RAI1

Summary

RAI1 (retinoic acid induced 1, HGNC:9834) is a protein-coding gene on chromosome 17p11.2, encoding Retinoic acid-induced protein 1 (Q7Z5J4). Transcriptional regulator of the circadian clock components: CLOCK, BMAL1, BMAL2, PER1/3, CRY1/2, NR1D1/2 and RORA/C. It is haploinsufficient (ClinGen: sufficient evidence).

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.

Source: NCBI Gene 10743 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Smith-Magenis syndrome (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 48
• Clinical variants (ClinVar): 2,752 total — 126 pathogenic, 63 likely-pathogenic
• Phenotypes (HPO): 92
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_030665

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9834
Approved symbol	RAI1
Name	retinoic acid induced 1
Location	17p11.2
Locus type	gene with protein product
Status	Approved
Aliases	DKFZP434A139, SMS, KIAA1820, MGC12824
Ensembl gene	ENSG00000108557
Ensembl biotype	protein_coding
OMIM	607642
Entrez	10743

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 7 protein_coding, 2 protein_coding_CDS_not_defined

ENST00000353383, ENST00000395774, ENST00000471135, ENST00000489697, ENST00000582514, ENST00000583166, ENST00000918590, ENST00000955422, ENST00000955423

RefSeq mRNA: 1 — MANE Select: NM_030665 NM_030665

CCDS: CCDS11188

Canonical transcript exons

ENST00000353383 — 6 exons

Exon	Start	End
ENSE00001215272	17724028	17724159
ENSE00001215280	17681458	17681793
ENSE00001291642	17792933	17798513
ENSE00001300411	17803756	17803849
ENSE00001318618	17809390	17809439
ENSE00001407314	17809970	17811453

Expression profiles

Bgee: expression breadth ubiquitous, 264 present calls, max score 96.90.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 23.9936 / max 315.6811, expressed in 1785 samples.

FANTOM5 promoters (9 alternative TSS)

Promoter ID	TPM avg	Samples expressed
159754	12.7759	1721
159753	6.7269	1625
159755	2.8153	1285
159752	0.6774	440
159769	0.4266	199
159770	0.3308	164
159771	0.1941	66
208081	0.0259	10
208080	0.0207	2

Top tissues by expression

288 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
pigmented layer of retina	UBERON:0001782	96.90	gold quality
nipple	UBERON:0002030	96.13	gold quality
palpebral conjunctiva	UBERON:0001812	95.88	gold quality
urethra	UBERON:0000057	95.80	gold quality
pylorus	UBERON:0001166	95.49	gold quality
tibia	UBERON:0000979	95.43	gold quality
Brodmann (1909) area 23	UBERON:0013554	95.24	gold quality
cardia of stomach	UBERON:0001162	95.14	gold quality
penis	UBERON:0000989	94.94	gold quality
parietal lobe	UBERON:0001872	94.75	gold quality
postcentral gyrus	UBERON:0002581	94.53	gold quality
pharyngeal mucosa	UBERON:0000355	94.50	gold quality
saphenous vein	UBERON:0007318	94.50	gold quality
mammary duct	UBERON:0001765	94.49	gold quality
lower lobe of lung	UBERON:0008949	94.47	gold quality
seminal vesicle	UBERON:0000998	94.34	gold quality
mucosa of paranasal sinus	UBERON:0005030	94.31	gold quality
superior vestibular nucleus	UBERON:0007227	94.18	gold quality
entorhinal cortex	UBERON:0002728	94.04	gold quality
middle temporal gyrus	UBERON:0002771	94.00	gold quality
caput epididymis	UBERON:0004358	93.95	gold quality
gingival epithelium	UBERON:0001949	93.93	gold quality
pons	UBERON:0000988	93.86	gold quality
cauda epididymis	UBERON:0004360	93.62	gold quality
gingiva	UBERON:0001828	93.56	gold quality
superior surface of tongue	UBERON:0007371	93.44	gold quality
epithelium of nasopharynx	UBERON:0001951	93.41	gold quality
vena cava	UBERON:0004087	93.36	gold quality
ventral tegmental area	UBERON:0002691	93.14	gold quality
trigeminal ganglion	UBERON:0001675	93.04	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.54
E-MTAB-7303	no	347.88

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

80 targeting RAI1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-4650-5P	99.98	64.69	999
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-3143	99.93	71.96	3104
HSA-MIR-6768-5P	99.92	67.36	1942
HSA-MIR-329-3P	99.91	66.56	1234
HSA-MIR-362-3P	99.91	66.38	1267
HSA-MIR-374A-5P	99.90	71.34	2923
HSA-MIR-374B-5P	99.90	69.98	2734
HSA-MIR-4302	99.89	67.94	1187
HSA-MIR-380-3P	99.89	70.18	1978
HSA-LET-7A-2-3P	99.87	70.53	1921
HSA-MIR-3941	99.86	70.54	2735
HSA-MIR-369-3P	99.85	70.52	2264
HSA-LET-7G-3P	99.85	70.43	1929

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 33)

• RAI1 may play a role in regulating behavior, as dominant frameshift mutations in RAI1 have been found in individuals with Smith-Magenis syndrome (PMID:12652298)
• Two novel mutations in RAI1 were found in nondeletion patients with Smith-Magenis syndrome. The RAI1 C-terminus was found to have a plant homeo domain (PHD); this domain is conserved in the trithorax group of chromatin-based transcription regulators. (PMID:15565467)
• Haploinsufficiency of the RAI1 gene is associated with most features of Smith-Magenis syndrome (PMID:15788730)
• RAI1 seems to be responsible for the main features found with heterozygous 17p11.2 deletions inn patients with Smith-Magenis syndrome. (PMID:17468296)
• gene expression profile of genes analyzed in RAI1 knockdown cells (PMID:19236431)
• haploinsufficiency affects feeding, satiety and fat deposition patterns; RAI1 directly regulates the expression of BDNF (PMID:20663924)
• Results indicate that transcription factor activity and subcellular localization signals reside in two separate domains of the protein and both are essential for the correct functionality of RAI1. (PMID:20738874)
• data on 2 cases of Smith-Magenis syndrome with mutation of RAI1; sequencing of RAI1 revealed mutation of the same heptameric C-tract (CCCCCCC) in exon 3 in both cases (c.3103delC one case and and c.3103insC in the other), resulting in frameshift mutations (PMID:20932317)
• Functional studies have shown that RAI1 gene dosage is crucial for normal regulation of circadian rhythm, lipid metabolism and neurotransmitter function. (PMID:21545756)
• Abnormal circadian rhythm of melatonin in Smith-Magenis syndrome patients with RAI1 point mutations (PMID:21739587)
• Data suggest that RAI1 expression emerged as a genetic target for development of therapeutic interventions for SMS. (PMID:21857958)
• Mutation screening of the coding region of the RAI1 gene in patients with with features suggestive of Smith-Magenis syndrome identified two patients with novel heterozygous nonsynonymous alterations of unknown significance. (PMID:21897445)
• RAI1 is a positive transcriptional regulator of CLOCK, pinpointing a novel and important role for this gene in the circadian oscillator (PMID:22578325)
• A reduction of total RAI1 transcription factor activity is at the heart of the Smith-Magenis Syndrome clinical presentation. (PMID:23028815)
• The Shc family protein adaptor, Rai, acts as a negative regulator of Th17 and Th1 cell development. (PMID:23345394)
• evolutionary conservation of chromatin binding of SPBP and RAI1 (PMID:24205348)
• Human RAI1 protein was found to be a highly expressed neuronal protein whose distribution matches well with its role in cognitive and motor skills. (PMID:24519454)
• RAI1 gene polyglutamine repeat has a different distribution in our population. The 14-repeat allele is associated with perinatal depression and more frequent experience of physical and psychological symptoms during menstrual period. (PMID:24751306)
• Results show that when MBD5 and RAI1 are haploinsufficient, they perturb several common pathways that are linked to neuronal and behavioral development. (PMID:25853262)
• South American cohort did not confirm the effect of the four candidate loci as modifier of onset age: mithocondrial A10398G polymorphism and CAGn at RAI1, CACNA1A, ATXN3, and ATXN7 genes (PMID:25869926)
• RAI1 Gene Duplication is associated with Potocki-Lupski syndrome. (PMID:26544804)
• RAI1 polymorphisms rs4925102 and rs9907986 are predicted to disrupt the binding of retinoic acid RXR-RAR receptors and the transcription factor DEAF1, respectively, in Smith-Magenis and Potocki-Lupski syndromes patients. (PMID:26743651)
• Mutations in RAI1, OTOF, and SLC26A4 may have roles in nonsyndromic hearing loss in Altaian families in Siberia (PMID:27082237)
• we report molecular and clinical characterizations of six subjects with the reciprocal phenomenon of deletions spanning both genes, i.e., PMP22-RAI1 deletions. Systematic clinical studies revealed features consistent with SMS, including features of intellectual disability, speech and gross motor delays, behavioral problems and ocular abnormalities. (PMID:27386852)
• This study provides information about the inheritance pattern and recurrence risk for patients with identified variants and demonstrates clinical and genetic overlap of neurodevelopmental disorders (PMID:28213671)
• This study identified from multiethnic meta-analyses stronger associations between the RAI1 locus and non-REM apnea-hypopnea index in men compared with women. (PMID:29077507)
• Sleep disturbances and phase-advanced circadian rhythm in bodytemperature may be related to a complex biology that stems from theinterstitial deletion or mutation ofRAI1within chromosome 17p11.2. (PMID:30690916)
• Possible underreporting of pathogenic variants in RAI1 causing Smith-Magenis syndrome. (PMID:34089220)
• N[6]-methyladenosine demethylase ALKBH5 suppresses malignancy of esophageal cancer by regulating microRNA biogenesis and RAI1 expression. (PMID:34312488)
• Intellectual and Behavioral Phenotypes of Smith-Magenis Syndrome: Comparisons between Individuals with a 17p11.2 Deletion and Pathogenic RAI1 Variant. (PMID:37628566)
• Pentanucleotide Repeat Insertions in RAI1 Cause Benign Adult Familial Myoclonic Epilepsy Type 8. (PMID:37994247)
• Allele-Specific Regulation of the Candidate Autism Liability Gene RAI1 by the Enhancer Variant rs4925102 (C/G). (PMID:38674394)
• Overlapping hearing and communication profiles for the deletion and the RAI1 variant form of Smith-Magenis Syndrome (SMS). (PMID:39213791)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	rai1	ENSDARG00000076679
mus_musculus	Rai1	ENSMUSG00000062115
rattus_norvegicus	Rai1	ENSRNOG00000060615
drosophila_melanogaster	CG5098	FBGN0034300

Paralogs (1): TCF20 (ENSG00000100207)

Protein

Protein identifiers

Retinoic acid-induced protein 1 — Q7Z5J4 (reviewed: Q7Z5J4)

All UniProt accessions (4): Q7Z5J4, A8MXE8, J3QLL5, J3QR08

UniProt curated annotations — full annotation on UniProt →

Function. Transcriptional regulator of the circadian clock components: CLOCK, BMAL1, BMAL2, PER1/3, CRY1/2, NR1D1/2 and RORA/C. Positively regulates the transcriptional activity of CLOCK a core component of the circadian clock. Regulates transcription through chromatin remodeling by interacting with other proteins in chromatin as well as proteins in the basic transcriptional machinery. May be important for embryonic and postnatal development. May be involved in neuronal differentiation.

Subcellular location. Cytoplasm. Nucleus.

Tissue specificity. Expressed in all tissues examined with higher expression in the heart and brain. No expression was seen in the corpus callosum of the brain.

Disease relevance. Smith-Magenis syndrome (SMS) [MIM:182290] Characterized by intellectual disability associated with development and growth delays. Affected persons have characteristic behavioral abnormalities, including self-injurious behaviors and sleep disturbance, and distinct craniofacial and skeletal anomalies. The disease is caused by variants affecting the gene represented in this entry.

Polymorphism. The poly-Gln tract is polymorphic and the number of Gln varies from 12 to 14. The size of the poly-Gln region may influence the age at onset of spinocerebellar ataxia type 2 (SCA2).

Isoforms (4)

UniProt ID	Names	Canonical?
Q7Z5J4-1	1	yes
Q7Z5J4-2	2
Q7Z5J4-3	3
Q7Z5J4-4	4

RefSeq proteins (1): NP_109590* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001965	Znf_PHD	Domain
IPR013083	Znf_RING/FYVE/PHD	Homologous_superfamily
IPR034732	EPHD	Domain
IPR052440	Trans_Reg/Chrom_Remod	Family

Pfam: PF13771

UniProt features (73 total): compositionally biased region 19, modified residue 16, region of interest 11, splice variant 9, cross-link 5, sequence variant 4, sequence conflict 4, zinc finger region 2, short sequence motif 2, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q7Z5J4-F1	39.62	0.05

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (21): 339, 345, 472, 568, 683, 696, 805, 880, 892, 1064, 1068, 1122, 1352, 1358, 1374, 1431, 811, 819, 901, 901 …

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-9707616	Heme signaling
R-HSA-9931509	Expression of BMAL (ARNTL), CLOCK, and NPAS2

MSigDB gene sets: 863 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_UP, GSE37336_LY6C_POS_VS_NEG_NAIVE_CD4_TCELL_UP, GSE18804_SPLEEN_MACROPHAGE_VS_COLON_TUMORAL_MACROPHAGE_DN, GOBP_CIRCADIAN_RHYTHM, ATF_B, TGGTGCT_MIR29A_MIR29B_MIR29C, LEE_NEURAL_CREST_STEM_CELL_DN, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, GGGNRMNNYCAT_UNKNOWN, GOBP_REGULATION_OF_DEVELOPMENTAL_GROWTH, GOBP_ALPHA_AMINO_ACID_METABOLIC_PROCESS, KEGG_CYSTEINE_AND_METHIONINE_METABOLISM, GOZGIT_ESR1_TARGETS_DN, GOBP_GROWTH, TATTATA_MIR374

GO Biological Process (6): skeletal system development (GO:0001501), regulation of transcription by RNA polymerase II (GO:0006357), circadian regulation of gene expression (GO:0032922), negative regulation of multicellular organism growth (GO:0040015), positive regulation of DNA-templated transcription (GO:0045893), rhythmic process (GO:0048511)

GO Molecular Function (3): zinc ion binding (GO:0008270), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (3): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Cellular responses to stress	1
Circadian clock	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regulation of DNA-templated transcription	2
cellular anatomical structure	2
system development	1
transcription by RNA polymerase II	1
circadian rhythm	1
regulation of gene expression	1
multicellular organism growth	1
regulation of multicellular organism growth	1
negative regulation of developmental growth	1
negative regulation of multicellular organismal process	1
DNA-templated transcription	1
positive regulation of RNA biosynthetic process	1
biological_process	1
transition metal ion binding	1
binding	1
cation binding	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

1774 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RAI1	WDR41	Q9HAD4	699
RAI1	C9orf72	Q96LT7	448
RAI1	SMCR8	Q8TEV9	431
RAI1	C9orf78	Q9NZ63	424
RAI1	KDM5C	P41229	392
RAI1	FLCN	Q8NFG4	384
RAI1	PRDM7	Q9NQW5	383
RAI1	CYP3A43	Q9HB55	364
RAI1	NSD1	Q96L73	361
RAI1	IL37	Q9NZH6	353
RAI1	ADAM2	P78326	353
RAI1	CYP2C18	P33260	353
RAI1	AMACR	Q9UHK6	353
RAI1	CCL26	Q9Y258	353
RAI1	GID4	Q8IVV7	327

IntAct

62 interactions, top by confidence:

A	B	Type	Score
CSNK1A1	FAM83G	psi-mi:“MI:0914”(association)	0.900
H2AZ1	ZNHIT1	psi-mi:“MI:0914”(association)	0.770
HMG20A	KDM1A	psi-mi:“MI:0914”(association)	0.730
PIN1	RAI1	psi-mi:“MI:0915”(physical association)	0.670
RAI1	PIN1	psi-mi:“MI:0915”(physical association)	0.670
NAGK	ZBTB43	psi-mi:“MI:0914”(association)	0.530
RAI1	RPL13	psi-mi:“MI:0915”(physical association)	0.400
RAI1	H2BC9	psi-mi:“MI:0915”(physical association)	0.400
DDIT3	RAI1	psi-mi:“MI:0915”(physical association)	0.370
GATA1	RAI1	psi-mi:“MI:0915”(physical association)	0.370
GLI1	RAI1	psi-mi:“MI:0915”(physical association)	0.370
LZTR1	RAI1	psi-mi:“MI:0915”(physical association)	0.370
RAI1	MAML3	psi-mi:“MI:0915”(physical association)	0.370
RAI1	ZNF496	psi-mi:“MI:0915”(physical association)	0.370
RAI1	CASP2	psi-mi:“MI:0915”(physical association)	0.370
RAI1	CDKN1A	psi-mi:“MI:0915”(physical association)	0.370
RAI1	GADD45A	psi-mi:“MI:0915”(physical association)	0.370
GSK3B	RAI1	psi-mi:“MI:0915”(physical association)	0.370
RAI1	MAPK8IP2	psi-mi:“MI:0915”(physical association)	0.370
RAI1	RPS6KA5	psi-mi:“MI:0915”(physical association)	0.370
TTR	RAI1	psi-mi:“MI:0915”(physical association)	0.370
RAI1	TESC	psi-mi:“MI:0915”(physical association)	0.370
Cbx1		psi-mi:“MI:0914”(association)	0.350
CDK2AP1	MTA3	psi-mi:“MI:0914”(association)	0.350
TCF20	MTA3	psi-mi:“MI:0914”(association)	0.350
DAXX	MACF1	psi-mi:“MI:0914”(association)	0.350
Mta1	MTA3	psi-mi:“MI:0914”(association)	0.350
MAPT	SHTN1	psi-mi:“MI:0914”(association)	0.350

BioGRID (143): RAI1 (Two-hybrid), RAI1 (Two-hybrid), TESC (Two-hybrid), RAI1 (Proximity Label-MS), RAI1 (Affinity Capture-MS), RAI1 (Affinity Capture-MS), RAI1 (Affinity Capture-MS), RAI1 (Affinity Capture-MS), RAI1 (Affinity Capture-MS), RAI1 (Affinity Capture-MS), RAI1 (Affinity Capture-MS), RAI1 (Proximity Label-MS), RAI1 (Proximity Label-MS), RAI1 (Affinity Capture-RNA), RAI1 (Affinity Capture-MS)

ESM2 similar proteins: A2VDR9, A5PKG8, A6NMT0, A7MB40, A8MUI8, E2R9X2, O00257, O15353, O43151, O55187, P19419, P30658, P48382, P52950, P59598, Q03989, Q0GGX2, Q13029, Q14781, Q28BT7, Q2MHN3, Q32MQ0, Q32N19, Q3SWY1, Q3TEI4, Q3U108, Q3UHR0, Q497V6, Q568E2, Q571I4, Q5JPB2, Q5NSW5, Q5TGY3, Q61818, Q6PAL7, Q6ZRI6, Q7TSH3, Q7Z5J4, Q811R2, Q86YN6

Diamond homologs: A6H5X4, F4I443, Q08DR0, Q2HJ93, Q4R9C4, Q5F4A1, Q5I0E2, Q5I0J8, Q5R5Z2, Q5RJY2, Q61818, Q6AXW4, Q7L622, Q7Z5J4, Q8BVM9, Q8IWS0, Q9BWX1, Q9D4J7, Q9DAG9, Q9UIL8, O14686, Q6PDK2, Q9EPQ8, Q9UGU0, Q9VKW2, Q6AWG9, Q8BRH4, Q8IRW8, Q8NEZ4, O08550, P20659, P55200, Q03164, Q24742, Q9UMN6

SIGNOR signaling

6 interactions.

A	Effect	B	Mechanism
RAI1	“up-regulates quantity by expression”	CLOCK	“transcriptional regulation”
RAI1	“up-regulates quantity by expression”	PER2	“transcriptional regulation”
RAI1	“up-regulates quantity by expression”	PER3	“transcriptional regulation”
RAI1	“up-regulates quantity by expression”	CRY1	“transcriptional regulation”
RAI1	“up-regulates quantity by expression”	ARNTL	“transcriptional regulation”
RAI1	“up-regulates quantity by expression”	CLOCK/BMAL1	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 80 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Regulation of PTEN gene transcription	7	21.5×	3e-06
NuRD complex assembly	8	19.4×	3e-06
ERCC6 (CSB) and EHMT2 (G9a) positively regulate rRNA expression	7	18.4×	9e-06
Interaction of NuRD complexes with transcription factors	8	17.5×	3e-06
HDACs deacetylate histones	8	16.6×	3e-06
Negative Regulation of CDH1 Gene Transcription	8	16.6×	3e-06
Regulation of endogenous retroelements by Piwi-interacting RNAs (piRNAs)	7	14.2×	4e-05
Deposition of new CENPA-containing nucleosomes at the centromere	5	13.7×	2e-03

GO biological processes:

GO term	Partners	Fold	FDR
heterochromatin formation	5	17.2×	1e-03
nucleosome assembly	8	15.2×	2e-05
chromatin remodeling	11	10.8×	3e-06
chromatin organization	6	8.0×	6e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

2752 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	126
Likely pathogenic	63
Uncertain significance	1062
Likely benign	856
Benign	217

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1047930	NM_030665.4(RAI1):c.3179_3180del (p.Leu1060fs)	Pathogenic
1098289	NM_030665.4(RAI1):c.4525del (p.Gln1509fs)	Pathogenic
11623	NM_004595.5(SMS):c.329+5G>A	Pathogenic
11624	NM_004595.5(SMS):c.166G>A (p.Gly56Ser)	Pathogenic
11625	NM_004595.5(SMS):c.395T>G (p.Val132Gly)	Pathogenic
1184907	NM_030665.4(RAI1):c.2223_2224dup (p.Asn742fs)	Pathogenic
1184965	NM_030665.4(RAI1):c.868C>T (p.Gln290Ter)	Pathogenic
1327891	NM_030665.4(RAI1):c.860_861del (p.Gln287fs)	Pathogenic
1330239	NM_030665.4(RAI1):c.4271del (p.Phe1424fs)	Pathogenic
143197	NM_030665.4(RAI1):c.2273G>A (p.Trp758Ter)	Pathogenic
1459297	NM_030665.4(RAI1):c.3265C>T (p.Arg1089Ter)	Pathogenic
167561	NM_030665.4(RAI1):c.3583A>T (p.Lys1195Ter)	Pathogenic
167563	NM_030665.4(RAI1):c.4678C>T (p.Arg1560Ter)	Pathogenic
1701312	NM_030665.4(RAI1):c.837_841delinsAT (p.Gln280_Gln281delinsTer)	Pathogenic
1709995	NM_030665.4(RAI1):c.1785dup (p.Arg596fs)	Pathogenic
1711431	NM_030665.4(RAI1):c.2386dup (p.Glu796fs)	Pathogenic
1711432	NM_030665.4(RAI1):c.3257dup (p.Lys1087fs)	Pathogenic
1800921	NM_030665.4(RAI1):c.1692_1693del (p.Met564fs)	Pathogenic
1802191	NM_030665.4(RAI1):c.848_851del (p.Gln283fs)	Pathogenic
1804465	NM_030665.4(RAI1):c.238C>T (p.Arg80Ter)	Pathogenic
1805893	NM_030665.4(RAI1):c.4317dup (p.Thr1440fs)	Pathogenic
196540	NM_030665.4(RAI1):c.3281C>A (p.Ser1094Ter)	Pathogenic
2026432	NM_030665.4(RAI1):c.1002del (p.Tyr335fs)	Pathogenic
2026770	NM_030665.4(RAI1):c.2229del (p.Phe744fs)	Pathogenic
2035807	NM_030665.4(RAI1):c.5145_5146del (p.Lys1716fs)	Pathogenic
2069660	NM_030665.4(RAI1):c.2875dup (p.Glu959fs)	Pathogenic
2116319	NM_030665.4(RAI1):c.466C>T (p.Gln156Ter)	Pathogenic
2134698	NM_030665.4(RAI1):c.4801del (p.Val1601fs)	Pathogenic
2252832	NM_030665.4(RAI1):c.3937dup (p.Ala1313fs)	Pathogenic
235845	NM_030665.4(RAI1):c.2332_2336del (p.Gly778fs)	Pathogenic

SpliceAI

0 predictions. Top by Δscore:

AlphaMissense

12330 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:17798007:T:C	C1687R	1.000
17:17798009:C:G	C1687W	1.000
17:17794294:T:A	V449D	0.999
17:17796939:G:C	A1331P	0.999
17:17796943:T:A	I1332N	0.999
17:17796955:T:C	I1336T	0.999
17:17798008:G:A	C1687Y	0.999
17:17798016:T:C	C1690R	0.999
17:17798018:C:G	C1690W	0.999
17:17798058:G:A	G1704R	0.999
17:17798058:G:C	G1704R	0.999
17:17798058:G:T	G1704W	0.999
17:17798059:G:A	G1704E	0.999
17:17798064:T:G	Y1706D	0.999
17:17798430:T:C	C1828R	0.999
17:17798431:G:A	C1828Y	0.999
17:17798432:T:G	C1828W	0.999
17:17809425:T:C	C1899R	0.999
17:17792958:T:C	F4L	0.998
17:17792960:T:A	F4L	0.998
17:17792960:T:G	F4L	0.998
17:17794261:T:C	L438P	0.998
17:17796924:G:C	G1326R	0.998
17:17796925:G:A	G1326D	0.998
17:17796930:A:G	K1328E	0.998
17:17796932:G:C	K1328N	0.998
17:17796932:G:T	K1328N	0.998
17:17796934:T:C	L1329P	0.998
17:17796937:A:T	E1330V	0.998
17:17796955:T:G	I1336S	0.998

dbSNP variants (sampled 300 via entrez): RS1000014021 (17:17737008 T>C), RS1000066389 (17:17736457 G>A), RS1000137879 (17:17742910 G>A), RS1000147080 (17:17764748 G>A,C), RS1000147268 (17:17796750 A>G), RS1000151503 (17:17704353 G>C), RS1000153450 (17:17783270 C>G,T), RS1000157491 (17:17713078 C>T), RS1000209559 (17:17712695 C>G,T), RS1000229193 (17:17721141 A>C), RS1000235532 (17:17679647 C>T), RS1000241863 (17:17742829 C>A), RS1000278919 (17:17798237 G>A,T), RS1000296739 (17:17748633 T>C), RS1000316878 (17:17718908 C>T)

Disease associations

OMIM: gene MIM:607642 | disease phenotypes: MIM:309583, MIM:182290, MIM:610883, MIM:616652, MIM:601071

GenCC curated gene-disease

Disease	Classification	Inheritance
Smith-Magenis syndrome	Definitive	Autosomal dominant
syndromic X-linked intellectual disability Snyder type	Strong	X-linked
Potocki-Lupski syndrome	Moderate	Autosomal dominant

ClinGen Gene-Disease Validity (2)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
Smith-Magenis syndrome	Definitive	AD
syndromic X-linked intellectual disability Snyder type	Definitive	XL

Mondo (9): syndromic X-linked intellectual disability Snyder type (MONDO:0010664), Smith-Magenis syndrome (MONDO:0008434), vascular disorder (MONDO:0005385), intellectual disability (MONDO:0001071), Potocki-Lupski syndrome (MONDO:0012574), PMP22-RAI1 contiguous gene duplication syndrome (MONDO:0014723), autosomal recessive nonsyndromic hearing loss 9 (MONDO:0010986), neurodevelopmental disorder (MONDO:0700092), syndromic intellectual disability (MONDO:0000508)

Orphanet (8): X-linked intellectual disability, Snyder type (Orphanet:3063), Smith-Magenis syndrome (Orphanet:819), 17p11.2 microduplication syndrome (Orphanet:1713), PMP22-RAI1 contiguous gene duplication syndrome (Orphanet:477817), Rare autosomal recessive non-syndromic sensorineural deafness type DFNB (Orphanet:90636), Rare genetic syndromic intellectual disability (Orphanet:183763), Rare genetic intellectual disability (Orphanet:183757), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

92 total (30 of 92 shown, HPO-id order):

HPO	Term
HP:0000028	Cryptorchidism
HP:0000029	Testicular atrophy
HP:0000047	Hypospadias
HP:0000086	Ectopic kidney
HP:0000098	Tall stature
HP:0000160	Narrow mouth
HP:0000175	Cleft palate
HP:0000179	Thick lower lip vermilion
HP:0000193	Bifid uvula
HP:0000218	High palate
HP:0000232	Everted lower lip vermilion
HP:0000248	Brachycephaly
HP:0000275	Narrow face
HP:0000276	Long face
HP:0000303	Mandibular prognathia
HP:0000316	Hypertelorism
HP:0000319	Smooth philtrum
HP:0000322	Short philtrum
HP:0000324	Facial asymmetry
HP:0000369	Low-set ears
HP:0000377	Abnormal pinna morphology
HP:0000378	Cupped ear
HP:0000385	Small earlobe
HP:0000391	Thickened helices
HP:0000414	Bulbous nose
HP:0000426	Prominent nasal bridge
HP:0000463	Anteverted nares
HP:0000465	Webbed neck
HP:0000470	Short neck
HP:0000508	Ptosis

GWAS associations

48 associations (top):

Study	Trait	p-value
GCST001126_7	Parkinson’s disease	6.000000e-08
GCST002287_3	Coronary artery disease or ischemic stroke	2.000000e-08
GCST002289_7	Coronary artery disease	2.000000e-07
GCST002290_12	Coronary artery disease or large artery stroke	2.000000e-10
GCST002539_86	Schizophrenia	2.000000e-08
GCST004066_130	Hip circumference	8.000000e-06
GCST004066_52	Hip circumference	3.000000e-08
GCST004627_169	Lymphocyte count	1.000000e-12
GCST004787_65	Coronary artery disease (myocardial infarction, percutaneous transluminal coronary angioplasty, coronary artery bypass grafting, angina or chromic ischemic heart disease)	3.000000e-06
GCST004904_188	Body mass index	3.000000e-08
GCST004946_149	Schizophrenia	7.000000e-10
GCST006269_1044	General cognitive ability	2.000000e-08
GCST006803_40	Schizophrenia	3.000000e-08
GCST006867_137	Type 2 diabetes	2.000000e-09
GCST008363_128	Offspring birth weight	8.000000e-09
GCST008745_17	Estimated glomerular filtration rate in non-diabetics	4.000000e-11
GCST008747_64	Estimated glomerular filtration rate	6.000000e-10
GCST008747_84	Estimated glomerular filtration rate	2.000000e-08
GCST009379_178	Type 2 diabetes	3.000000e-12
GCST010204_65	Low density lipoprotein cholesterol levels	6.000000e-09
GCST010796_1895	Electrocardiogram morphology (amplitude at temporal datapoints)	4.000000e-09
GCST010796_1896	Electrocardiogram morphology (amplitude at temporal datapoints)	3.000000e-08
GCST010796_1897	Electrocardiogram morphology (amplitude at temporal datapoints)	1.000000e-08
GCST010796_1898	Electrocardiogram morphology (amplitude at temporal datapoints)	9.000000e-09
GCST010796_1899	Electrocardiogram morphology (amplitude at temporal datapoints)	4.000000e-08
GCST010796_1900	Electrocardiogram morphology (amplitude at temporal datapoints)	3.000000e-08
GCST010796_2651	Electrocardiogram morphology (amplitude at temporal datapoints)	2.000000e-08
GCST010796_2652	Electrocardiogram morphology (amplitude at temporal datapoints)	3.000000e-08
GCST011125_24	Caffeine consumption from coffee	1.000000e-10
GCST012228_519	Waist-hip index	6.000000e-10

EFO canonical traits (12, from GWAS)

EFO ID	Trait name
EFO:0004587	lymphocyte count
EFO:0004340	body mass index
EFO:0004337	intelligence
EFO:0004344	birth weight
EFO:0005939	parental genotype effect measurement
EFO:0004611	low density lipoprotein cholesterol measurement
EFO:0004327	electrocardiography
EFO:0006781	coffee consumption measurement
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0008039	BMI-adjusted hip circumference
EFO:0005091	monocyte count
EFO:0007789	BMI-adjusted waist circumference

MeSH disease descriptors (5)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D065886	Neurodevelopmental Disorders	F03.625
D058496	Smith-Magenis Syndrome	C10.281.900; C16.131.077.879; C16.131.260.887; C16.320.180.887
D014652	Vascular Diseases	C14.907
C536678	Snyder Robinson syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

47 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression, increases methylation	4
Benzo(a)pyrene	decreases methylation, affects methylation, decreases expression	2
Estradiol	affects cotreatment, increases expression	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	affects expression, decreases expression	2
aristolochic acid I	decreases expression	1
FR900359	affects phosphorylation	1
bisphenol F	affects cotreatment, decreases expression	1
TAK-243	decreases sumoylation	1
dicrotophos	increases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	decreases methylation	1
sodium arsenate	increases abundance, increases expression	1
trichostatin A	decreases expression	1
sodium arsenite	increases expression	1
butyraldehyde	decreases expression	1
coumarin	affects phosphorylation	1
beta-methylcholine	affects expression	1
di-n-butylphosphoric acid	affects expression	1
tebuconazole	decreases expression	1
CGP 52608	affects binding, increases reaction	1
2-palmitoylglycerol	increases expression	1
bisphenol S	decreases methylation	1
Sunitinib	increases expression	1
Acetaminophen	decreases expression	1
Arsenic	increases abundance, increases expression	1
Caffeine	affects phosphorylation	1
Coumestrol	decreases expression	1
Dexamethasone	affects cotreatment, decreases expression	1
Doxorubicin	decreases expression	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1

Cellosaurus cell lines

8 cell lines: 6 transformed cell line, 2 induced pluripotent stem cell

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_5K20	GM20734	Transformed cell line	Female
CVCL_5K21	GM20735	Transformed cell line	Female
CVCL_5K22	GM20742	Transformed cell line	Male
CVCL_5K24	GM22766	Transformed cell line	Female
CVCL_5K25	GM22767	Transformed cell line	Female
CVCL_E3U3	CSSi020-A	Induced pluripotent stem cell	Female
CVCL_VD30	CSSi003-A	Induced pluripotent stem cell	Female
CVCL_VJ12	GM25401	Transformed cell line	Male

Clinical trials (associated diseases)

230 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT06457906	PHASE3	RECRUITING	SRS/SRT/Hypo-RT Versus HA-WBRT for No More Than 10 Brain Metastases in SCLC
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT04180501	PHASE2	UNKNOWN	SRS Sequential Sindilimab in Brain Metastasis of NSLSC
NCT04899908	PHASE2	ACTIVE_NOT_RECRUITING	Stereotactic Brain-directed Radiation With or Without Aguix Gadolinium-Based Nanoparticles in Brain Metastases
NCT07162246	PHASE2	RECRUITING	Combined Gamma Knife/Linac Radiosurgery for Large Brain Tumors / Metastases
NCT03537742	PHASE2	COMPLETED	Cardiac Allograft Vasculopathy Inhibition With Alirocumab
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT02776215	PHASE1	COMPLETED	Study of the Pharmacokinetics and Safety of Tasimelteon in Children and Adolescents
NCT07075185	PHASE1	RECRUITING	A Study to Evaluate a Novel Gene Therapy in Patients With Relapsed and Refractory Multiple Myeloma
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT02231008	PHASE2/PHASE3	COMPLETED	Evaluating the Effects of Tasimelteon vs Placebo on Sleep Disturbances in SMS
NCT00004351	Not specified	COMPLETED	Study of Phenotype and Genotype Correlations in Patients With Contiguous Gene Deletion Syndromes
NCT00013559	Not specified	ACTIVE_NOT_RECRUITING	Natural History Study of Smith-Magenis Syndrome
NCT01837121	Not specified	COMPLETED	a Trial of Using SMS Reminder Among Diabetic Retinopathy Patients in Rural China
NCT02180451	Not specified	UNKNOWN	Observational Study to Investigate the Melatonin and Cortisol Circadian Rhythms of Individuals With Smith-Magenis Syndrome (SMS)
NCT02400671	Not specified	COMPLETED	Mobile Strategies for Women’s and Children’s Health: Optimizing Adherence and Efficacy of PMTCT/ART
NCT03346616	Not specified	COMPLETED	Text4Peds: Short Message Service Evaluating Medical Student Education
NCT03379467	Not specified	COMPLETED	Use of SMS and Interactive Reminders to Improve Timely Immunization Coverage
NCT03492970	Not specified	COMPLETED	Melatonin in Adults With SMS
NCT03836300	Not specified	ENROLLING_BY_INVITATION	Parent and Infant Inter(X)Action Intervention (PIXI)
NCT04768803	Not specified	UNKNOWN	Ghrelin in Patients With a Rare Disease Associated With Intellectual Disability, and Hyperphagia, and/or Overweight, and/or Obesity
NCT05116904	Not specified	RECRUITING	Smith Magenis Syndrome and Autism Spectrum Disorders
NCT06247852	Not specified	COMPLETED	Persistent Pain After Cesarean Delivery - A Danish Multicenter Cohort Study
NCT07510971	Not specified	NOT_YET_RECRUITING	mHealth Intervention for Improving Vaccination Coverage in Bangladesh
NCT03915106	Not specified	RECRUITING	Quality of Life (HRQoL) of AIS Patients Who Require Bracing or Surgery Using SRS-22 Questionnaire
NCT06466720	Not specified	ACTIVE_NOT_RECRUITING	Measuring and Mapping Cognitive Decline After Brain Radiosurgery
NCT06852001	Not specified	NOT_YET_RECRUITING	Efficacy of the RayerKnife X Stereotactic Radiotherapy System in the Treatment of Brain Metastases
NCT07405112	Not specified	COMPLETED	Impact of Curve Magnitude on Pain and Body Image in Patients With Adolescents Idiopathic Scoliosis
NCT00384540	Not specified	COMPLETED	Cardiac Allograft Vasculopathy and Dobutamine Stress Echocardiography / Brain Natriuretic Peptide Coupling