RARB

Chr 3

retinoic acid receptor beta

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

NCBI Gene: 5915 ENSG00000077092 UniProt: P10826

This gene encodes retinoic acid receptor beta, a nuclear transcriptional regulator that binds retinoic acid (vitamin A) and forms heterodimers to regulate gene expression during embryonic development, cell growth, and differentiation. Mutations cause syndromic microphthalmia 12 with both autosomal dominant and autosomal recessive inheritance patterns reported. The gene is highly constrained against loss-of-function variants (pLI 0.9998, LOEUF 0.12), indicating that complete loss of protein function is typically incompatible with normal development.

ResearchSummary from RefSeq, OMIM, UniProt

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]

ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

UniProtMicrophthalmia, syndromic, 12

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · microphthalmia, syndromic 12 · AD · ClinGen 2023

Interpreting a novel variant

The dominant disease is caused by gain-of-function changes and the recessive disease by loss of function (Gene2Phenotype). A single heterozygous truncating variant therefore fits the recessive disease and does not by itself explain a dominant presentation; a novel missense has to be read against the dominant mechanism.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.12

LOEUF· LoF intol.

Multiple*

Mechanism· G2P

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

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?

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?

LoF OE?0.00 (0.00–0.12)

0≤0.351.4

Missense OE?0.49 (0.42–0.57)

0≤0.61.4

Synonymous OE?1.24

0≤1.21.6

LoF obs/exp: 0 / 24.8Missense obs/exp: 123 / 250.7Syn Z: -1.82

Background carrier burden — how many people carry a rare variant somewhere in RARB?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 130

510 rare PASS variants

Rare truncating (LoF)

1 in 5,200

47 rare PASS variants

Rare synonymous (reference)

1 in 190

272 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for RARB. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 150	1 in 5,400
South Asian	~43k	1 in 220	1 in 1,700
Remaining (unassigned)	~30k	1 in 120	1 in 2,900
European (Finnish)	~27k	1 in 380	≈ 1 in 13,000
Admixed American	~22k	1 in 200	≈ 1 in 6,700
African / African American	~21k	1 in 110	1 in 2,600
East Asian	~20k	1 in 280	≈ 1 in 9,600
Ashkenazi Jewish	~13k	1 in 2,600	≈ 1 in 13,000
Middle Eastern	~2,884	1 in 170	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 8 coding exons well covered in gnomAD exomes and genomes.? see exons ↓