USH2A

Chr 1AR

usherin

NCBI Gene: 7399ENSG00000042781UniProt: O75445

Involved in hearing and vision as member of the USH2 complex. In the inner ear, required for the maintenance of the hair bundle ankle formation, which connects growing stereocilia in developing cochlear hair cells. In retina photoreceptors, the USH2 complex is required for the maintenance of periciliary membrane complex that seems to play a role in regulating intracellular protein transport

Primary Disease Associations & Inheritance

Usher syndrome, type 2AMIM #276901
AR
{Retinal disease in Usher syndrome type IIA, modifier of}MIM #276901
AR
Retinitis pigmentosa 39MIM #613809
AR
Usher syndrome, type 2AMIM #276901
AR
UniProtUsher syndrome 2A
579
ClinVar variants
74
Pathogenic / LP
0.00
pLI score
2
Active trials
Clinical Summary— USH2A
🧬
Gene-Disease Validity (ClinGen)
Usher syndrome type 2 · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
74 Pathogenic / Likely Pathogenic· 418 VUS of 579 total submissions
💊
Clinical Trials
2 active or recruiting trials — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.86LOEUF
pLI 0.000
Z-score 3.46
OE 0.76 (0.67–0.86)
Tolerant

Typical tolerance to LoF variation

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
-2.47Z-score
OE missense 1.13 (1.10–1.17)
3076 obs / 2713.4 exp
Tolerant

Tolerant to missense variation

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.76 (0.67–0.86)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.1.13 (1.10–1.17)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.16
0≤1.21.6
LoF obs/exp: 178 / 235.3Missense obs/exp: 3076 / 2713.4Syn Z: -4.00

ClinVar Variant Classifications

579 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic42
Likely Pathogenic32
VUS418
Likely Benign87
42
Pathogenic
32
Likely Pathogenic
418
VUS
87
Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
26
3
13
0
42
Likely Pathogenic
13
6
13
0
32
VUS
0
363
26
29
418
Likely Benign
0
3
28
56
87
Benign
0
0
0
0
0
Total393758085579

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

USH2A · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

USH2A-related Usher syndrome

definitive
ARLoss Of FunctionAbsent Gene Product
EyeEar
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

2 OMIM entries

OMIM

Usher syndrome, type 2A

MIM #276901

Molecular basis of disorder known

Autosomal recessive

{Retinal disease in Usher syndrome type IIA, modifier of}

MIM #276901

Molecular basis of disorder known

Autosomal recessive
USHERIN; USH2A
MIM #608400 · *

Retinitis pigmentosa 39

MIM #613809

Molecular basis of disorder known

Autosomal recessive

Usher syndrome, type 2A

MIM #276901

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — USH2A
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Spectrum of Genetic Variants in the Most Common Genes Causing Inherited Retinal Disease in a Large Molecularly Characterized United Kingdom Cohort.
Lin S et al.·Ophthalmol Retina
2024Cohort
Genetic epidemiology of inherited retinal diseases in a large patient cohort followed at a single center in Italy.
Karali M et al.·Sci Rep
2022Cohort
Genetic characteristics of retinitis pigmentosa in 1204 Japanese patients.
Koyanagi Y et al.·J Med Genet
2019Cohort
Genetic screening of a Chinese cohort of children with hearing loss using a next-generation sequencing panel.
Ma J et al.·Hum Genomics
2023Cohort
Comprehensive Molecular Screening in Chinese Usher Syndrome Patients.
Sun T et al.·Invest Ophthalmol Vis Sci
2018Cohort
USH2A variants in Chinese patients with Usher syndrome type II and non-syndromic retinitis pigmentosa.
Zhu T et al.·Br J Ophthalmol
2021Cohort
Comprehensive sequence analysis of nine Usher syndrome genes in the UK National Collaborative Usher Study.
Le Quesne Stabej P et al.·J Med Genet
2012
Impact of Next Generation Sequencing in Unraveling the Genetics of 1036 Spanish Families With Inherited Macular Dystrophies.
Del Pozo-Valero M et al.·Invest Ophthalmol Vis Sci
2022
Prevalence and genetic-phenotypic characteristics of patients with USH2A mutations in a large cohort of Chinese patients with inherited retinal disease.
Gao FJ et al.·Br J Ophthalmol
2021Cohort
A nationwide genetic analysis of inherited retinal diseases in Israel as assessed by the Israeli inherited retinal disease consortium (IIRDC).
Sharon D et al.·Hum Mutat
2020
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Retinal DegenerationsRetinitis Pigmentosa (RP)Stargardt Disease

Inherited Retinal Diseases: Natural History and Genotype-Phenotype Correlations

NOT YET RECRUITING
NCT07265895IRCCS San RaffaeleStarted 2026-01-01
No Intervention: Observational Cohort
Retinitis Pigmentosa (RP)Usher Syndrome Type 2Deaf Blind

Study to Evaluate Ultevursen in Subjects With Retinitis Pigmentosa (RP) Due to Mutations in Exon 13 of the USH2A Gene

RECRUITING
NCT06627179Phase PHASE2Laboratoires TheaStarted 2024-12-11
Intravitreal Injection of UltevursenNo intervention, will not receive any active study intervention

External Resources

Links to major genomics databases and tools