RARB

Chr 3ADAR

retinoic acid receptor beta

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

NCBI Gene: 5915 ENSG00000077092 UniProt: P10826 OMIM: 180220

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.

OMIM 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]

OMIM ResearchGenerating clinical summary…

MultiplemechanismAD/ARLOEUF 0.121 OMIM phenotype

Clinical Summary— RARB

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Gene-Disease Validity (ClinGen)

microphthalmia, syndromic 12 · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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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.

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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

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveRARB-related microphthalmia syndromicGOFAD

definitiveRARB-related microphthalmia syndromicLOFAR

This gene — mechanism propensity

0.2997th %ile

GOF

0.3292th %ile

LOF

0.82top 5%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFprediction above median · LOEUF 0.12

GOF1 literature citation

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

GOFGain-of-Function Mutations in RARB Cause Intellectual Disability with Progressive Motor Impairment.1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References