PCDH15

Chr 10ARDigenic recessive

protocadherin related 15

Also known as: CDHR15, DFNB23, USH1F

NCBI Gene: 65217ENSG00000150275UniProt: Q96QU1

This gene is a member of the cadherin superfamily. Family members encode integral membrane proteins that mediate calcium-dependent cell-cell adhesion. It plays an essential role in maintenance of normal retinal and cochlear function. Mutations in this gene result in hearing loss and Usher Syndrome Type IF (USH1F). Extensive alternative splicing resulting in multiple isoforms has been observed in the mouse ortholog. Similar alternatively spliced transcripts are inferred to occur in human, and additional variants are likely to occur. [provided by RefSeq, Dec 2008]

Primary Disease Associations & Inheritance

Deafness, autosomal recessive 23MIM #609533
AR
Usher syndrome, type 1D/F digenicMIM #601067
ARDigenic recessive
Usher syndrome, type 1FMIM #602083
AR
UniProtUsher syndrome 1F
UniProtUsher syndrome 1D/F
3940
ClinVar variants
60
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— PCDH15
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
60 Pathogenic / Likely Pathogenic· 278 VUS of 3940 total submissions

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.
0.79LOEUF
pLI 0.000
Z-score 3.11
OE 0.63 (0.50–0.79)
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.
-1.68Z-score
OE missense 1.15 (1.09–1.20)
1196 obs / 1043.6 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.0.63 (0.50–0.79)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.1.15 (1.09–1.20)
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.1.12
0≤1.21.6
LoF obs/exp: 52 / 82.5Missense obs/exp: 1196 / 1043.6Syn Z: -1.87

ClinVar Variant Classifications

3940 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic42
Likely Pathogenic18
VUS278
Likely Benign152
Benign1
Conflicting1
42
Pathogenic
18
Likely Pathogenic
278
VUS
152
Likely Benign
1
Benign
1
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
29
0
13
0
42
Likely Pathogenic
15
0
3
0
18
VUS
6
229
25
18
278
Likely Benign
9
2
46
95
152
Benign
0
0
1
0
1
Conflicting
—1
Total5923188113492

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

View in ClinVar →

Protein Context — Lollipop Plot

PCDH15 · protein map & ClinVar variants

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

Gene2Phenotype Curations

PCDH15-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

1 OMIM entry

OMIM
PROTOCADHERIN 15; PCDH15
MIM #605514 · *

Deafness, autosomal recessive 23

MIM #609533

Molecular basis of disorder known

Autosomal recessive

Usher syndrome, type 1D/F digenic

MIM #601067

Molecular basis of disorder known

Autosomal recessiveDigenic recessive

Usher syndrome, type 1F

MIM #602083

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Comprehensive Molecular Screening in Chinese Usher Syndrome Patients.
Sun T et al.·Invest Ophthalmol Vis Sci
2018Cohort
De Novo Mutations Contributes Approximately 7% of Pathogenicity in Inherited Eye Diseases.
Li W et al.·Invest Ophthalmol Vis Sci
2023
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
The genetic and phenotypic landscapes of Usher syndrome: from disease mechanisms to a new classification.
Delmaghani S et al.·Hum Genet
2022Review
New Candidates for Autism/Intellectual Disability Identified by Whole-Exome Sequencing.
Bruno LP et al.·Int J Mol Sci
2021Clinical trial
Gene Therapy for Hearing Loss: Which Genes Next?
Carlson RJ et al.·Otol Neurotol
2025Review
Mutation spectrum of hearing loss patients in Northwest China: Identification of 20 novel variants.
Ma P et al.·Mol Genet Genomic Med
2024Cohort
Cross-Disorder Analysis of Genic and Regulatory Copy Number Variations in Bipolar Disorder, Schizophrenia, and Autism Spectrum Disorder.
Kushima I et al.·Biol Psychiatry
2022
Whole genome sequencing identifies elusive variants in genetically unsolved Italian inherited retinal disease patients.
Zeuli R et al.·HGG Adv
2024Cohort
Gene structure and mutant alleles of PCDH15: nonsyndromic deafness DFNB23 and type 1 Usher syndrome.
Ahmed ZM et al.·Hum Genet
2008
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
The Impact of Pcdh15 Deficiency on Cellular Energy Metabolism and Oxidative Stress, and Its Role and Mechanism in Hearing Loss.
Lan Y et al.·Clin Exp Otorhinolaryngol
2026Functional
A Novel Intronic Variant Causes Aberrant Splicing of PCDH15 in a Family With Usher Syndrome Type 1F.
Ma Q et al.·Mol Genet Genomic Med
2026🔓 Open Access
Compound heterozygous variants in PCDH15 non-coding regions in an Usher Syndrome Type 1F patient: minigene assay reveals pathogenicity of c.3123-1G>C.
Wang J et al.·Ophthalmic Genet
2026
[Analysis of pathogenic variant carriage for MYO7A, PCDH15, and CDH23 genes among newborns based on high-throughput sequencing technique].
Li Y et al.·Zhonghua Yi Xue Yi Chuan Xue Za Zhi
2025
Role of Pcdh15 in the development of intrinsic polarity of inner ear hair cells.
Kaushik R et al.·PLoS Genet
2025🔓 Open Access
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools