RAI1

Chr 17ADIsolated cases

retinoic acid induced 1

Also known as: SMCR, SMS

NCBI Gene: 10743ENSG00000108557UniProt: Q7Z5J4

This gene is located within the Smith-Magenis syndrome region on chromosome 17. It is highly similar to its mouse counterpart and is expressed at high levels mainly in neuronal tissues. The protein encoded by this gene includes a polymorphic polyglutamine tract in the N-terminal domain. Expression of the mouse counterpart in neurons is induced by retinoic acid. This gene is associated with both the severity of the phenotype and the response to medication in schizophrenic patients. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

Smith-Magenis syndromeMIM #182290
ADIsolated cases
482
ClinVar variants
34
Pathogenic / LP
1.00
pLI score· haploinsufficient
2
Active trials
Clinical Summary— RAI1
🧬
Gene-Disease Validity (ClinGen)
Smith-Magenis syndrome · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
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
34 Pathogenic / Likely Pathogenic· 263 VUS of 482 total submissions
💊
Clinical Trials
2 active or recruiting trials — potential therapeutic options may be available

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 6.58
OE 0.04 (0.01–0.12)
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.
1.12Z-score
OE missense 0.91 (0.86–0.95)
1029 obs / 1134.7 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.0.04 (0.01–0.12)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.91 (0.86–0.95)
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.1.17
0≤1.21.6
LoF obs/exp: 2 / 54.4Missense obs/exp: 1029 / 1134.7Syn Z: -3.04

ClinVar Variant Classifications

482 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic27
Likely Pathogenic7
VUS263
Likely Benign151
Benign24
Conflicting10
27
Pathogenic
7
Likely Pathogenic
263
VUS
151
Likely Benign
24
Benign
10
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
15
0
12
0
27
Likely Pathogenic
4
1
2
0
7
VUS
0
256
7
0
263
Likely Benign
1
17
3
130
151
Benign
0
24
0
0
24
Conflicting
—10
Total2029824130482

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.

Gene2Phenotype Curations

RAI1-related Smith-Magenis syndrome

definitive
ADLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Smith-Magenis syndrome

MIM #182290

Molecular basis of disorder known

Autosomal dominantIsolated cases
📖
GeneReview available — RAI1
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
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
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
Intellectual and Behavioral Phenotypes of Smith-Magenis Syndrome: Comparisons between Individuals with a 17p11.2 Deletion and Pathogenic RAI1 Variant.
Linders CC et al.·Genes (Basel)
2023Review
Smith-Magenis syndrome: haploinsufficiency of RAI1 results in altered gene regulation in neurological and metabolic pathways.
Elsea SH et al.·Expert Rev Mol Med
2011Review
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
Epigenetic Regulation and Neurodevelopmental Disorders: From MeCP2 to the TCF20/PHF14 Complex.
Dominguez G et al.·Genes (Basel)
2024Review
Neurological phenotype of Potocki-Lupski syndrome.
Ciaccio C et al.·Am J Med Genet A
2020
Overlapping hearing and communication profiles for the deletion and the RAI1 variant form of Smith-Magenis Syndrome (SMS).
Brennan C et al.·J Commun Disord
2024
Management of Sleep Disturbances Associated with Smith-Magenis Syndrome.
Kaplan KA et al.·CNS Drugs
2020Review
Top 10 resultsSearch 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
2026🔓 Open 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
2025🔓 Open 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 ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Morbid ObesityBariatric SurgeryTelerehabilitation

Exercise to Fight Obesity

RECRUITING
NCT06934681Phase NAInstituto de Investigacion Sanitaria La FeStarted 2025-05-19
Usual Care GroupControlled exercise with telerehabilitation
RAI1 Gene 17P11.2 Deletion+Duplication

Clinical and Molecular Biomarker Studies in RAI1 (Retinoic Acid-Induced 1) -Related Disorders

RECRUITING
NCT06274164Baylor College of MedicineStarted 2024-03-13
Electroencephalography/Polysomnography (EEG/PSG)Skin BiopsyBlood draw

External Resources

Links to major genomics databases and tools