Usher syndrome type 1

Summary

Usher syndrome type 1 (MONDO:0010168) is a disease (an umbrella term covering 9 Mondo subtypes) caused by variants in CDH23, MYO7A, PCDH15, and 2 other genes, with 12 cohort genes. The dominant Reactome pathway is Sensory processing of sound by outer hair cells of the cochlea (7 cohort genes).

At a glance

• Prevalence: 1-9 / 100 000 (Denmark) [Orphanet-validated]
• Causal genes: CDH23 (GenCC Definitive), MYO7A (GenCC Definitive), PCDH15 (GenCC Definitive), USH1C (GenCC Definitive) (+1 more)
• Umbrella term: 9 Mondo subtypes
• Cohort genes: 12
• ClinVar variants: 2,122
• Phenotypes (HPO): 16

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 100 000	1.5	Denmark	Validated
Point prevalence	1-9 / 100 000		Europe	Not yet validated

Signs & symptoms

Clinical features (HPO)

16 HPO clinical features (Orphanet curated; top 16 by frequency):

HPO ID	Term	Frequency
HP:0000375	Abnormal cochlea morphology	Very frequent (80-99%)
HP:0000407	Sensorineural hearing impairment	Very frequent (80-99%)
HP:0000510	Rod-cone dystrophy	Very frequent (80-99%)
HP:0000512	Abnormal electroretinogram	Very frequent (80-99%)
HP:0000572	Visual loss	Very frequent (80-99%)
HP:0000575	Scotoma	Very frequent (80-99%)
HP:0000662	Nyctalopia	Very frequent (80-99%)
HP:0000518	Cataract	Frequent (30-79%)
HP:0000750	Delayed speech and language development	Frequent (30-79%)
HP:0001270	Motor delay	Frequent (30-79%)
HP:0001751	Abnormal vestibular function	Frequent (30-79%)
HP:0002141	Gait imbalance	Frequent (30-79%)
HP:0007663	Reduced visual acuity	Frequent (30-79%)
HP:0007994	Peripheral visual field loss	Frequent (30-79%)
HP:0000716	Depression	Occasional (5-29%)
HP:0000739	Anxiety	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Usher syndrome type 1
Mondo ID	MONDO:0010168
Orphanet	231169
DOID	DOID:0110826
ICD-11	237039059
NCIT	C126327
SNOMED CT	232057003
UMLS	C1568247
MedGen	292820
GARD	0005435
Is cancer (heuristic)	no

Also known as: retinitis pigmentosa and congenital deafness · USH1 · USH1A · Usher syndrome type 1 · Usher syndrome, type 1 · Usher syndrome, type 1A · USHER syndrome, type I

Data availability: 2,122 ClinVar variants · 1 ClinGen variant curation · 14 GenCC gene-disease records · 27 cell lines.

Disease family

An umbrella term covering 9 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › syndromic disease › Usher syndrome › Usher syndrome type 1

Related subtypes (4): retinitis pigmentosa-deafness syndrome, Usher syndrome type 2, Usher syndrome type 3, Usher syndrome, type 4

Subtypes (9): Usher syndrome type 1C, Usher syndrome type 1D, Usher syndrome type 1F, Usher syndrome type 1E, Usher syndrome type 1G, Usher syndrome type 1H, Usher syndrome type 1K, Usher syndrome, type 1D/F, Usher syndrome type 1B

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

600 retrieved; paginated sample, class counts are floors:

251 uncertain significance, 132 conflicting classifications of pathogenicity, 59 likely pathogenic, 47 pathogenic/likely pathogenic, 45 likely benign, 36 pathogenic, 16 benign, 14 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1066744	NM_022124.6(CDH23):c.6050-1G>C	CDH23	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1067155	NM_022124.6(CDH23):c.8064+1G>A	CDH23	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1068921	NM_022124.6(CDH23):c.8383C>T (p.Arg2795Ter)	CDH23	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1071895	NM_022124.6(CDH23):c.8432G>A (p.Trp2811Ter)	CDH23	Pathogenic	criteria provided, multiple submitters, no conflicts
1072295	NM_022124.6(CDH23):c.871G>T (p.Gly291Ter)	CDH23	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1073475	NM_022124.6(CDH23):c.9167del (p.Val3056fs)	CDH23	Pathogenic	criteria provided, multiple submitters, no conflicts
1074713	NM_022124.6(CDH23):c.214G>T (p.Glu72Ter)	CDH23	Pathogenic	criteria provided, multiple submitters, no conflicts
1075704	NM_022124.6(CDH23):c.8343_8346dup (p.Gly2783fs)	CDH23	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1180612	NM_022124.6(CDH23):c.4562A>G (p.Asn1521Ser)	CDH23	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1457571	NM_022124.6(CDH23):c.6933del (p.Thr2313fs)	CDH23	Pathogenic	criteria provided, multiple submitters, no conflicts
1459177	NM_022124.6(CDH23):c.934del (p.Ile311_Leu312insTer)	CDH23	Pathogenic	criteria provided, multiple submitters, no conflicts
2009133	NM_022124.6(CDH23):c.2328del (p.Thr777fs)	CDH23	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2017022	NM_022124.6(CDH23):c.1891C>T (p.Gln631Ter)	CDH23	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2117564	NM_022124.6(CDH23):c.6253+2T>C	CDH23	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2128803	NM_022124.6(CDH23):c.6925del (p.Ala2309fs)	CDH23	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2136881	NM_022124.6(CDH23):c.2752G>A (p.Asp918Asn)	CDH23	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2501245	NM_022124.6(CDH23):c.1152C>A (p.Ser384Arg)	CDH23	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2680504	NM_022124.6(CDH23):c.7908C>A (p.Tyr2636Ter)	CDH23	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2713476	NM_022124.6(CDH23):c.5245G>T (p.Glu1749Ter)	CDH23	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2769924	NM_022124.6(CDH23):c.6463_6464dup (p.Gly2156fs)	CDH23	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2971009	NM_022124.6(CDH23):c.8847C>G (p.Tyr2949Ter)	CDH23	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2980941	NM_022124.6(CDH23):c.1179del (p.Asn393fs)	CDH23	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1068100	NM_000260.4(MYO7A):c.5169-2A>G	MYO7A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1071057	NM_000260.4(MYO7A):c.5428A>T (p.Lys1810Ter)	MYO7A	Pathogenic	criteria provided, multiple submitters, no conflicts
1076122	NM_000260.4(MYO7A):c.6126C>G (p.Tyr2042Ter)	MYO7A	Pathogenic	criteria provided, multiple submitters, no conflicts
1076994	NM_000260.4(MYO7A):c.1717del (p.Leu573fs)	MYO7A	Pathogenic	criteria provided, multiple submitters, no conflicts
1172719	NM_000260.4(MYO7A):c.6071G>C (p.Arg2024Pro)	MYO7A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
11848	NM_000260.4(MYO7A):c.700C>T (p.Gln234Ter)	MYO7A	Pathogenic	criteria provided, multiple submitters, no conflicts
11850	NM_000260.4(MYO7A):c.635G>A (p.Arg212His)	MYO7A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1185084	NM_000260.4(MYO7A):c.4972C>T (p.Gln1658Ter)	MYO7A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 72 · Orphanet: 23 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
CDH23	Definitive	Unknown	Usher syndrome type 1	8
CIB2	Definitive	Autosomal recessive	Usher syndrome type 1J	7
MYO7A	Definitive	Autosomal recessive	Usher syndrome type 1	15
PCDH15	Definitive	Unknown	Usher syndrome type 1	9
USH1C	Definitive	Autosomal recessive	Usher syndrome type 1C	13
USH1G	Definitive	Unknown	Usher syndrome type 1	8
ESPN	Supportive	Autosomal recessive	Usher syndrome type 1	12

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
USH1C	Orphanet:231169	Usher syndrome type 1
USH1C	Orphanet:90636	Rare autosomal recessive non-syndromic sensorineural deafness type DFNB
ESPN	Orphanet:231169	Usher syndrome type 1
ESPN	Orphanet:90636	Rare autosomal recessive non-syndromic sensorineural deafness type DFNB
CDH23	Orphanet:231169	Usher syndrome type 1
CDH23	Orphanet:2965	Prolactinoma
CDH23	Orphanet:314777	Familial isolated pituitary adenoma
CDH23	Orphanet:90636	Rare autosomal recessive non-syndromic sensorineural deafness type DFNB
CDH23	Orphanet:91347	TSH-secreting pituitary adenoma
CDH23	Orphanet:96253	Cushing disease
PCDH15	Orphanet:231169	Usher syndrome type 1
PCDH15	Orphanet:90636	Rare autosomal recessive non-syndromic sensorineural deafness type DFNB
USH1G	Orphanet:231169	Usher syndrome type 1
CIB2	Orphanet:231169	Usher syndrome type 1
CIB2	Orphanet:90636	Rare autosomal recessive non-syndromic sensorineural deafness type DFNB
MYO7A	Orphanet:231169	Usher syndrome type 1
MYO7A	Orphanet:231178	Usher syndrome type 2
MYO7A	Orphanet:90635	Rare autosomal dominant non-syndromic sensorineural deafness type DFNA
MYO7A	Orphanet:90636	Rare autosomal recessive non-syndromic sensorineural deafness type DFNB
USH2A	Orphanet:231178	Usher syndrome type 2
USH2A	Orphanet:791	Retinitis pigmentosa
ADGRV1	Orphanet:231178	Usher syndrome type 2
ADGRV1	Orphanet:36387	Genetic epilepsy with febrile seizure plus

Cohort genes → proteins

12 cohort genes, 10 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	12

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
USH1C	HGNC:12597	ENSG00000006611	Q9Y6N9	Harmonin	gencc,clinvar
ESPN	HGNC:13281	ENSG00000187017	B1AK53	Espin	gencc,clinvar
CDH23	HGNC:13733	ENSG00000107736	Q9H251	Cadherin-23	gencc,clinvar
PCDH15	HGNC:14674	ENSG00000150275	Q96QU1	Protocadherin-15	gencc,clinvar
USH1G	HGNC:16356	ENSG00000182040	Q495M9	pre-mRNA splicing regulator USH1G	gencc,clinvar
CIB2	HGNC:24579	ENSG00000136425	O75838	Calcium and integrin-binding family member 2	gencc,clinvar
MYO7A	HGNC:7606	ENSG00000137474	Q13402	Unconventional myosin-VIIa	gencc,clinvar
USH2A	HGNC:12601	ENSG00000042781	O75445	Usherin	clinvar
ADGRV1	HGNC:17416	ENSG00000164199	Q8WXG9	Adhesion G-protein coupled receptor V1	clinvar
C10orf105	HGNC:20304	ENSG00000214688	Q8TEF2	Uncharacterized protein C10orf105	clinvar
CDH23-AS1	HGNC:31433	ENSG00000223817		CDH23 antisense RNA 1	clinvar
USH2A-AS1	HGNC:40606	ENSG00000236292		USH2A antisense RNA 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
USH1C	Harmonin	Anchoring/scaffolding protein that is a part of the functional network formed by USH1C, USH1G, CDH23 and MYO7A that mediates mechanotransduction in cochlear hair cells.
ESPN	Espin	Multifunctional actin-bundling protein.
CDH23	Cadherin-23	Cadherins are calcium-dependent cell adhesion proteins.
PCDH15	Protocadherin-15	Calcium-dependent cell-adhesion protein.
USH1G	pre-mRNA splicing regulator USH1G	Plays a role in pre-mRNA splicing by regulating the release and transfer of U4/U6.U5 tri-small nuclear ribonucleoprotein (tri-snRNP) complexes from their assembly site in Cajal bodies to nuclear speckles, thereby contributing to the assemb…
CIB2	Calcium and integrin-binding family member 2	Calcium- and integrin-binding protein that plays a role in intracellular calcium homeostasis.
MYO7A	Unconventional myosin-VIIa	Myosins are actin-based motor molecules with ATPase activity.
USH2A	Usherin	Involved in hearing and vision as member of the USH2 complex.
ADGRV1	Adhesion G-protein coupled receptor V1	G-protein coupled receptor which has an essential role in the development of hearing and vision.

Protein-family classification

Druggable: 2 · Difficult: 4 · Unknown: 6 · Druggable fraction: 0.17

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Scaffold/PPI	4	5.8×	0.015
Antibody/Immunoglobulin	1	2.4×	0.534
GPCR	1	2.0×	0.534
Other/Unknown	6	0.9×	0.758

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
USH1C	Scaffold/PPI	no		PDZ, Harmonin_N, PDZ_sf
ESPN	Scaffold/PPI	no		Ankyrin_rpt, WH2_dom, Ankyrin_rpt-contain_sf
CDH23	Other/Unknown	no		Cadherin-like_dom, Cadherin-like_sf, Cadherin_CS
PCDH15	Other/Unknown	no		Cadherin-like_dom, Cadherin-like_sf, Cadherin_CS
USH1G	Scaffold/PPI	no		SAM, Ankyrin_rpt, SAM/pointed_sf
CIB2	Other/Unknown	no		EF_hand_dom, EF-hand-dom_pair, EF_Hand_1_Ca_BS
MYO7A	Scaffold/PPI	no		IQ_motif_EF-hand-BS, FERM_domain, MyTH4_dom
USH2A	Antibody/Immunoglobulin	yes		Laminin_G, LE_dom, FN3_dom
ADGRV1	GPCR	yes		GPCR_2_secretin-like, Calx_beta, EPTP
C10orf105	Other/Unknown	no		DUF5527
CDH23-AS1	Other/Unknown	no
USH2A-AS1	Other/Unknown	no

Expression context

Cohort genes with no expression data: 0.

8 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	12
unknown	0

Top tissues across cohort

Tissue	Cohort genes
male germ line stem cell (sensu Vertebrata) in testis	3
left adrenal gland	2
right adrenal gland	2
right adrenal gland cortex	2
blood	2
C1 segment of cervical spinal cord	1
mucosa of transverse colon	1
rectum	1
left testis	1
right testis	1
right uterine tube	1
left ovary	1
right ovary	1
ventricular zone	1
adrenal tissue	1
left adrenal gland cortex	1
esophagus squamous epithelium	1
lower esophagus mucosa	1
apex of heart	1
cardiac atrium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
USH1C	203	broad	marker	mucosa of transverse colon, C1 segment of cervical spinal cord, rectum
ESPN	184	broad	marker	right testis, left testis, right uterine tube
CDH23	161	broad	marker	ventricular zone, left ovary, right ovary
PCDH15	130	tissue_specific	marker	left adrenal gland cortex, male germ line stem cell (sensu Vertebrata) in testis, adrenal tissue
USH1G	69	broad	yes	lower esophagus mucosa, male germ line stem cell (sensu Vertebrata) in testis, esophagus squamous epithelium
CIB2	272	ubiquitous	marker	right atrium auricular region, cardiac atrium, apex of heart
MYO7A	186	broad	marker	right adrenal gland cortex, right adrenal gland, left adrenal gland
USH2A	30	tissue_specific	marker	male germ line stem cell (sensu Vertebrata) in testis, right lobe of liver, buccal mucosa cell
ADGRV1	196	broad	marker	right adrenal gland cortex, right adrenal gland, left adrenal gland
C10orf105	107	tissue_specific	yes	quadriceps femoris, blood, cerebellar vermis
CDH23-AS1	51		yes	blood, monocyte, thoracic mammary gland
USH2A-AS1	21		yes	liver, bone marrow, spinal cord

Protein interactions among cohort

Intra-cohort edges: 20.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
USH2A	2,332
CIB2	2,249
PCDH15	1,732
ESPN	1,702
ADGRV1	1,658
CDH23	1,575
USH1G	1,354
USH1C	291
C10orf105	53
MYO7A	43

Intra-cohort edges

A	B	Sources
ADGRV1	CDH23	string_interaction
ADGRV1	CIB2	string_interaction
ADGRV1	PCDH15	string_interaction
ADGRV1	USH1G	string_interaction
ADGRV1	USH2A	string_interaction
C10orf105	CDH23	string_interaction
CDH23	CIB2	string_interaction
CDH23	ESPN	string_interaction
CDH23	PCDH15	string_interaction
CDH23	USH1C	biogrid_interaction, intact
CDH23	USH1G	string_interaction
CDH23	USH2A	string_interaction
CIB2	PCDH15	string_interaction
CIB2	USH1G	string_interaction
CIB2	USH2A	string_interaction
MYO7A	USH1C	biogrid_interaction
PCDH15	USH1G	string_interaction
PCDH15	USH2A	string_interaction
USH1C	USH1G	biogrid_interaction, intact
USH1G	USH2A	string_interaction

Structural data

PDB: 6 · AlphaFold-only: 4 · No structure: 2

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
USH1C	Q9Y6N9	11
PCDH15	Q96QU1	8
CDH23	Q9H251	6
USH1G	Q495M9	3
CIB2	O75838	1
MYO7A	Q13402	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ESPN	B1AK53	68.76
C10orf105	Q8TEF2	63.46
USH2A	O75445
ADGRV1	Q8WXG9

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 9. Enrichment computed across 12 evidence-associated genes (8 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 8 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Sensory processing of sound by outer hair cells of the cochlea	7	178.4×	3e-15	USH1C, ESPN, CDH23, PCDH15, USH1G, CIB2, MYO7A
Sensory processing of sound by inner hair cells of the cochlea	7	142.8×	9e-15	USH1C, ESPN, CDH23, PCDH15, USH1G, CIB2, MYO7A
Sensory processing of sound	2	77.2×	8e-04	CDH23, MYO7A
Sensory Perception	2	23.8×	0.007	CDH23, MYO7A
The canonical retinoid cycle in rods (twilight vision)	1	64.9×	0.028	MYO7A
EGR2 and SOX10-mediated initiation of Schwann cell myelination	1	46.0×	0.032	ADGRV1
Visual phototransduction	1	32.4×	0.039	MYO7A
Nervous system development	1	5.4×	0.193	ADGRV1
Developmental Biology	1	1.8×	0.437	ADGRV1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 9 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
sensory perception of light stimulus	7	1456.3×	1e-21	USH1C, CDH23, PCDH15, USH1G, MYO7A, USH2A, ADGRV1
photoreceptor cell maintenance	7	278.9×	9e-16	USH1C, CDH23, PCDH15, USH1G, CIB2, USH2A, ADGRV1
equilibrioception	5	1337.5×	5e-15	USH1C, CDH23, PCDH15, USH1G, MYO7A
sensory perception of sound	8	89.7×	1e-14	USH1C, ESPN, CDH23, PCDH15, USH1G, MYO7A, USH2A, ADGRV1
inner ear receptor cell stereocilium organization	3	280.9×	1e-06	USH1C, USH1G, ADGRV1
maintenance of animal organ identity	2	749.0×	2e-05	USH2A, ADGRV1
inner ear receptor cell differentiation	2	749.0×	2e-05	USH2A, ADGRV1
visual perception	4	35.3×	2e-05	CDH23, MYO7A, USH2A, ADGRV1
inner ear auditory receptor cell differentiation	2	267.5×	2e-04	USH1C, USH2A
auditory receptor cell stereocilium organization	2	187.2×	3e-04	CDH23, MYO7A
cochlea development	2	104.0×	8e-04	CDH23, MYO7A
actin filament bundle assembly	2	101.2×	8e-04	USH1C, ESPN
establishment of protein localization	2	96.0×	9e-04	USH2A, ADGRV1
inner ear development	2	83.2×	0.001	PCDH15, ADGRV1
inner ear morphogenesis	2	66.9×	0.002	USH1C, USH1G
microvillar actin bundle assembly	1	1872.4×	0.002	ESPN
pigment granule transport	1	1872.4×	0.002	MYO7A
protein localization to microvillus	1	936.2×	0.004	USH1C
parallel actin filament bundle assembly	1	624.1×	0.005	USH1C
homophilic cell-cell adhesion	2	31.2×	0.005	CDH23, PCDH15
auditory receptor cell morphogenesis	1	468.1×	0.006	USH1C
phagolysosome assembly	1	374.5×	0.007	MYO7A
mechanoreceptor differentiation	1	374.5×	0.007	MYO7A
regulation of microvillus length	1	267.5×	0.009	USH1C
brush border assembly	1	267.5×	0.009	USH1C
hair cell differentiation	1	234.1×	0.010	USH2A
regulation of clathrin-dependent endocytosis	1	187.2×	0.012	USH1G
self proteolysis	1	170.2×	0.013	ADGRV1
retinal cone cell development	1	156.0×	0.013	USH1C
nervous system process	1	133.8×	0.015	ADGRV1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 12

Druggability breadth: 1 of 12 evidence-associated genes (8%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
USH1C	0	0
ESPN	0	0
CDH23	0	0
PCDH15	0	0
USH1G	0	0
CIB2	0	0
MYO7A	0	0
USH2A	0	0
ADGRV1	0	0
C10orf105	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
PCDH15	9	Binding:9

Pharmacogenomics

Cohort genes with a PharmGKB record: 11; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	2	USH2A, ADGRV1
E	Difficult family or no structure, no drug	10	USH1C, ESPN, CDH23, PCDH15, USH1G, CIB2, MYO7A, C10orf105, CDH23-AS1, USH2A-AS1

Undrugged target profiles

12 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
USH1C	0	—
ESPN	0	—
CDH23	0	—
PCDH15	9	—
USH1G	0	—
CIB2	0	—
MYO7A	0	—
USH2A	0	—
ADGRV1	0	—
C10orf105	0	—
CDH23-AS1	0	—
USH2A-AS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.