ESRRB

Chr 14AR

estrogen related receptor beta

Also known as: DFNB35, ERR beta-2, ERR2, ERRb, ERRbeta2, ESRL2, NR3B2

NCBI Gene: 2103ENSG00000119715UniProt: O95718

This gene encodes a protein with similarity to the estrogen receptor. Its function is unknown; however, a similar protein in mouse plays an essential role in placental development. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

Deafness, autosomal recessive 35MIM #608565
AR
349
ClinVar variants
40
Pathogenic / LP
0.13
pLI score
0
Active trials
Clinical Summary— ESRRB
🧬
Gene-Disease Validity (ClinGen)
nonsyndromic genetic hearing loss · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.26) despite low pLI — interpret in context.
📋
ClinVar Variants
40 Pathogenic / Likely Pathogenic· 165 VUS of 349 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
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.
0.52LOEUF
pLI 0.126
Z-score 3.26
OE 0.26 (0.14–0.52)
Moderately constrained

More LoF-intolerant than ~75% of genes

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.
1.56Z-score
OE missense 0.75 (0.67–0.84)
229 obs / 305.8 exp
Tolerant

Mild missense constraint

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.0.26 (0.14–0.52)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.75 (0.67–0.84)
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.0.93
0≤1.21.6
LoF obs/exp: 6 / 22.8Missense obs/exp: 229 / 305.8Syn Z: 0.63

ClinVar Variant Classifications

349 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic22
Likely Pathogenic18
VUS165
Likely Benign92
Benign27
Conflicting25
22
Pathogenic
18
Likely Pathogenic
165
VUS
92
Likely Benign
27
Benign
25
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
3
5
14
0
22
Likely Pathogenic
7
2
9
0
18
VUS
2
111
47
5
165
Likely Benign
0
4
50
38
92
Benign
0
1
24
2
27
Conflicting
—25
Total1212314445349

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

View in ClinVar →

Protein Context — Lollipop Plot

ESRRB · protein map & ClinVar variants

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

Gene2Phenotype Curations

ESRRB-related deafness

definitive
ARLoss Of FunctionAbsent Gene Product
Ear
G2P ↗

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Deafness, autosomal recessive 35

MIM #608565

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — ESRRB
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Whole exome sequencing of 491 individuals with inherited retinal diseases reveals a large spectrum of variants and identification of novel candidate genes.
Hayman T et al.·J Med Genet
2024
Genetic architecture of Meniere's disease.
Gallego-Martinez A et al.·Hear Res
2020Review
Chromatin accessibility during human first-trimester neurodevelopment.
Mannens CCA et al.·Nature
2025
Functional pathogenicity of ESRRB variant of uncertain significance contributes to hearing loss (DFNB35).
Choi WH et al.·Sci Rep
2024Functional
What makes a pluripotency reprogramming factor?
Jauch R et al.·Curr Mol Med
2013Review
The orphan nuclear receptor estrogen-related receptor beta (ERRβ) in triple-negative breast cancer.
Fernandez AI et al.·Breast Cancer Res Treat
2020
A Systematic Review on the Role of the Stria Vascularis in Menière's Disease Pathogenesis.
Cruz-Granados P et al.·J Assoc Res Otolaryngol
2025Review
Novel pathogenic mutations and further evidence for clinical relevance of genes and variants causing hearing impairment in Tunisian population.
Souissi A et al.·J Adv Res
2021
A novel missense variant in ESRRB gene causing autosomal recessive non-syndromic hearing loss: in silico analysis of a case.
Ghasemnejad T et al.·BMC Med Genomics
2022Case report
Mutations of ESRRB encoding estrogen-related receptor beta cause autosomal-recessive nonsyndromic hearing impairment DFNB35.
Collin RW et al.·Am J Hum Genet
2008
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

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools