RARB

Chr 3ADAR

retinoic acid receptor beta

Also known as: HAP, MCOPS12, NR1B2, RARbeta, RARbeta1, RRB2

NCBI Gene: 5915ENSG00000077092UniProt: P10826

This gene encodes retinoic acid receptor beta, a member of the thyroid-steroid hormone receptor superfamily of nuclear transcriptional regulators. This receptor localizes to the cytoplasm and to subnuclear compartments. It binds retinoic acid, the biologically active form of vitamin A which mediates cellular signalling in embryonic morphogenesis, cell growth and differentiation. It is thought that this protein limits growth of many cell types by regulating gene expression. The gene was first identified in a hepatocellular carcinoma where it flanks a hepatitis B virus integration site. Alternate promoter usage and differential splicing result in multiple transcript variants. [provided by RefSeq, Mar 2014]

Primary Disease Associations & Inheritance

Microphthalmia, syndromic 12MIM #615524
ADAR
190
ClinVar variants
45
Pathogenic / LP
1.00
pLI score· haploinsufficient
0
Active trials
Clinical Summary— RARB
⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
45 Pathogenic / Likely Pathogenic· 70 VUS of 190 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
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.
0.12LOEUF
pLI 1.000
Z-score 4.61
OE 0.00 (0.00–0.12)
Highly constrained

Among the most LoF-intolerant genes (~top 3%)

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.
2.87Z-score
OE missense 0.49 (0.42–0.57)
123 obs / 250.7 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

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.0.00 (0.00–0.12)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.49 (0.42–0.57)
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.1.24
0≤1.21.6
LoF obs/exp: 0 / 24.8Missense obs/exp: 123 / 250.7Syn Z: -1.82

ClinVar Variant Classifications

190 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic23
Likely Pathogenic22
VUS70
Likely Benign27
Benign23
Conflicting4
23
Pathogenic
22
Likely Pathogenic
70
VUS
27
Likely Benign
23
Benign
4
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
2
3
18
0
23
Likely Pathogenic
1
15
6
0
22
VUS
7
50
13
0
70
Likely Benign
0
6
10
11
27
Benign
0
2
18
3
23
Conflicting
—4
Total10766514169

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

View in ClinVar →

Protein Context — Lollipop Plot

RARB · protein map & ClinVar variants

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

Gene2Phenotype Curations

RARB-related microphthalmia syndromic

definitive
ADGain Of FunctionAltered Gene Product Structure
Dev. DisordersEye
G2P ↗
missense variant

RARB-related microphthalmia syndromic

definitive
ARLoss Of FunctionAbsent Gene Product
Dev. DisordersEye
G2P ↗
frameshift variant

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Microphthalmia, syndromic 12

MIM #615524

Molecular basis of disorder known

Autosomal dominantAutosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
A De Novo Noncoding RARB Variant Associated with Complex Microphthalmia Alters a Putative Regulatory Element.
Replogle MR et al.·Hum Mutat
2024
Clinical and genomic characterization of an ATRA-insensitive acute promyelocytic leukemia variant with a FNDC3B::RARB fusion.
Kirkham JK et al.·Genes Chromosomes Cancer
2023Case report
Genetics of prion disease.
Lloyd S et al.·Top Curr Chem
2011Review
Genetics of prion diseases.
Lloyd SE et al.·Curr Opin Genet Dev
2013Review
De novo retinoic acid receptor beta (RARB) variant associated with microphthalmia and dystonia.
Trieschmann G et al.·Eur J Med Genet
2023Case report
Recurrent RARB Translocations in Acute Promyelocytic Leukemia Lacking RARA Translocation.
Osumi T et al.·Cancer Res
2018
Clinical and functional heterogeneity associated with the disruption of retinoic acid receptor beta.
Caron V et al.·Genet Med
2023Functional
Promoter hypermethylation of RARB and GSTP1 genes in plasma cell-free DNA as breast cancer biomarkers in Peruvian women.
Danos P et al.·Mol Genet Genomic Med
2023
The genetic architecture of microphthalmia, anophthalmia and coloboma.
Williamson KA et al.·Eur J Med Genet
2014Review
Prognostic DNA methylation markers for hormone receptor breast cancer: a systematic review.
de Ruijter TC et al.·Breast Cancer Res
2020Review
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