:0048593), neuron development (GO:0048666), regulation of homophilic cell adhesion (GO:1903385), cell adhesion (GO:0007155), cell differentiation (GO:0030154)

GO Molecular Function (4): protein homodimerization activity (GO:0042803), protein heterodimerization activity (GO:0046982), cell adhesion molecule binding (GO:0050839), protein binding (GO:0005515)

GO Cellular Component (5): plasma membrane (GO:0005886), membrane (GO:0016020), axon (GO:0030424), neuron projection (GO:0043005), cell projection (GO:0042995)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular process	2
protein dimerization activity	2
cellular anatomical structure	2
cell-cell adhesion	1
cell communication	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
regulation of neuron projection development	1
neuron projection development	1
positive regulation of cell projection organization	1
camera-type eye development	1
eye morphogenesis	1
neuron differentiation	1
cell development	1
homophilic cell-cell adhesion	1
regulation of cell-cell adhesion	1
cellular developmental process	1
identical protein binding	1
protein binding	1
binding	1
membrane	1
cell periphery	1
neuron projection	1
plasma membrane bounded cell projection	1

Protein interactions and networks

STRING

1533 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TENM3	ADGRL3	Q9HAR2	611
TENM3	EGF	P01133	536
TENM3	ADGRL2	O95490	490
TENM3	ROBO2	Q9HCK4	490
TENM3	ZIC1	Q15915	489
TENM3	VSX2	P58304	471
TENM3	ADGRL1	O94910	460
TENM3	NPAS3	Q8IXF0	444
TENM3	ROBO1	Q9Y6N7	443
TENM3	WNT7A	O00755	418
TENM3	HARS1	P12081	410
TENM3	FOXP2	O15409	391
TENM3	PCDHAC2	Q9Y5I4	387
TENM3	ZIC2	O95409	387
TENM3	EFNA2	O43921	384

IntAct

92 interactions, top by confidence:

A	B	Type	Score
TSPAN15	ADAM10	psi-mi:“MI:0914”(association)	0.840
TSPAN5	ADAM10	psi-mi:“MI:0914”(association)	0.800
CD9	ADAM10	psi-mi:“MI:0914”(association)	0.750
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
KCNJ2	KCNJ18	psi-mi:“MI:2364”(proximity)	0.660
TRDN	TMEM223	psi-mi:“MI:0914”(association)	0.640
MME	TMEM223	psi-mi:“MI:0914”(association)	0.530
PSG8	PEX7	psi-mi:“MI:0914”(association)	0.530
SERPINA12	TSPAN6	psi-mi:“MI:0914”(association)	0.530
FBXO2	TMEM131L	psi-mi:“MI:0914”(association)	0.530
LGALS1	PODXL	psi-mi:“MI:0914”(association)	0.530
DNAJC3	DEDD	psi-mi:“MI:0914”(association)	0.530
OS9	AGRN	psi-mi:“MI:0914”(association)	0.530
B4GAT1	ADCY6	psi-mi:“MI:0914”(association)	0.530
CLEC4A	SEMA7A	psi-mi:“MI:0914”(association)	0.530
EVA1C	STK25	psi-mi:“MI:0914”(association)	0.530
KCNE3	RIOK3	psi-mi:“MI:0914”(association)	0.530
SDC1	ILVBL	psi-mi:“MI:0915”(physical association)	0.400
TENM3	SMAD4	psi-mi:“MI:0915”(physical association)	0.370
RBCK1	UMAD1	psi-mi:“MI:0914”(association)	0.350
SHARPIN	MAP3K7	psi-mi:“MI:0914”(association)	0.350
TANK	CNOT1	psi-mi:“MI:0914”(association)	0.350

BioGRID (79): TENM3 (Affinity Capture-MS), TENM3 (Affinity Capture-MS), TENM3 (Proximity Label-MS), TENM3 (Affinity Capture-MS), TENM3 (Affinity Capture-MS), TENM3 (Affinity Capture-MS), TENM3 (Affinity Capture-MS), TENM3 (Affinity Capture-MS), TENM3 (Affinity Capture-MS), TENM3 (Affinity Capture-MS), TENM3 (Proximity Label-MS), TENM3 (Affinity Capture-RNA), TENM3 (Affinity Capture-MS), TENM3 (Affinity Capture-MS), TENM3 (Affinity Capture-MS)

ESM2 similar proteins: A0A088MLT8, A0JPH4, A2A8U2, A2ATD1, A6QLD2, B1AKI9, B1AL88, B3KU38, O14525, O35757, O75129, P0DPB3, P0DPB4, P12755, P17863, P27424, P49140, P55001, P55002, P85299, P97953, Q3V1G4, Q58CS8, Q5EGE1, Q5QQ56, Q5QQ57, Q60698, Q61137, Q68BL8, Q6DVA0, Q6L8S8, Q6L9W6, Q6S5C2, Q6ZWB6, Q80U62, Q80Z10, Q812A5, Q86Y38, Q8CCS2, Q8JG33

Diamond homologs: O61307, Q3UHK6, Q6N022, Q9DER5, Q9NT68, Q9P273, Q9R1K2, Q9UKZ4, Q9VYN8, Q9W6V6, Q9W7R3, Q9W7R4, Q9WTS4, Q9WTS5, Q9WTS6, Q7Z7M0, Q80Z71, G5EGQ6, Q55AP8

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 127 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
TNFR1-induced NF-kappa-B signaling pathway	6	26.2×	5e-05
Regulation of TNFR1 signaling	5	14.5×	4e-03

GO biological processes:

GO term	Partners	Fold	FDR
canonical NF-kappaB signal transduction	7	23.1×	9e-06
negative regulation of canonical NF-kappaB signal transduction	9	13.9×	9e-06
response to endoplasmic reticulum stress	6	9.0×	8e-03
positive regulation of canonical NF-kappaB signal transduction	11	7.2×	1e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	5
Likely pathogenic	5
Uncertain significance	389
Likely benign	111
Benign	126

Top pathogenic / likely-pathogenic (10)

Variant ID	HGVS	Classification
1699299	NM_001080477.4(TENM3):c.2279G>A (p.Trp760Ter)	Pathogenic
253150	NM_001080477.4(TENM3):c.2968-2A>T	Pathogenic
41420	NM_001080477.4(TENM3):c.2083dup (p.Thr695fs)	Pathogenic
638054	NM_001080477.4(TENM3):c.1558C>T (p.Arg520Ter)	Pathogenic
638273	NM_001080477.4(TENM3):c.1857T>A (p.Cys619Ter)	Pathogenic
3362545	NM_001080477.4(TENM3):c.6006_6009del (p.Gln2003fs)	Likely pathogenic
3777050	NM_001080477.4(TENM3):c.5500C>T (p.Arg1834Ter)	Likely pathogenic
4734830	NM_001080477.4(TENM3):c.7214-1G>A	Likely pathogenic
487482	NM_001080477.4(TENM3):c.7687C>T (p.Arg2563Trp)	Likely pathogenic
487483	NM_001080477.4(TENM3):c.4046C>G (p.Ala1349Gly)	Likely pathogenic

SpliceAI

4353 predictions. Top by Δscore:

Variant	Effect	Δscore
4:182296991:G:T	donor_gain	1.0000
4:182323945:GA:G	acceptor_gain	1.0000
4:182323945:GAGA:G	acceptor_gain	1.0000
4:182476828:G:GT	donor_gain	1.0000
4:182552459:A:AG	donor_gain	1.0000
4:182601140:G:GG	donor_gain	1.0000
4:182601157:AGCAG:A	donor_loss	1.0000
4:182601158:GCAG:G	donor_gain	1.0000
4:182601159:CAG:C	donor_loss	1.0000
4:182601160:AGG:A	donor_loss	1.0000
4:182601161:GGTAA:G	donor_loss	1.0000
4:182601162:GTAAC:G	donor_loss	1.0000
4:182601163:T:A	donor_loss	1.0000
4:182628649:A:AG	acceptor_gain	1.0000
4:182628649:A:AT	acceptor_loss	1.0000
4:182628650:G:GG	acceptor_gain	1.0000
4:182628650:GGC:G	acceptor_gain	1.0000
4:182628650:GGCA:G	acceptor_gain	1.0000
4:182628886:ATAGG:A	donor_loss	1.0000
4:182628887:TAGG:T	donor_loss	1.0000
4:182628888:AGG:A	donor_loss	1.0000
4:182628889:GGTA:G	donor_loss	1.0000
4:182628890:G:C	donor_loss	1.0000
4:182628891:T:A	donor_loss	1.0000
4:182244671:G:GT	donor_gain	0.9900
4:182249638:GGCAC:G	donor_gain	0.9900
4:182346925:GAATG:G	donor_gain	0.9900
4:182346930:G:A	donor_loss	0.9900
4:182346931:TAAG:T	donor_loss	0.9900
4:182349305:A:G	donor_gain	0.9900

AlphaMissense

17766 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:182673191:G:C	R433P	1.000
4:182673206:C:A	P438H	1.000
4:182680560:T:A	C553S	1.000
4:182680560:T:C	C553R	1.000
4:182680561:G:C	C553S	1.000
4:182680562:T:G	C553W	1.000
4:182680573:G:A	G557E	1.000
4:182680593:T:A	C564S	1.000
4:182680593:T:C	C564R	1.000
4:182680594:G:C	C564S	1.000
4:182680601:T:G	C566W	1.000
4:182680626:T:A	C575S	1.000
4:182680626:T:C	C575R	1.000
4:182680627:G:C	C575S	1.000
4:182680628:T:G	C575W	1.000
4:182680647:T:A	C582S	1.000
4:182680647:T:C	C582R	1.000
4:182680648:G:C	C582S	1.000
4:182681902:T:G	C641W	1.000
4:182681933:T:A	C652S	1.000
4:182681934:G:C	C652S	1.000
4:182681992:G:C	W671C	1.000
4:182681992:G:T	W671C	1.000
4:182682005:T:A	C676S	1.000
4:182682006:G:C	C676S	1.000
4:182682007:C:G	C676W	1.000
4:182688309:T:A	C727S	1.000
4:182688309:T:C	C727R	1.000
4:182688310:G:C	C727S	1.000
4:182688329:G:C	W733C	1.000

dbSNP variants (sampled 300 via entrez): RS1000003483 (4:182340028 G>A), RS1000004233 (4:182482788 G>A,T), RS10000045 (4:182367127 T>A,C,G), RS1000005552 (4:181865649 A>G,T), RS1000005638 (4:182384464 T>C), RS1000007120 (4:181484258 A>G), RS10000076 (4:182367207 T>G), RS10000088 (4:181684197 G>C,T), RS1000012298 (4:181653661 A>C), RS1000012606 (4:182093831 C>T), RS1000016030 (4:181990330 G>A), RS1000016447 (4:182216929 A>G), RS1000016532 (4:182549916 A>G), RS1000020588 (4:181867140 C>T), RS1000025476 (4:182756181 G>C,T)

Disease associations

OMIM: gene MIM:610083 | disease phenotypes: MIM:615145, MIM:156000

GenCC curated gene-disease

Disease	Classification	Inheritance
microphthalmia, isolated, with coloboma 9	Strong	Autosomal recessive
microphthalmia, isolated, with coloboma	Supportive	Autosomal dominant

Mondo (4): microphthalmia, isolated, with coloboma 9 (MONDO:0014059), myoepithelial tumor (MONDO:0002380), Meniere disease (MONDO:0007972), microphthalmia, isolated, with coloboma (MONDO:0000170)

Orphanet (2): Colobomatous microphthalmia (Orphanet:98938), NON RARE IN EUROPE: Menière disease (Orphanet:45360)

HPO phenotypes

22 total (22 of 22 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000316	Hypertelorism
HP:0000343	Long philtrum
HP:0000369	Low-set ears
HP:0000400	Macrotia
HP:0000482	Microcornea
HP:0000505	Visual impairment
HP:0000508	Ptosis
HP:0000541	Retinal detachment
HP:0000565	Esotropia
HP:0000568	Microphthalmia
HP:0000612	Iris coloboma
HP:0000647	Sclerocornea
HP:0000750	Delayed speech and language development
HP:0001116	Macular pseudocoloboma
HP:0001249	Intellectual disability
HP:0001263	Global developmental delay
HP:0003577	Congenital onset
HP:0007663	Reduced visual acuity
HP:0007700	Ocular anterior segment dysgenesis
HP:0012043	Pendular nystagmus
HP:0045025	Narrow palpebral fissure

GWAS associations

17 associations (top):

Study	Trait	p-value
GCST002396_24	Smoking initiation	3.000000e-07
GCST002596_3	Colorectal cancer (calcium intake interaction)	7.000000e-07
GCST002714_1	Plasma renin activity levels	7.000000e-09
GCST003859_8	Oropharynx cancer	5.000000e-06
GCST003964_1	Bortezomib-induced peripheral neuropathy in multiple myeloma	8.000000e-06
GCST004032_13	JT interval (sulfonylurea treatment interaction)	5.000000e-09
GCST005830_53	Hand grip strength	1.000000e-08
GCST007325_222	General risk tolerance (MTAG)	3.000000e-09
GCST007709_18	General factor of neuroticism	4.000000e-09
GCST007709_19	General factor of neuroticism	1.000000e-08
GCST008476_20	Emphysema annual change measurement in smokers (percent low attenuation area)	3.000000e-07
GCST009303_6	Abstraction and mental flexibility	8.000000e-07
GCST010002_21	Refractive error	2.000000e-11
GCST010552_2	Chronic kidney disease x type 2 diabetes interaction	3.000000e-08
GCST011768_3	Schizophrenia	5.000000e-08
GCST012145_20	Ferritin levels	6.000000e-06
GCST90007004_7	Gut microbiota relative abundance (unassigned genus belonging to family Clostridiales)	8.000000e-06

EFO canonical traits (12, from GWAS)

EFO ID	Trait name
EFO:0005670	smoking initiation
EFO:0006521	calcium intake measurement
EFO:0006828	plasma renin activity measurement
EFO:0007885	JT interval
EFO:0007922	response to sulfonylurea
EFO:0006941	grip strength measurement
EFO:0008579	risk-taking behaviour
EFO:0007660	neuroticism measurement
EFO:0007626	emphysema imaging measurement
EFO:0009332	executive function measurement
EFO:0004459	ferritin measurement
EFO:0007874	gut microbiome measurement

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D008575	Meniere Disease	C09.218.568.217.500
D009208	Myoepithelioma	C04.557.435.585
C537463	Microphthalmia associated with colobomatous cyst (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects cotreatment, decreases methylation, decreases expression	2
sodium arsenite	decreases expression, affects cotreatment, increases abundance	2
bisphenol S	decreases expression, decreases methylation	2
Benzo(a)pyrene	decreases methylation, affects methylation	2
Cadmium	increases palmitoylation, increases expression, decreases reaction, increases abundance	2
Estradiol	affects cotreatment, decreases expression	2
Valproic Acid	affects expression, increases methylation	2
Aflatoxin B1	increases methylation	2
Cadmium Chloride	decreases reaction, increases abundance, increases palmitoylation, increases expression	2
aristolochic acid I	decreases expression	1
bisphenol F	increases methylation, decreases methylation, affects cotreatment	1
2,4,6-tribromophenol	increases expression	1
decabromobiphenyl ether	increases expression	1
tris(2-butoxyethyl) phosphate	affects expression	1
2,4,5,2’,4’,5’-hexachlorobiphenyl	decreases expression	1
arsenite	affects binding, decreases reaction	1
butyraldehyde	decreases expression	1
tetrabromobisphenol A	increases expression	1
2-bromopalmitate	decreases reaction, increases abundance, increases palmitoylation	1
3,4,5,3’,4’-pentachlorobiphenyl	decreases expression	1
perfluorooctanoic acid	decreases expression	1
zinc chromate	decreases expression, increases abundance	1
manganese chloride	affects cotreatment, decreases expression, increases abundance	1
benzo(e)pyrene	increases methylation	1
nickel sulfate	decreases expression	1
beta-methylcholine	affects expression	1
chromium hexavalent ion	decreases expression, increases abundance	1
CGP 52608	affects binding, increases reaction	1
monomethylarsonous acid	increases expression	1
abrine	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01574313	PHASE4	COMPLETED	Effect of Stellate Ganglion Block on Meniere’s Disease
NCT02529475	PHASE4	TERMINATED	Evaluation of Inner Ear and Brain Structures With Contrast-enhanced MRI in Healthy Subjects (HYDROPS)
NCT04815187	PHASE4	ACTIVE_NOT_RECRUITING	Repurposed Use of Allergic Rhinitis and Allergic Asthma Drug to Reduce Vertigo and Hearing Loss in Meniere’s Disease
NCT03664674	PHASE3	COMPLETED	Phase 3 Study of OTO-104 in Subjects With Unilateral Meniere’s Disease
NCT04677972	PHASE3	COMPLETED	SPI-1005 for the Treatment of Meniere’s Disease
NCT05851508	PHASE3	RECRUITING	The Effecttiveness of Intratympanic Methylprednisolon Injections Compared to Placebo in the Treatment of Vertigo Attacks in Meniere’s Disease
NCT05420350	PHASE2	UNKNOWN	Lamotrigine and Bupropion for Meniere’s Disease
NCT06544434	PHASE2	RECRUITING	Laser Acupuncture for Meniere Disease
NCT03600649	PHASE1	UNKNOWN	Clinical Trial of SP-2577 (Seclidemstat) in Patients With Relapsed or Refractory Ewing or Ewing-related Sarcomas
NCT04674735	PHASE1	WITHDRAWN	Safety of APSLXR in Patients Presenting Vertigo of Vestibular Origin or Meniere’s Disease
NCT05266196	PHASE1/PHASE2	UNKNOWN	A Rollover Protocol to Allow for Continued Access to the LSD1 Inhibitor Seclidemstat (SP-2577)
NCT06239272	PHASE1/PHASE2	RECRUITING	NRSTS2021, A Risk Adapted Study Evaluating Maintenance Pazopanib, Limited Margin, Dose-Escalated Radiation Therapy and Selinexor in Non-Rhabdomyosarcoma Soft Tissue Sarcoma (NRSTS)
NCT06625190	PHASE1/PHASE2	RECRUITING	Alpha/Beta T and B Cell Depletion With Zoledronic Acid for Solid Tumors
NCT06244420	Not specified	COMPLETED	Malignant Myoepithelioma of Bone and Soft Tissues: Diagnostic Imaging and Histology in Relation to Prognosis
NCT04218123	PHASE2/PHASE3	COMPLETED	Assessing the Efficacy of a Serotonin and Norepinephrine Reuptake Inhibitor for Improving Meniere’s Disease Outcomes
NCT04766853	PHASE1/PHASE2	COMPLETED	Verification of the Efficacy/safety of the Intratympanic Drug Delivery for Hearing Loss
NCT04794842	EARLY_PHASE1	UNKNOWN	Comparing Topical Tetracaine Drops to Topical Focal Phenol for Local Anesthesia During Intratympanic Steroid Injection
NCT00599560	Not specified	COMPLETED	Vasopressin and V2 Receptor in Meniere’s Disease
NCT02371798	Not specified	WITHDRAWN	Unilateral Meniere Disease: Can Double Dose Gadolinium and Delayed Imaging Make the Diagnosis?
NCT03520322	Not specified	TERMINATED	A Study of a Mastoid Device in Subjects With Ménière’s Disease
NCT03795675	Not specified	ACTIVE_NOT_RECRUITING	CI Following VS Removal or Labyrinthectomy
NCT04370366	Not specified	RECRUITING	Imaging of Endolymphatic Hydrops at 7T MRI
NCT04569175	Not specified	COMPLETED	Non Enhanced Labyrinth Imaging for the Detection of Endolymphatic Hydrops in Meniere’s Disease NELI Study
NCT04686695	Not specified	COMPLETED	Transcutaneous Auricular Vagus Nerve Stimulation Treatment on Meniere Disease
NCT04835688	Not specified	UNKNOWN	Ventilation Tube Insertion for Unilateral Menière’s Disease
NCT04902963	Not specified	COMPLETED	What is the Tympanic Membrane Healing Time After Insertion of a Gelfoam PE Tube?
NCT04935970	Not specified	UNKNOWN	Metabolic Disorders and Vertigo
NCT05322538	Not specified	NOT_YET_RECRUITING	Menier’s Disease - Bone Density Study
NCT05328895	Not specified	COMPLETED	Transcutaneous Auricular Vagus Nerve Stimulation for Meniere Disease
NCT05424302	Not specified	RECRUITING	Effect of Peripheral Vestibular Disease Location on Outcomes Following Home-based Virtual Reality Vestibular Therapy
NCT05582148	Not specified	UNKNOWN	Meniere Disease and Hearing Aids
NCT05844657	Not specified	COMPLETED	Comprehensive Evaluation in Patients With Meniere’s Disease
NCT05960786	Not specified	COMPLETED	Treating the Symptoms of Vertigo in a Real-world Setting Using the OtoBand
NCT06278129	Not specified	UNKNOWN	Evaluation of the Diagnostic and Prognostic Efficacy of MRI in Acute Sensorineural Hearing Loss and Ménière’s Disease
NCT06544590	Not specified	COMPLETED	Transcutaneous Auricular Vagus Nerve Stimulation for Meniere Disease
NCT07272473	Not specified	RECRUITING	Effects of Cervical Mobilization on Dizziness, Balance, and Joint Position Sense in Patients With Meniere’s Disease