CLRN1

Summary

CLRN1 (clarin 1, HGNC:12605) is a protein-coding gene on chromosome 3q25.1, encoding Clarin-1 (P58418). May have a role in the excitatory ribbon synapse junctions between hair cells and cochlear ganglion cells and presumably also in analogous synapses within the retina.

This gene encodes a protein that contains a cytosolic N-terminus, multiple helical transmembrane domains, and an endoplasmic reticulum membrane retention signal, TKGH, in the C-terminus. The encoded protein may be important in development and homeostasis of the inner ear and retina. Mutations within this gene have been associated with Usher syndrome type IIIa. Multiple transcript variants encoding distinct isoforms have been identified for this gene.

Source: NCBI Gene 7401 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Usher syndrome type 3 (Definitive, ClinGen) — +3 more curated relationships
• GWAS associations: 3
• Clinical variants (ClinVar): 449 total — 34 pathogenic, 42 likely-pathogenic
• Phenotypes (HPO): 49
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_174878

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12605
Approved symbol	CLRN1
Name	clarin 1
Location	3q25.1
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000163646
Ensembl biotype	protein_coding
OMIM	606397
Entrez	7401

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 4 protein_coding, 2 nonsense_mediated_decay, 1 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000295911, ENST00000327047, ENST00000328863, ENST00000468836, ENST00000472224, ENST00000485607, ENST00000644099, ENST00000645441

RefSeq mRNA: 4 — MANE Select: NM_174878 NM_001195794, NM_001256819, NM_052995, NM_174878

CCDS: CCDS3153, CCDS35492, CCDS56285

Canonical transcript exons

ENST00000327047 — 3 exons

Exon	Start	End
ENSE00001230843	150972456	150972727
ENSE00001342698	150926567	150928201
ENSE00003573924	150941582	150941761

Expression profiles

Bgee: expression breadth broad, 61 present calls, max score 82.67.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.0987 / max 44.7488, expressed in 39 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
45122	0.0516	23
45124	0.0275	10
45125	0.0144	4
45123	0.0052	2

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
adrenal tissue	UBERON:0018303	82.67	gold quality
right adrenal gland cortex	UBERON:0035827	78.95	gold quality
right adrenal gland	UBERON:0001233	78.93	gold quality
buccal mucosa cell	CL:0002336	78.30	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	76.87	gold quality
adrenal cortex	UBERON:0001235	72.32	gold quality
left adrenal gland cortex	UBERON:0035825	71.89	gold quality
left adrenal gland	UBERON:0001234	70.81	gold quality
adrenal gland	UBERON:0002369	70.67	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	69.10	gold quality
jejunal mucosa	UBERON:0000399	61.77	gold quality
epithelium of nasopharynx	UBERON:0001951	55.72	gold quality
duodenum	UBERON:0002114	53.44	gold quality
jejunum	UBERON:0002115	52.03	silver quality
skin of hip	UBERON:0001554	46.32	gold quality
upper leg skin	UBERON:0004262	46.22	silver quality
blood	UBERON:0000178	45.73	gold quality
amniotic fluid	UBERON:0000173	44.06	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	43.37	gold quality
oviduct epithelium	UBERON:0004804	43.35	silver quality
trachea	UBERON:0003126	42.76	gold quality
substantia nigra pars compacta	UBERON:0001965	42.70	gold quality
secondary oocyte	CL:0000655	42.57	gold quality
substantia nigra pars reticulata	UBERON:0001966	42.01	gold quality
pituitary gland	UBERON:0000007	41.91	gold quality
metanephros	UBERON:0000081	41.84	gold quality
germinal epithelium of ovary	UBERON:0001304	41.69	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	41.48	gold quality
vastus lateralis	UBERON:0001379	41.41	gold quality
quadriceps femoris	UBERON:0001377	41.37	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-MTAB-7316	yes	23.08
E-ANND-3	yes	3.26
E-ENAD-17	no	97.10

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

60 targeting CLRN1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-190A-3P	100.00	80.35	5520
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-1277-5P	100.00	73.95	5056
HSA-MIR-188-3P	100.00	68.76	1240
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-3605-5P	99.96	67.12	932
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-4778-3P	99.93	70.40	1818
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-3065-3P	99.87	70.25	1407
HSA-MIR-4659A-3P	99.80	72.62	4248
HSA-MIR-4659B-3P	99.80	72.62	4248
HSA-MIR-448	99.79	72.37	2103
HSA-MIR-1299	99.77	71.24	2389
HSA-MIR-3156-3P	99.76	66.72	939
HSA-MIR-623	99.76	68.16	1170
HSA-MIR-3680-3P	99.75	72.51	3095
HSA-MIR-7856-5P	99.75	69.99	2901
HSA-MIR-452-5P	99.65	69.63	1762
HSA-MIR-4676-3P	99.65	69.31	1733
HSA-MIR-892C-3P	99.65	69.38	1745
HSA-MIR-6512-3P	99.65	66.07	1468

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 19)

• Mutations in the USH3 gene underlie Usher syndrome type 3. (PMID:11524702)
• a role for clarin-1 in hair cell and photoreceptor cell synapses, as well as a common pathophysiological pathway for different Usher syndromes (PMID:12080385)
• revised structure of USH3 gene: new translation start site, 5’ untranslated region, and transcript encoding 232-amino acid protein; four new disease-causing mutations; identified mouse and rat orthologues, and two human paralogues on chromosomes 4 and 10 (PMID:12145752)
• USH3A and USH2A share patterns of rod and cone dysfunction and retinal structural abnormalities. (PMID:18281613)
• clarin-1 has a role in the regulation and homeostasis of actin filaments (PMID:19423712)
• Part of the pathogenesis of USH3 may be associated with defective intracellular trafficking as well as decreased stability of mutant CLRN1 proteins. (PMID:19753315)
• The complexity of the CLRN1 gene and the identification of multiple splice variants may partially explain why mutations in CLRN1 result in substantial variation in clinical phenotype. (PMID:20717163)
• Retinitis pigmentosa-associated mutations p.Pro31Leu and p.Leu154Trp may represent hypomorphic mutations, because substituted amino acids in transmembrane domains remain polar. (PMID:21310491)
• Here we describe a novel deletion in CLRN1. Our data support previously reported intra familial variability in the clinical features of Usher syndrome type I and III. (PMID:21675857)
• Possible digenism could not be excluded in two families segregating genomic variations in both MYO7A and USH2A, and two families with CLRN1 and USH2A. (PMID:22681893)
• This study confirmed using a novel mouse model carrying a Clrn1N48K knock-in mutation to investigate the consequence of the missense mutation N48K in mCLRN1 in vivo. (PMID:22787034)
• High-resolution measures of retinal structure demonstrate patterns of cone loss associated with CLRN1 mutations. (PMID:22964989)
• Two novel mutations in the CLRN1 gene, p.R207X and p.I168N, have been found in patients with Usher syndrome type 3. (PMID:23304067)
• This is the first report of Usher syndrome type 3 with a CLRN1 gene mutation in Asian populations. (PMID:25743179)
• Study founds 1 deep intronic CLRN1 (USH3A) founder mutation generates an aberrant exon that underlies severe Usher syndrome in a family on the Arabian Peninsula. (PMID:28469144)
• We report here novel homozygous mutations in various genes causing USH, extending the spectrum of causative mutations. We also prove combined sequencing techniques as useful tools to identify novel disease-causing mutations. To the best of our knowledge, this is the largest report of a genetic analysis of Israeli and Palestinian families (n = 74) with different USH subtypes. (PMID:29490346)
• Studied role of clarin1 (CLRN1) in activation of hair cell mechanotransduction function through an unconventional secretory pathway, and the possibility this activation may be therapeutic to prevent hair cell dysfunction. (PMID:31097578)
• Extending the spectrum of CLRN1- and ABCA4-associated inherited retinal dystrophies caused by novel and recurrent variants using exome sequencing. (PMID:31968401)
• Retinal Phenotype of Patients with CLRN1-Associated Usher 3A Syndrome in French Light4Deaf Cohort. (PMID:35481838)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	clrn1	ENSDARG00000102890
mus_musculus	Clrn1	ENSMUSG00000043850
rattus_norvegicus	Clrn1	ENSRNOG00000042477
drosophila_melanogaster	CG1103	FBGN0037235
caenorhabditis_elegans		WBGENE00235279

Paralogs (2): CLRN3 (ENSG00000180745), CLRN2 (ENSG00000249581)

Protein

Protein identifiers

Clarin-1 — P58418 (reviewed: P58418)

Alternative names: Usher syndrome type-3 protein

All UniProt accessions (4): A0A2R8Y8A4, C9JYI2, P58418, E1ACV0

UniProt curated annotations — full annotation on UniProt →

Function. May have a role in the excitatory ribbon synapse junctions between hair cells and cochlear ganglion cells and presumably also in analogous synapses within the retina.

Subcellular location. Cell membrane.

Tissue specificity. Widely expressed. Found in the retina.

Disease relevance. Usher syndrome 3A (USH3A) [MIM:276902] USH is a genetically heterogeneous condition characterized by the association of retinitis pigmentosa with sensorineural deafness. Age at onset and differences in auditory and vestibular function distinguish Usher syndrome type 1 (USH1), Usher syndrome type 2 (USH2) and Usher syndrome type 3 (USH3). USH3 is characterized by postlingual, progressive hearing loss, variable vestibular dysfunction, and onset of retinitis pigmentosa symptoms, including nyctalopia, constriction of the visual fields, and loss of central visual acuity, usually by the second decade of life. The disease is caused by variants affecting the gene represented in this entry. Retinitis pigmentosa 61 (RP61) [MIM:614180] A retinal dystrophy belonging to the group of pigmentary retinopathies. Retinitis pigmentosa is characterized by retinal pigment deposits visible on fundus examination and primary loss of rod photoreceptor cells followed by secondary loss of cone photoreceptors. Patients typically have night vision blindness and loss of midperipheral visual field. As their condition progresses, they lose their far peripheral visual field and eventually central vision as well. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the clarin family.

Isoforms (3)

UniProt ID	Names	Canonical?
P58418-3	1	yes
P58418-1	2, A
P58418-4	3, 0-2-2b-3

RefSeq proteins (4): NP_001182723, NP_001243748, NP_443721, NP_777367* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR026748	Clarin	Family

Pfam: PF25807

UniProt features (19 total): sequence variant 10, transmembrane region 4, splice variant 3, chain 1, glycosylation site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P58418-F1	90.74	0.77

Functional residue map

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

Glycosylation sites (1): 48

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 226 (showing top): AP1_01, GOBP_EPITHELIUM_DEVELOPMENT, YAATNRNNNYNATT_UNKNOWN, RORA1_01, GOBP_SENSORY_PERCEPTION_OF_MECHANICAL_STIMULUS, GOBP_NEUROGENESIS, HNF1_Q6, LHX3_01, GOBP_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, GOBP_REGULATION_OF_LAMELLIPODIUM_ASSEMBLY, GOBP_NEUROMUSCULAR_PROCESS_CONTROLLING_BALANCE, NKX61_01, GOBP_EPIDERMAL_CELL_DIFFERENTIATION, CEBP_Q2, GOBP_ANIMAL_ORGAN_MORPHOGENESIS

GO Biological Process (11): actin filament organization (GO:0007015), visual perception (GO:0007601), sensory perception of sound (GO:0007605), positive regulation of lamellipodium assembly (GO:0010592), photoreceptor cell maintenance (GO:0045494), cell motility (GO:0048870), sensory perception of light stimulus (GO:0050953), equilibrioception (GO:0050957), auditory receptor cell stereocilium organization (GO:0060088), neuromuscular process controlling balance (GO:0050885), auditory receptor cell development (GO:0060117)

GO Molecular Function (1): protein binding (GO:0005515)

GO Cellular Component (9): plasma membrane (GO:0005886), microvillus (GO:0005902), microtubule cytoskeleton (GO:0015630), lamellipodium (GO:0030027), trans-Golgi network transport vesicle (GO:0030140), stereocilium (GO:0032420), basal part of cell (GO:0045178), membrane (GO:0016020), actin-based cell projection (GO:0098858)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
sensory perception	2
actin-based cell projection	2
plasma membrane bounded cell projection	2
cellular anatomical structure	2
actin cytoskeleton organization	1
supramolecular fiber organization	1
sensory perception of light stimulus	1
sensory perception of mechanical stimulus	1
regulation of lamellipodium assembly	1
lamellipodium assembly	1
positive regulation of plasma membrane bounded cell projection assembly	1
positive regulation of lamellipodium organization	1
retina homeostasis	1
multicellular organismal process	1
cellular process	1
neuromuscular process controlling balance	1
auditory receptor cell morphogenesis	1
inner ear receptor cell stereocilium organization	1
musculoskeletal movement	1
neuromuscular process	1
inner ear auditory receptor cell differentiation	1
inner ear receptor cell development	1
binding	1
membrane	1
cell periphery	1
actin filament bundle	1
cytoskeleton	1
cell leading edge	1
Golgi-associated vesicle	1
transport vesicle	1
clathrin-coated vesicle	1
stereocilium bundle	1
neuron projection	1
actin cytoskeleton	1

Protein interactions and networks

STRING

614 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CLRN1	MYO7A	P78427	952
CLRN1	E9PNW1	E9PNW1	910
CLRN1	USH1G	Q495M9	893
CLRN1	WHRN	Q9P202	890
CLRN1	USH2A	O75445	883
CLRN1	PCDH15	Q96QU1	868
CLRN1	ADGRV1	Q8WXG9	866
CLRN1	CDH23	Q9H251	849
CLRN1	CIB2	O75838	807
CLRN1	CACNG2	Q9Y698	804
CLRN1	PDZD7	Q9H5P4	802
CLRN1	PCARE	A6NGG8	595
CLRN1	CERKL	Q49MI3	583
CLRN1	CEP250	Q9BV73	583
CLRN1	ZNF513	Q8N8E2	582

IntAct

85 interactions, top by confidence:

A	B	Type	Score
CTXN3	CLRN1	psi-mi:“MI:0915”(physical association)	0.560
SLC34A3	CLRN1	psi-mi:“MI:0915”(physical association)	0.560
TMEM147	CLRN1	psi-mi:“MI:0915”(physical association)	0.560
FUT9	CLRN1	psi-mi:“MI:0915”(physical association)	0.560
CLDN19	CLRN1	psi-mi:“MI:0915”(physical association)	0.560
TMEM86B	CLRN1	psi-mi:“MI:0915”(physical association)	0.560
CLRN1	TMEM86B	psi-mi:“MI:0915”(physical association)	0.560
CLRN1	ZDHHC15	psi-mi:“MI:0915”(physical association)	0.560
CLRN1	FAM24B	psi-mi:“MI:0915”(physical association)	0.560
	CLRN1	psi-mi:“MI:0915”(physical association)	0.560
CLRN1	CTXN3	psi-mi:“MI:0915”(physical association)	0.560
CLRN1	TMEM239	psi-mi:“MI:0915”(physical association)	0.560
CLRN1	SLC34A3	psi-mi:“MI:0915”(physical association)	0.560
SEC22B	CLRN1	psi-mi:“MI:0915”(physical association)	0.560
CLRN1	TMEM140	psi-mi:“MI:0915”(physical association)	0.560
CLRN1	CANT1	psi-mi:“MI:0915”(physical association)	0.560
CLRN1	DRAM1	psi-mi:“MI:0915”(physical association)	0.560
CLRN1	TMEM147	psi-mi:“MI:0915”(physical association)	0.560
C2CD2L	CLRN1	psi-mi:“MI:0915”(physical association)	0.560
CLRN1	MFSD5	psi-mi:“MI:0915”(physical association)	0.560
CLRN1	FUT9	psi-mi:“MI:0915”(physical association)	0.560
CLRN1	TMPPE	psi-mi:“MI:0915”(physical association)	0.560
CLRN1	CLDN19	psi-mi:“MI:0915”(physical association)	0.560
CLRN1	CCL4L1	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (28): CLRN1 (Two-hybrid), CLRN1 (Two-hybrid), CLRN1 (Two-hybrid), CLRN1 (Two-hybrid), CLRN1 (Two-hybrid), CLRN1 (Two-hybrid), CLRN1 (Two-hybrid), CLRN1 (Two-hybrid), CLRN1 (Two-hybrid), CLRN1 (Two-hybrid), CLDN19 (Two-hybrid), ITGAM (Two-hybrid), CANT1 (Two-hybrid), C2CD2L (Two-hybrid), FUT9 (Two-hybrid)

ESM2 similar proteins: A0A2R8RY99, A0PK11, A9UL59, B2RVW2, B4L184, B4LC58, B4N5D3, D3ZFW5, O95473, P23290, P35801, P35802, P35803, P36964, P36965, P51674, P56749, P58418, P79826, Q0IIL2, Q0P4G7, Q0VD07, Q11085, Q13491, Q2YDD6, Q53R12, Q5R603, Q5R9K1, Q5R9Q3, Q5R9R3, Q5T9L3, Q5ZLR1, Q6AYR5, Q6CRM6, Q6DID7, Q6P689, Q6UX40, Q754N9, Q7YWX7, Q812E9

Diamond homologs: A0A2R8RY99, A0PK11, B2RVW2, P58418, Q8CJ58, Q8K445

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	34
Likely pathogenic	42
Uncertain significance	171
Likely benign	141
Benign	26

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1073695	NM_174878.3(CLRN1):c.292del (p.His98fs)	Pathogenic
1275768	NM_174878.3(CLRN1):c.148_149insTGTC (p.Ser50fs)	Pathogenic
1427384	NM_174878.3(CLRN1):c.494del (p.Leu164_Ser165insTer)	Pathogenic
1451157	NM_174878.3(CLRN1):c.563C>A (p.Ser188Ter)	Pathogenic
1453129	NM_174878.3(CLRN1):c.433+1G>C	Pathogenic
1455436	NM_174878.3(CLRN1):c.181del (p.Met61fs)	Pathogenic
188726	NM_001195794.1(CLRN1):c.149_152delinsTGTCCAAT (p.Ser50fs)	Pathogenic
1971725	NM_174878.3(CLRN1):c.591del (p.Phe197fs)	Pathogenic
2088011	NM_174878.3(CLRN1):c.488_492del (p.His163fs)	Pathogenic
2203454	NM_174878.3(CLRN1):c.176del (p.Gly59fs)	Pathogenic
2203455	NM_174878.3(CLRN1):c.149C>A (p.Ser50Ter)	Pathogenic
2750069	NM_174878.3(CLRN1):c.556del (p.Thr186fs)	Pathogenic
2800316	NM_174878.3(CLRN1):c.127G>C (p.Gly43Arg)	Pathogenic
2839908	NM_174878.3(CLRN1):c.60T>A (p.Cys20Ter)	Pathogenic
3027587	NM_174878.3(CLRN1):c.253+2T>C	Pathogenic
30575	NM_174878.3(CLRN1):c.92C>T (p.Pro31Leu)	Pathogenic
3601046	NM_174878.3(CLRN1):c.227del (p.Leu76fs)	Pathogenic
3601049	NM_174878.3(CLRN1):c.96del (p.Leu32fs)	Pathogenic
4081989	NM_174878.3(CLRN1):c.-10_253+10del	Pathogenic
4082235	Single allele	Pathogenic
4395	NM_174878.3(CLRN1):c.144T>G (p.Asn48Lys)	Pathogenic
4397	NM_174878.3(CLRN1):c.189C>A (p.Tyr63Ter)	Pathogenic
4398	NM_174878.3(CLRN1):c.188_210del (p.Tyr63fs)	Pathogenic
48145	NM_174878.3(CLRN1):c.301_305del (p.Val101fs)	Pathogenic
558249	NM_174878.3(CLRN1):c.40G>T (p.Gly14Ter)	Pathogenic
633701	NM_174878.3(CLRN1):c.323T>C (p.Leu108Pro)	Pathogenic
642630	NC_000003.12:g.(?150972446)(150973009_?)del	Pathogenic
812104	NM_174878.3(CLRN1):c.65T>A (p.Leu22His)	Pathogenic
812272	NM_174878.3(CLRN1):c.349_358del (p.Ala117fs)	Pathogenic
838097	NM_174878.3(CLRN1):c.67G>T (p.Gly23Ter)	Pathogenic

SpliceAI

946 predictions. Top by Δscore:

Variant	Effect	Δscore
3:150941577:CTTA:C	donor_loss	1.0000
3:150941578:TTA:T	donor_loss	1.0000
3:150941579:TACC:T	donor_loss	1.0000
3:150941580:A:AC	donor_gain	1.0000
3:150941580:A:AT	donor_loss	1.0000
3:150941581:C:CC	donor_gain	1.0000
3:150941581:C:CT	donor_loss	1.0000
3:150941757:AAAAA:A	acceptor_gain	1.0000
3:150941758:AAAA:A	acceptor_gain	1.0000
3:150941759:AAA:A	acceptor_gain	1.0000
3:150941760:AA:A	acceptor_gain	1.0000
3:150941762:C:CC	acceptor_gain	1.0000
3:150972522:A:AC	donor_gain	1.0000
3:150972523:C:CC	donor_gain	1.0000
3:150941579:TAC:T	donor_loss	0.9900
3:150941580:AC:A	donor_gain	0.9900
3:150941580:ACCTG:A	donor_loss	0.9900
3:150941581:CC:C	donor_gain	0.9900
3:150941581:CCT:C	donor_gain	0.9900
3:150941581:CCTGA:C	donor_gain	0.9900
3:150942552:A:AC	donor_gain	0.9900
3:150942553:C:CC	donor_gain	0.9900
3:150928109:AAGTC:A	donor_gain	0.9800
3:150941581:CCTG:C	donor_gain	0.9800
3:150942543:TGAG:T	donor_gain	0.9800
3:150972454:A:AC	donor_gain	0.9800
3:150972455:C:CC	donor_gain	0.9800
3:150972581:C:CA	donor_gain	0.9800
3:150972555:G:A	donor_gain	0.9700
3:150941576:ACTT:A	donor_loss	0.9600

AlphaMissense

1525 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:150972538:A:C	F57L	0.993
3:150972538:A:T	F57L	0.993
3:150972540:A:G	F57L	0.993
3:150972539:A:C	F57C	0.985
3:150972612:A:G	W33R	0.985
3:150972612:A:T	W33R	0.985
3:150972539:A:G	F57S	0.983
3:150972589:G:C	C40W	0.982
3:150972590:C:G	C40S	0.981
3:150972591:A:T	C40S	0.981
3:150972591:A:G	C40R	0.980
3:150972488:C:G	C74S	0.977
3:150972489:A:T	C74S	0.977
3:150972590:C:T	C40Y	0.977
3:150972489:A:G	C74R	0.973
3:150972610:C:A	W33C	0.964
3:150972610:C:G	W33C	0.964
3:150941592:G:C	S141R	0.961
3:150941592:G:T	S141R	0.961
3:150941594:T:G	S141R	0.961
3:150972658:A:C	S17R	0.961
3:150972658:A:T	S17R	0.961
3:150972660:T:G	S17R	0.961
3:150972518:C:T	G64E	0.957
3:150928068:G:C	F189L	0.955
3:150928068:G:T	F189L	0.955
3:150928070:A:G	F189L	0.955
3:150972487:A:C	C74W	0.954
3:150972590:C:A	C40F	0.954
3:150972485:C:T	G75E	0.952

dbSNP variants (sampled 300 via entrez): RS1000018613 (3:150933965 T>C), RS1000070442 (3:150973739 A>G), RS1000076196 (3:150954292 C>T), RS1000076226 (3:150967584 T>C,G), RS1000151955 (3:150928957 G>T), RS1000196782 (3:150933708 A>G), RS1000213647 (3:150936948 A>T), RS1000226824 (3:150940589 G>A,T), RS1000346374 (3:150960348 T>C), RS1000378867 (3:150972200 A>G), RS1000453579 (3:150946549 C>A,T), RS1000495176 (3:150935996 G>A), RS1000599138 (3:150929838 G>A,C,T), RS1000607270 (3:150972003 G>T), RS1000633103 (3:150939470 T>C)

Disease associations

OMIM: gene MIM:606397 | disease phenotypes: MIM:113650, MIM:614180, MIM:276902, MIM:268000, MIM:276900, MIM:256730

GenCC curated gene-disease

Disease	Classification	Inheritance
Usher syndrome type 3	Definitive	Unknown
Usher syndrome type 3A	Definitive	Autosomal recessive
retinitis pigmentosa 61	Strong	Autosomal recessive
retinitis pigmentosa	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
Usher syndrome type 3	Definitive	AR

Mondo (11): Usher syndrome type 3 (MONDO:0016485), inherited retinal dystrophy (MONDO:0019118), branchio-oto-renal syndrome (MONDO:0007029), retinitis pigmentosa 61 (MONDO:0013610), Usher syndrome type 3A (MONDO:0010170), retinal disorder (MONDO:0005283), retinitis pigmentosa (MONDO:0019200), Usher syndrome (MONDO:0019501), neuronal ceroid lipofuscinosis (MONDO:0016295), optic atrophy (MONDO:0003608), hearing loss disorder (MONDO:0005365)

Orphanet (8): Usher syndrome type 3 (Orphanet:231183), OBSOLETE: Inherited retinal disorder (Orphanet:71862), BOR syndrome (Orphanet:107), Retinitis pigmentosa (Orphanet:791), Usher syndrome (Orphanet:886), Rare genetic deafness (Orphanet:96210), Neuronal ceroid lipofuscinosis (Orphanet:216), OBSOLETE: Infantile neuronal ceroid lipofuscinosis (Orphanet:79263)

HPO phenotypes

49 total (30 of 49 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000375	Abnormal cochlea morphology
HP:0000405	Conductive hearing impairment
HP:0000407	Sensorineural hearing impairment
HP:0000501	Glaucoma
HP:0000505	Visual impairment
HP:0000510	Rod-cone dystrophy
HP:0000512	Abnormal electroretinogram
HP:0000543	Optic disc pallor
HP:0000546	Retinal degeneration
HP:0000551	Color vision defect
HP:0000563	Keratoconus
HP:0000572	Visual loss
HP:0000575	Scotoma
HP:0000602	Ophthalmoplegia
HP:0000613	Photophobia
HP:0000618	Blindness
HP:0000639	Nystagmus
HP:0000648	Optic atrophy
HP:0000662	Nyctalopia
HP:0000716	Depression
HP:0000739	Anxiety
HP:0000842	Hyperinsulinemia
HP:0001105	Retinal atrophy
HP:0001123	Visual field defect
HP:0001133	Constriction of peripheral visual field
HP:0001419	X-linked recessive inheritance
HP:0001751	Abnormal vestibular function
HP:0001756	Vestibular hyporeflexia

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST007576_190	Chronotype	6.000000e-09
GCST008471_4	Non-alcoholic fatty liver disease activity score in non-alcoholic fatty liver disease	3.000000e-06
GCST012244_3	Childhood asthma exacerbations in long-acting beta2-agonist treatment	5.000000e-06

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0008328	chronotype measurement
EFO:0008421	non-alcoholic fatty liver disease severity measurement
EFO:0007614	asthma exacerbation measurement

MeSH disease descriptors (7)

Descriptor	Name	Tree numbers
D019280	Branchio-Oto-Renal Syndrome	C16.131.077.208; C16.131.260.090; C16.320.180.090
D034381	Hearing Loss	C09.218.458.341; C10.597.751.418.341; C23.888.592.763.393.341
D009896	Optic Atrophy	C10.292.700.225; C11.640.451
D012164	Retinal Diseases	C11.768
D058499	Retinal Dystrophies	C11.768.585.658
D012174	Retinitis Pigmentosa	C11.270.684; C11.768.585.658.500; C16.320.290.684
D052245	Usher Syndromes	C09.218.458.341.186.500.500; C09.218.458.341.887.886; C10.597.751.418.341.186.500.500; C10.597.751.418.341.887.886; C10.597.751.941.162.625.500; C11.768.585.658.500.813; C11.966.075.375.500; C16.131.077.299.500; C16.320.290.684.500; C23.888.592.763.393.341.887.886

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

7 total (human), top 7 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects methylation	1
CGP 52608	affects binding, increases reaction	1
belinostat	increases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Vorinostat	increases expression	1
Benzo(a)pyrene	affects methylation	1
Plant Extracts	affects cotreatment, decreases expression	1

Clinical trials (associated diseases)

286 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
NCT01955135	PHASE4	COMPLETED	Anesthesia for Retinopathy of Prematurity
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
NCT01530659	PHASE2	COMPLETED	Retinal Imaging in CNTF -Releasing Encapsulated Cell Implant Treated Patients for Early-stage Retinitis Pigmentosa
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
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)
NCT03763227	PHASE2	COMPLETED	Intravitreal Ranibizumab (Lucentis®) in the Treatment of Non-leaking Macular Cysts in Retinal Dystrophy
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