RAI1

Chr 17ADIsolated cases

retinoic acid induced 1

Also known as: SMCR, SMS

NCBI Gene: 10743ENSG00000108557UniProt: Q7Z5J4OMIM: 607642

RAI1 encodes a protein that contains a polyglutamine tract and is highly expressed in neuronal tissues, where its expression is induced by retinoic acid. Loss-of-function mutations cause Smith-Magenis syndrome through an autosomal dominant inheritance pattern, though most cases are isolated (de novo) occurrences. The protein localizes to the cytoplasm and is highly intolerant to loss-of-function variants, consistent with haploinsufficiency as the disease mechanism.

GeneReviewsOMIMResearchSummary from RefSeq, OMIM, UniProt, Mechanism
LOFmechanismAD/Isolated casesLOEUF 0.121 OMIM phenotype
Clinical Summary— RAI1
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Gene-Disease Validity (ClinGen)
Smith-Magenis syndrome · 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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ClinVar Variants
29 unique Pathogenic / Likely Pathogenic· 231 VUS of 400 total submissions
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Clinical Trials
2 active or recruiting trials — potential therapeutic options may be available
Explore recent and relevant literature in Research Assistant →
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GeneReview available — RAI1
Authoritative clinical overview · Recommended first read
Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
LoF Constraint
0.12LOEUF
pLI 1.000
Z-score 6.58
OE 0.04 (0.01–0.12)
Highly constrained

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

Missense Constraint
1.12Z-score
OE missense 0.91 (0.86–0.95)
1029 obs / 1134.7 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios
LoF OE0.04 (0.01–0.12)
0≤0.351.4
Missense OE0.91 (0.86–0.95)
0≤0.61.4
Synonymous OE1.17
0≤1.21.6
LoF obs/exp: 2 / 54.4Missense obs/exp: 1029 / 1134.7Syn Z: -3.04
Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗
definitiveRAI1-related Smith-Magenis syndromeLOFAD
DN
0.2399th %ile
GOF
0.1899th %ile
LOF
0.87top 5%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · 1 literature citation · 86% of P/LP variants are LoF · LOEUF 0.12

Literature Evidence

LOFTo study the role of RAI1 in obesity, we investigated the growth and obesity phenotype in a mouse model haploinsufficient for Rai1.PMID:20663924

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

ClinVar Variant Classifications

400 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic25
Likely Pathogenic4
VUS231
Likely Benign104
Benign14
Conflicting4
25
Pathogenic
4
Likely Pathogenic
231
VUS
104
Likely Benign
14
Benign
4
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
23
0
2
0
25
Likely Pathogenic
2
1
1
0
4
VUS
0
227
4
0
231
Likely Benign
1
10
3
90
104
Benign
0
14
0
0
14
Conflicting
—4
Total262521090382

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

View in ClinVar →

Protein Context — Lollipop Plot

RAI1 · protein map & ClinVar variants

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

3D Protein StructureAlphaFold
Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Smith-Magenis Syndrome-Clinical Review, Biological Background and Related Disorders.
Rinaldi B et al.·Genes (Basel)
2022Review
Epigenetic Regulation and Neurodevelopmental Disorders: From MeCP2 to the TCF20/PHF14 Complex.
Dominguez G et al.·Genes (Basel)
2024Review
Retinoic Acid-Induced 1 Gene and Neuropsychiatric Diseases: A Systematic Review.
Yang T et al.·Expert Rev Mol Med
2025Review
Multiethnic Meta-Analysis Identifies RAI1 as a Possible Obstructive Sleep Apnea-related Quantitative Trait Locus in Men.
Chen H et al.·Am J Respir Cell Mol Biol
2018Meta-analysis
De novo and inherited TCF20 pathogenic variants are associated with intellectual disability, dysmorphic features, hypotonia, and neurological impairments with similarities to Smith-Magenis syndrome.
Vetrini F et al.·Genome Med
2019Case report
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Behavioral Phenotype and Neuropsychological Profile of an Adult With Smith-Magenis Syndrome due to a Previously Unreported RAI1 Mutation: A Case Report.
Chavarría-Martínez EA et al.·Clin Case Rep
2026Open AccessCase report
Generation and characterization of the CSSi021-A (15665) human induced pluripotent stem cell line from a Smith-Magenis syndrome patient with a heterozygous RAI1 mutation.
Giovenale AMG et al.·Stem Cell Res
2025
Molecular basis for the interaction between Saccharomyces cerevisiae Rtt103 and the Rat1-Rai1 complex.
Chu HF et al.·Nat Commun
2025Open Access
Deletion of RAI1 noncoding exons 1-2 causes Smith-Magenis syndrome.
Hamiel U et al.·J Genet
2025
Assembly of the Xrn2/Rat1-Rai1-Rtt103 termination complexes in mesophilic and thermophilic organisms.
Dikunova A et al.·Structure
2025
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients