RARA

Summary

RARA (retinoic acid receptor alpha, HGNC:9864) is a protein-coding gene on chromosome 17q21.2, encoding Retinoic acid receptor alpha (P10276). Receptor for retinoic acid.

This gene represents a nuclear retinoic acid receptor. The encoded protein, retinoic acid receptor alpha, regulates transcription in a ligand-dependent manner. This gene has been implicated in regulation of development, differentiation, apoptosis, granulopoeisis, and transcription of clock genes. Translocations between this locus and several other loci have been associated with acute promyelocytic leukemia. Alternatively spliced transcript variants have been found for this locus.

Source: NCBI Gene 5914 — RefSeq curated summary.

At a glance

• Gene–disease (curated): craniosynostosis (Moderate, GenCC) — +2 more curated relationships
• GWAS associations: 1
• Clinical variants (ClinVar): 67 total
• Phenotypes (HPO): 39
• Druggable target: yes — 11 molecules with ChEMBL bioactivity
• Transcription factor: yes — 207 downstream targets (CollecTRI)
• MANE Select transcript: NM_000964

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9864
Approved symbol	RARA
Name	retinoic acid receptor alpha
Location	17q21.2
Locus type	gene with protein product
Status	Approved
Aliases	RAR, NR1B1, RARalpha, RAR-alpha
Ensembl gene	ENSG00000131759
Ensembl biotype	protein_coding
OMIM	180240
Entrez	5914

Gene structure

Transcript identifiers

Ensembl transcripts: 22 — 19 protein_coding, 3 protein_coding_CDS_not_defined

ENST00000254066, ENST00000394081, ENST00000394086, ENST00000394089, ENST00000420042, ENST00000425707, ENST00000475125, ENST00000577646, ENST00000579727, ENST00000582914, ENST00000857081, ENST00000857082, ENST00000857083, ENST00000857084, ENST00000857085, ENST00000857086, ENST00000857087, ENST00000857088, ENST00000857089, ENST00000920590, ENST00000920591, ENST00000951717

RefSeq mRNA: 4 — MANE Select: NM_000964 NM_000964, NM_001024809, NM_001145301, NM_001145302

CCDS: CCDS11366, CCDS42317, CCDS45671

Canonical transcript exons

ENST00000254066 — 9 exons

Exon	Start	End
ENSE00001422265	40330857	40331396
ENSE00002686208	40309180	40309286
ENSE00002732713	40356009	40357643
ENSE00003517181	40349784	40349925
ENSE00003521579	40354302	40354506
ENSE00003521943	40348316	40348464
ENSE00003536421	40352331	40352507
ENSE00003550692	40355263	40355421
ENSE00003634582	40351910	40352070

Expression profiles

Bgee: expression breadth ubiquitous, 276 present calls, max score 96.16.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 58.2925 / max 1452.2315, expressed in 1822 samples.

FANTOM5 promoters (18 alternative TSS)

Promoter ID	TPM avg	Samples expressed
160712	41.3712	1815
160734	4.6622	1146
160736	4.4283	1055
160730	2.0129	266
160709	1.7474	697
160710	1.0930	513
160735	0.5053	289
160731	0.4863	113
160739	0.4857	232
160727	0.3463	178

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
mammary duct	UBERON:0001765	96.16	gold quality
monocyte	CL:0000576	95.47	gold quality
granulocyte	CL:0000094	95.21	gold quality
leukocyte	CL:0000738	94.99	gold quality
mononuclear cell	CL:0000842	94.93	gold quality
blood	UBERON:0000178	94.63	gold quality
gall bladder	UBERON:0002110	94.58	gold quality
right lung	UBERON:0002167	94.35	gold quality
left uterine tube	UBERON:0001303	94.08	gold quality
upper lobe of left lung	UBERON:0008952	93.72	gold quality
epithelium of mammary gland	UBERON:0003244	93.28	gold quality
tibial artery	UBERON:0007610	93.22	gold quality
popliteal artery	UBERON:0002250	93.19	gold quality
endocervix	UBERON:0000458	93.00	gold quality
upper lobe of lung	UBERON:0008948	92.66	gold quality
right coronary artery	UBERON:0001625	92.63	gold quality
omental fat pad	UBERON:0010414	92.53	gold quality
peritoneum	UBERON:0002358	92.48	gold quality
aorta	UBERON:0000947	92.39	gold quality
descending thoracic aorta	UBERON:0002345	92.31	gold quality
gastrocnemius	UBERON:0001388	92.06	gold quality
right ovary	UBERON:0002118	91.90	gold quality
ascending aorta	UBERON:0001496	91.57	gold quality
thoracic aorta	UBERON:0001515	91.44	gold quality
ectocervix	UBERON:0012249	91.39	gold quality
left ovary	UBERON:0002119	91.35	gold quality
adipose tissue of abdominal region	UBERON:0007808	91.34	gold quality
right lobe of liver	UBERON:0001114	90.91	gold quality
hindlimb stylopod muscle	UBERON:0004252	90.89	gold quality
right atrium auricular region	UBERON:0006631	90.88	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	9.42

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

207 targets.

Target	Regulation
ABCA1	Unknown
ABCA12	Activation
ABCC2
ABCC3	Repression
ABCG1
ABCG2	Activation
ACACB	Repression
ACTG2	Repression
ADA
ADRB1
AKT1
ALDH1A1
ALDH2
ALOX5
ANXA8	Repression
AP1	Activation
APLN
APOA2
APOC3	Activation
APP	Repression
APRT
ASB2
BABAM2
BCL2
BHLHE40
BTG2	Unknown
CADM1
CALCA
CASP9	Unknown
CAT

JASPAR motifs

Motif	Name	Family
MA0159.1	RARA::RXRA	Thyroid hormone receptor-related factors (NR1)::RXR-related receptors (NR2)
MA0729.1	RARA	Thyroid hormone receptor-related factors (NR1)
MA0730.1	RARA	Thyroid hormone receptor-related factors (NR1)
MA1149.1	RARA::RXRG	Thyroid hormone receptor-related factors (NR1)::RXR-related receptors (NR2)
MA1149.2	RARA::RXRG	Thyroid hormone receptor-related factors (NR1)::RXR-related receptors (NR2)

JASPAR matrix evidence (PMIDs): PMID:17916232, PMID:15019979, PMID:10698945

Upstream regulators (CollecTRI, top): AP1, AR, ASXL1, BATF, CEBPB, CRABP2, CREBBP, CTNNBL1, ESR1, ESR2, ETV7, FLI1, HNF4A, JUN, KLF4, KLF5, MED25, MYC, NCOA1, NCOR2, NR1H3, NR5A1, RARA, RARB, RARG, RUNX2, SP1, SPI1, THRA, VDR, WT1, ZBTB16

miRNA regulators (miRDB)

106 targeting RARA, 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-6867-5P	100.00	82.21	3464
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-12118	100.00	65.88	1270
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-4650-5P	99.98	64.69	999
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-4487	99.96	64.58	1252
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-218-5P	99.93	72.22	2103
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-3681-3P	99.88	70.46	2254
HSA-MIR-12119	99.87	68.35	1653
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-4447	99.85	67.81	2900

Literature-anchored findings (GeneRIF, showing 40)

• two critical hits for promyelocytic leukemia (PMID:11106752)
• UBE1L is a retinoid target that triggers PML/RARalpha degradation and apoptosis in acute promyelocytic leukemia (PMID:11891284)
• Interactions of STAT5b-RARalpha, a novel acute promyelocytic leukemia fusion protein, with retinoic acid receptor and STAT3 signaling pathways. (PMID:11929748)
• Results show that both RARalpha and RARbeta are mediators in the anticancer function of All-trans retinoic acid via AP-1 activity inhibition. (PMID:12009305)
• induces acute promyelocytic leukemia in a mouse model (PMID:12060771)
• obesity is associated with an inverse relationship between peroxisome proliferator-activated receptor gamma and RARalpha expressions in subcutaneous adipose tissue (PMID:12080444)
• the silencing of the RAR alpha2 promoter by hypermethylation may play a contributory role in the dysregulation of RA signaling in mammary tumorigenesis. (PMID:12193472)
• Retinoid-induced G1 arrest and differentiation activation are associated with a switch to cyclin-dependent kinase-activating kinase hypophosphorylation of the receptor. (PMID:12213824)
• IL-3-induced enhancement of retinoic acid receptor activity is mediated through Stat5, which physically associates with recombinant human retinoic acid receptors in an IL-3-dependent manner. (PMID:12393611)
• In normal epithelium, both RAR-alpha and -gamma present with minimal nuclear accumulation. Increased in luminal epithelial nuclei in prostatic intra-epithelial neoplasia (PMID:12399530)
• RAR pan-agonists and the RARalpha-selective agonist Am580, but not RXR agonists, stimulate the expression of SOX9 in a wide variety of retinoid-inhibited breast cancer cell lines. (PMID:12420222)
• mutational analysis of human retinoic acid receptor alpha ligand binding domain (PMID:12468549)
• Cryptic translocation of PML/RARA on 17q. A rare event in acute promyelocytic leukemia. (PMID:12505266)
• endocrine molecule retinoic acid, and its receptor RARs play a critical role in alveolarization during the neonatal period of the lung. (PMID:12810556)
• REVIEW the biology of RARalpha, and the RARalpha fusion proteins created in APL and the normal forms of the partner proteins (PMID:12935958)
• data suggest that Sp110b is a transcriptional cofactor negatively regulating retinoic acid receptor alpha-mediated transcription (PMID:14559998)
• RARA has a distinct role and functional mode in mediating tretinoin-induced signalling. (PMID:14592536)
• In a 9-cis retinoic acid-dependent fashion in cells in vitro, retinoic acid receptor alpha isoform stimulates the expression of reporter constructs containing the site that binds aldehyde dehydrogenase-2. (PMID:14691372)
• depletion of vitamin A and retinoid receptors by UV irradiation, together with unchanged or even increased c-Jun levels, might seriously interfere with retinoid signaling and thus promote future tumor development, especially in keratinocytes. (PMID:14705796)
• role in development of myelodi leukemia with promyelocytic features (PMID:14737102)
• Results show an increased DNA binding of the retinoic acid receptor alpha/retinoid X receptor alpha heterodimer and the stability of nuclear localization of this heterodimer, which facilitates signal transduction. (PMID:15171703)
• intrinsic ageing of human skin is accompanied by significant elevation in the content of RAR alpha (PMID:15246741)
• Increase in expression of RARalpha is associated with esophageal squamous cell carcinomas (PMID:15255287)
• retinoic acid receptor-alpha is synthesized by activated polymorphonuclear leukocytes (PMID:15337793)
• PML-retinoic acid receptor alpha activities are regulated by neutrophil elastase in early myeloid cells (PMID:15601827)
• CDDO-Im downregulates RARA expression in acute promyelocytic leukemic cells. (PMID:15746941)
• inhibition of monocyte differentiation all contribute to the oncogenic activity of PML-RARalpha (PMID:15809060)
• analysis of estrogen activation of the retinoic acid receptor alpha1 gene in breast cancer cells (PMID:15831516)
• Transient transfection of either all-trans-retinoic acid (ATRA) receptor alpha or estrogen receptor alpha expression vectors increased cellular retinoic acid binding protein II expression in MDA-MB-231 cells (PMID:15870697)
• all-trans-retinoic acid, an RARalpha ligand, regulates IFNgamma-induced IRF-1 by affecting multiple components of the IFNgamma signaling pathway, from the plasma membrane to the nuclear transcription factors (PMID:16085646)
• loss of one copy of PU.1 through deletion, plus down-regulation of the residual allele caused by PML-RARalpha expression, synergizes to expand myeloid progenitors susceptible to transformation, increasing the penetrance of acute promyelocytic leukemia (PMID:16113082)
• p16INK4a, RARbeta, and MGMT expression is activated by genistein and related soy isoflavones partially through a direct inhibition of DNA methyltransferase (PMID:16203797)
• RARA is the first myeloid-specific transcription factor shown to be dysregulated by both translocation and aberrant methylation (PMID:16239915)
• All trans retinoic acid suppresses 24-hydroxylase expression through RARalpha-dependent signaling pathway and can enhance vitamin D action in suppression of cell growth. (PMID:16289102)
• protein kinase b interacts with RARalpha and phosphorylates the Ser96 residue of its DNA-binding domain. (PMID:16417524)
• Ski seems to be involved in the blocking of differentiation in AML via inhibition of RARalpha signaling (PMID:16424870)
• PML-RARalpha functions by recruiting an HDAC3-MBD1 complex that contributes to the establishment and maintenance of the silenced chromatin state (PMID:16432238)
• permanent transcriptional silencing is mediated by the association of PML-RAR with chromatin-modifying enzymes and by recruitment of the histone methyltransferase SUV39H1, responsible for trimethylation of lysine 9 of histone H3 (PMID:16449642)
• The aryl hydrocarbon receptor activates the retinoic acid receptoralpha through SMRT antagonism (PMID:16480812)
• The NPM-RAR localizes diffusely throughout the nucleoplasm. NPM-RAR does not alter the localization of PML in transfected HeLa cells, and does not associate with PML in vitro. (PMID:16504291)

Cross-species orthologs

185 orthologs

Organism	Symbol	Gene ID
mus_musculus	Rara	ENSMUSG00000037992
rattus_norvegicus	Rara	ENSRNOG00000009972
drosophila_melanogaster	EcR	FBGN0000546
drosophila_melanogaster	Hr96	FBGN0015240
caenorhabditis_elegans		WBGENE00001062
caenorhabditis_elegans	nhr-2	WBGENE00003601
caenorhabditis_elegans		WBGENE00003608
caenorhabditis_elegans		WBGENE00003611
caenorhabditis_elegans		WBGENE00003614
caenorhabditis_elegans		WBGENE00003615
caenorhabditis_elegans		WBGENE00003617
caenorhabditis_elegans		WBGENE00003618
caenorhabditis_elegans		WBGENE00003620
caenorhabditis_elegans		WBGENE00003624
caenorhabditis_elegans		WBGENE00003632
caenorhabditis_elegans		WBGENE00003634
caenorhabditis_elegans		WBGENE00003638
caenorhabditis_elegans		WBGENE00003640
caenorhabditis_elegans		WBGENE00003641
caenorhabditis_elegans		WBGENE00003642
caenorhabditis_elegans		WBGENE00003643
caenorhabditis_elegans		WBGENE00003644
caenorhabditis_elegans		WBGENE00003645
caenorhabditis_elegans		WBGENE00003646
caenorhabditis_elegans		WBGENE00003648
caenorhabditis_elegans		WBGENE00003649
caenorhabditis_elegans		WBGENE00003651
caenorhabditis_elegans		WBGENE00003653
caenorhabditis_elegans		WBGENE00003655
caenorhabditis_elegans		WBGENE00003658
caenorhabditis_elegans		WBGENE00003660
caenorhabditis_elegans		WBGENE00003662
caenorhabditis_elegans	nhr-73	WBGENE00003663
caenorhabditis_elegans	nhr-77	WBGENE00003667
caenorhabditis_elegans		WBGENE00003669
caenorhabditis_elegans	nhr-81	WBGENE00003671
caenorhabditis_elegans	nhr-82	WBGENE00003672
caenorhabditis_elegans		WBGENE00003676
caenorhabditis_elegans		WBGENE00003677
caenorhabditis_elegans		WBGENE00003680
caenorhabditis_elegans		WBGENE00003682
caenorhabditis_elegans		WBGENE00003684
caenorhabditis_elegans		WBGENE00003685
caenorhabditis_elegans		WBGENE00003686
caenorhabditis_elegans		WBGENE00003688
caenorhabditis_elegans		WBGENE00003689
caenorhabditis_elegans		WBGENE00003692
caenorhabditis_elegans		WBGENE00003693
caenorhabditis_elegans		WBGENE00003694
caenorhabditis_elegans		WBGENE00003696
caenorhabditis_elegans		WBGENE00003698
caenorhabditis_elegans		WBGENE00003699
caenorhabditis_elegans		WBGENE00003700
caenorhabditis_elegans		WBGENE00003702
caenorhabditis_elegans		WBGENE00003704
caenorhabditis_elegans		WBGENE00003705
caenorhabditis_elegans		WBGENE00003707
caenorhabditis_elegans		WBGENE00003708
caenorhabditis_elegans		WBGENE00003712
caenorhabditis_elegans		WBGENE00003713
caenorhabditis_elegans		WBGENE00003714
caenorhabditis_elegans		WBGENE00003715
caenorhabditis_elegans		WBGENE00003716
caenorhabditis_elegans		WBGENE00003717
caenorhabditis_elegans		WBGENE00003718
caenorhabditis_elegans		WBGENE00003720
caenorhabditis_elegans		WBGENE00003721
caenorhabditis_elegans		WBGENE00003722
caenorhabditis_elegans		WBGENE00003723
caenorhabditis_elegans		WBGENE00003724
caenorhabditis_elegans		WBGENE00003725
caenorhabditis_elegans		WBGENE00003728
caenorhabditis_elegans		WBGENE00006471
caenorhabditis_elegans	unc-55	WBGENE00006790
caenorhabditis_elegans		WBGENE00007367
caenorhabditis_elegans		WBGENE00008056
caenorhabditis_elegans	nhr-165	WBGENE00008158
caenorhabditis_elegans		WBGENE00008208
caenorhabditis_elegans	nhr-169	WBGENE00008289
caenorhabditis_elegans		WBGENE00008309
caenorhabditis_elegans	nhr-174	WBGENE00008474
caenorhabditis_elegans		WBGENE00008619
caenorhabditis_elegans		WBGENE00008630
caenorhabditis_elegans		WBGENE00008778
caenorhabditis_elegans		WBGENE00008830
caenorhabditis_elegans		WBGENE00008884
caenorhabditis_elegans		WBGENE00008901
caenorhabditis_elegans	nhr-265	WBGENE00009608
caenorhabditis_elegans		WBGENE00010017
caenorhabditis_elegans		WBGENE00010180
caenorhabditis_elegans		WBGENE00010186
caenorhabditis_elegans		WBGENE00010215
caenorhabditis_elegans		WBGENE00010410
caenorhabditis_elegans		WBGENE00010600
caenorhabditis_elegans		WBGENE00010601
caenorhabditis_elegans		WBGENE00010602
caenorhabditis_elegans		WBGENE00010603
caenorhabditis_elegans		WBGENE00010604
caenorhabditis_elegans		WBGENE00011002
caenorhabditis_elegans		WBGENE00011150
caenorhabditis_elegans		WBGENE00011396
caenorhabditis_elegans		WBGENE00011520
caenorhabditis_elegans		WBGENE00011565
caenorhabditis_elegans		WBGENE00011566
caenorhabditis_elegans		WBGENE00011568
caenorhabditis_elegans	nhr-217	WBGENE00011651
caenorhabditis_elegans		WBGENE00011750
caenorhabditis_elegans		WBGENE00012050
caenorhabditis_elegans		WBGENE00012056
caenorhabditis_elegans		WBGENE00012446
caenorhabditis_elegans		WBGENE00012449
caenorhabditis_elegans		WBGENE00012596
caenorhabditis_elegans		WBGENE00012703
caenorhabditis_elegans		WBGENE00013067
caenorhabditis_elegans		WBGENE00013483
caenorhabditis_elegans	nhr-276	WBGENE00013512
caenorhabditis_elegans		WBGENE00013584
caenorhabditis_elegans		WBGENE00013940
caenorhabditis_elegans		WBGENE00014068
caenorhabditis_elegans	nhr-245	WBGENE00014189
caenorhabditis_elegans		WBGENE00014193
caenorhabditis_elegans		WBGENE00015497
caenorhabditis_elegans		WBGENE00015758
caenorhabditis_elegans		WBGENE00015897
caenorhabditis_elegans		WBGENE00015900
caenorhabditis_elegans		WBGENE00015901
caenorhabditis_elegans		WBGENE00015902
caenorhabditis_elegans		WBGENE00016091
caenorhabditis_elegans		WBGENE00016233
caenorhabditis_elegans		WBGENE00016364
caenorhabditis_elegans		WBGENE00016365
caenorhabditis_elegans		WBGENE00016366
caenorhabditis_elegans		WBGENE00016367
caenorhabditis_elegans		WBGENE00016368
caenorhabditis_elegans		WBGENE00016517
caenorhabditis_elegans		WBGENE00016772
caenorhabditis_elegans		WBGENE00016926
caenorhabditis_elegans		WBGENE00016927
caenorhabditis_elegans		WBGENE00017503
caenorhabditis_elegans		WBGENE00017512
caenorhabditis_elegans		WBGENE00017961
caenorhabditis_elegans		WBGENE00018189
caenorhabditis_elegans		WBGENE00018265
caenorhabditis_elegans		WBGENE00018266
caenorhabditis_elegans		WBGENE00018404
caenorhabditis_elegans		WBGENE00018412
caenorhabditis_elegans		WBGENE00018415
caenorhabditis_elegans		WBGENE00018539
caenorhabditis_elegans		WBGENE00018541
caenorhabditis_elegans		WBGENE00018542
caenorhabditis_elegans		WBGENE00018544
caenorhabditis_elegans		WBGENE00018545
caenorhabditis_elegans		WBGENE00018622
caenorhabditis_elegans		WBGENE00019115
caenorhabditis_elegans		WBGENE00019116
caenorhabditis_elegans		WBGENE00019741
caenorhabditis_elegans		WBGENE00019742
caenorhabditis_elegans		WBGENE00019743
caenorhabditis_elegans		WBGENE00020015
caenorhabditis_elegans		WBGENE00020062
caenorhabditis_elegans		WBGENE00020152
caenorhabditis_elegans		WBGENE00020153
caenorhabditis_elegans		WBGENE00020385
caenorhabditis_elegans		WBGENE00020460
caenorhabditis_elegans		WBGENE00020555
caenorhabditis_elegans		WBGENE00020750
caenorhabditis_elegans		WBGENE00020849
caenorhabditis_elegans		WBGENE00020850
caenorhabditis_elegans		WBGENE00020851
caenorhabditis_elegans		WBGENE00020852
caenorhabditis_elegans		WBGENE00021163
caenorhabditis_elegans		WBGENE00021522
caenorhabditis_elegans		WBGENE00021610
caenorhabditis_elegans		WBGENE00021611
caenorhabditis_elegans		WBGENE00021617
caenorhabditis_elegans		WBGENE00022097
caenorhabditis_elegans		WBGENE00022637
caenorhabditis_elegans		WBGENE00022639
caenorhabditis_elegans		WBGENE00022640
caenorhabditis_elegans		WBGENE00022726
caenorhabditis_elegans		WBGENE00022756
caenorhabditis_elegans		WBGENE00022805
caenorhabditis_elegans		WBGENE00044353
caenorhabditis_elegans		WBGENE00044699
caenorhabditis_elegans		WBGENE00045515

Paralogs (18): NR1H4 (ENSG00000012504), NR1H3 (ENSG00000025434), RORA (ENSG00000069667), RARB (ENSG00000077092), VDR (ENSG00000111424), PPARD (ENSG00000112033), THRA (ENSG00000126351), NR1D1 (ENSG00000126368), NR1H2 (ENSG00000131408), PPARG (ENSG00000132170), NR1I3 (ENSG00000143257), RORC (ENSG00000143365), NR1I2 (ENSG00000144852), THRB (ENSG00000151090), RARG (ENSG00000172819), NR1D2 (ENSG00000174738), PPARA (ENSG00000186951), RORB (ENSG00000198963)

Protein

Protein identifiers

Retinoic acid receptor alpha — P10276 (reviewed: P10276)

Alternative names: Nuclear receptor subfamily 1 group B member 1

All UniProt accessions (6): A8MUP8, P10276, F1D8N9, J3KSJ4, J3QRM2, Q6I9R7

UniProt curated annotations — full annotation on UniProt →

Function. Receptor for retinoic acid. Retinoic acid receptors bind as heterodimers to their target response elements in response to their ligands, all-trans or 9-cis retinoic acid, and regulate gene expression in various biological processes. The RXR/RAR heterodimers bind to the retinoic acid response elements (RARE) composed of tandem 5’-AGGTCA-3’ sites known as DR1-DR5. In the absence of ligand, the RXR-RAR heterodimers associate with a multiprotein complex containing transcription corepressors that induce histone deacetylation, chromatin condensation and transcriptional suppression. On ligand binding, the corepressors dissociate from the receptors and associate with the coactivators leading to transcriptional activation. Formation of a complex with histone deacetylases might lead to inhibition of RARE DNA element binding and to transcriptional repression. Transcriptional activation and RARE DNA element binding might be supported by the transcription factor KLF2. RARA plays an essential role in the regulation of retinoic acid-induced germ cell development during spermatogenesis. Has a role in the survival of early spermatocytes at the beginning prophase of meiosis. In Sertoli cells, may promote the survival and development of early meiotic prophase spermatocytes. In concert with RARG, required for skeletal growth, matrix homeostasis and growth plate function. Together with RXRA, positively regulates microRNA-10a expression, thereby inhibiting the GATA6/VCAM1 signaling response to pulsatile shear stress in vascular endothelial cells. In association with HDAC3, HDAC5 and HDAC7 corepressors, plays a role in the repression of microRNA-10a and thereby promotes the inflammatory response.

Subunit / interactions. Heterodimer; with RXRA (via C-terminus); association with RXRA is enhanced by pulsatile shear stress. Binds DNA preferentially as a heterodimer. RXRA serves as enhancer to induce RARA binding to RARE. Interacts with RXRG. Interacts with coactivators NCOA3 and NCOA6. Interacts with NCOA7; the interaction requires ligand-binding. Interacts (via the ligand-binding domain) with PRAME; the interaction is ligand (retinoic acid)-dependent. Interacts with AKT1; the interaction phosphorylates RARA and represses transactivation. Interacts with PRKAR1A; the interaction negatively regulates RARA transcriptional activity. Interacts with NCOR1 and NCOR2. Interacts with PRMT2. Interacts with LRIF1. Interacts with ASXL1 and NCOA1. Interacts with ACTN4. In a complex with HDAC3, HDAC5 and HDAC7; the HDACs serve as corepressors of RARA, causing its deacetylation and inhibition of RARE DNA element binding; association with HDAC3, HDAC5 and HDAC7 is increased upon oscillatory shear stress. Interacts with CDK7. In the absence of hormonal ligand, interacts with TACC1.

Subcellular location. Nucleus. Cytoplasm.

Tissue specificity. Expressed in monocytes.

Post-translational modifications. Phosphorylated on serine and threonine residues. Phosphorylation does not change during cell cycle. Phosphorylation on Ser-77 is crucial for transcriptional activity. Phosphorylation by AKT1 is required for the repressor activity but has no effect on DNA binding, protein stability nor subcellular localization. Phosphorylated by PKA in vitro. This phosphorylation on Ser-219 and Ser-369 is critical for ligand binding, nuclear localization and transcriptional activity in response to FSH signaling. Sumoylated with SUMO2, mainly on Lys-399 which is also required for SENP6 binding. On all-trans retinoic acid (ATRA) binding, a conformational change may occur that allows sumoylation on two additional site, Lys-166 and Lys-171. Probably desumoylated by SENP6. Sumoylation levels determine nuclear localization and regulate ATRA-mediated transcriptional activity. Trimethylation enhances heterodimerization with RXRA and positively modulates the transcriptional activation. Ubiquitinated by UBR5, leading to its degradation: UBR5 specifically recognizes and binds ligand-bound RARA when it is not associated with coactivators (NCOAs). In presence of NCOAs, the UBR5-degron is not accessible, preventing its ubiquitination and degradation. Acetylated; acetylation is increased upon pulsatile shear stress and decreased upon oscillatory shear stress.

Disease relevance. Chromosomal aberrations involving RARA are commonly found in acute promyelocytic leukemia. Translocation t(11;17)(q32;q21) with ZBTB16/PLZF; translocation t(15;17)(q21;q21) with PML; translocation t(5;17)(q32;q11) with NPM. The PML-RARA oncoprotein requires both the PML ring structure and coiled-coil domain for both interaction with UBE2I, nuclear microspeckle location and sumoylation. In addition, the coiled-coil domain functions in blocking RA-mediated transactivation and cell differentiation.

Domain organisation. Composed of three domains: a modulating N-terminal domain, a DNA-binding domain and a C-terminal ligand-binding domain. The 9aaTAD motif is a transactivation domain present in a large number of yeast and animal transcription factors.

Induction. Expression is induced ba retinoic acid. Down-regulated by aging. Induced by pulsatile shear stress.

Miscellaneous. Does not bind nor transactivate RARE on its own but may do so as a heterodimer with Alpha-1.

Similarity. Belongs to the nuclear hormone receptor family. NR1 subfamily.

Isoforms (3)

UniProt ID	Names	Canonical?
P10276-1	Alpha-1	yes
P10276-2	Alpha-2
P10276-3	Alpha-1-deltaBC

RefSeq proteins (4): NP_000955, NP_001019980, NP_001138773, NP_001138774 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000536	Nucl_hrmn_rcpt_lig-bd	Domain
IPR001628	Znf_hrmn_rcpt	Domain
IPR001723	Nuclear_hrmn_rcpt	Family
IPR003078	Retinoic_acid_rcpt	Family
IPR013088	Znf_NHR/GATA	Homologous_superfamily
IPR035500	NHR-like_dom_sf	Homologous_superfamily
IPR047158	NR_LBD_RAR	Domain
IPR047159	NR_DBD_RAR	Domain

Pfam: PF00104, PF00105

UniProt features (74 total): mutagenesis site 20, helix 17, strand 6, region of interest 5, modified residue 4, compositionally biased region 3, cross-link 3, turn 3, short sequence motif 2, binding site 2, splice variant 2, zinc finger region 2, chain 1, domain 1, site 1, DNA-binding region 1, sequence conflict 1

Structure

Experimental structures (PDB)

14 structures.

PDB	Method	Resolution (Å)
9GFE	X-RAY DIFFRACTION	1.58
1DSZ	X-RAY DIFFRACTION	1.7
3KMR	X-RAY DIFFRACTION	1.8
5K13	X-RAY DIFFRACTION	1.85
7WQQ	X-RAY DIFFRACTION	1.9
3KMZ	X-RAY DIFFRACTION	2.1
9GFI	X-RAY DIFFRACTION	2.1
6XWG	X-RAY DIFFRACTION	2.4
7APO	X-RAY DIFFRACTION	2.4
1DKF	X-RAY DIFFRACTION	2.5
7AOS	X-RAY DIFFRACTION	2.55
3A9E	X-RAY DIFFRACTION	2.75
4DQM	X-RAY DIFFRACTION	2.75
7QAA	X-RAY DIFFRACTION	2.76

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P10276-F1	79.49	0.61

Functional residue map

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

Catalytic / active sites (1): 60–61 (breakpoint for translocation to form plzf-rar-alpha, rar-alpha1-plzf and pml-rar-alpha oncogenes)

Ligand- & substrate-binding residues (2): 235; 287

Post-translational modifications (7): 77, 96, 219, 369, 166, 171, 399

Mutagenesis-validated functional residues (20):

Position	Phenotype
95	no effect on pkb/akt1-mediated phosphorylation. repressed transactivation.
96	abolishes pkb/akt1-mediated phosphorylation. repressed transactivation.
147	abrogates sumoylation in the presence or absence of atra and primarily nuclear localization and enhanced atra-mediated t
154	no effect on pkb/akt1-mediated phosphorylation. no repression of transactivation.
157	no effect on pkb/akt1-mediated phosphorylation. repressed transactivation.
166	cytoplasmic in the absence of atra and reduced transcriptional activity in the presence of atra. low sumoylation levels
171	cytoplasmic in the absence of atra and reduced transcriptional activity in the presence of atra. low sumoylation levels
219	no effect on heterodimerization with rara. on atra treatment, localizes to the nucleus, and increased protein levels; wh
219	no effect on heterodimerization with rara. on atra treatment, localizes to both nucleus and cytoplasm, no increase in pr
240	abolished ubiquitination and degradation by ubr5.
254	reduced ubiquitination and degradation by ubr5.
258	reduced ubiquitination and degradation by ubr5.
369	no effect on heterodimerization with rara. on atra treatment, localizes to the nucleus, and increased protein levels; wh
369	some inhibition of heterodimerization with rara. on atra treatment, localizes to both nucleus and cytoplasm, increase in
396	abrogates interaction with ncor1 or ncor2. increased affinity for ncor1 and ncor2 in the presence of bms493. increased t
399	in the absence of atra, abolishes sumoylation and is mainly nuclear. in the presence of atra, some sumoylation, cytoplas
409–410	abolishes interaction with asxl1 and ncoa1.
412	impairs interaction with asxl1 and ncoa1; when associated with q-415.
413–414	abolishes interaction with asxl1 and ncoa1.
415	impairs interaction with asxl1 and ncoa1; when associated with q-412.

Function

Pathways and Gene Ontology

Reactome pathways

6 pathways

ID	Pathway
R-HSA-383280	Nuclear Receptor transcription pathway
R-HSA-4090294	SUMOylation of intracellular receptors
R-HSA-5362517	Signaling by Retinoic Acid
R-HSA-5617472	Activation of anterior HOX genes in hindbrain development during early embryogenesis
R-HSA-9616222	Transcriptional regulation of granulopoiesis
R-HSA-9839394	TGFBR3 expression

MSigDB gene sets: 681 (showing top): GSE45365_HEALTHY_VS_MCMV_INFECTION_CD8_TCELL_IFNAR_KO_DN, GOBP_MYELOID_CELL_DIFFERENTIATION, GSE18804_BRAIN_VS_COLON_TUMORAL_MACROPHAGE_UP, GOBP_CARDIAC_CHAMBER_DEVELOPMENT, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, TAKEDA_TARGETS_OF_NUP98_HOXA9_FUSION_6HR_DN, GOBP_REGULATION_OF_CELL_ACTIVATION, RNGTGGGC_UNKNOWN, FXR_IR1_Q6, GOBP_RESPONSE_TO_ETHANOL, GOBP_HEPATICOBILIARY_SYSTEM_DEVELOPMENT, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_NEGATIVE_REGULATION_OF_CELL_DEVELOPMENT, FREAC2_01

GO Biological Process (64): negative regulation of transcription by RNA polymerase II (GO:0000122), ureteric bud development (GO:0001657), neural tube closure (GO:0001843), liver development (GO:0001889), glandular epithelial cell development (GO:0002068), outflow tract septum morphogenesis (GO:0003148), growth plate cartilage development (GO:0003417), protein phosphorylation (GO:0006468), germ cell development (GO:0007281), spermatogenesis (GO:0007283), female pregnancy (GO:0007565), positive regulation of cell population proliferation (GO:0008284), negative regulation of cell population proliferation (GO:0008285), hippocampus development (GO:0021766), cell differentiation (GO:0030154), prostate gland development (GO:0030850), negative regulation of granulocyte differentiation (GO:0030853), embryonic camera-type eye development (GO:0031076), regulation of myelination (GO:0031641), response to estradiol (GO:0032355), response to retinoic acid (GO:0032526), negative regulation of type II interferon production (GO:0032689), negative regulation of tumor necrosis factor production (GO:0032720), positive regulation of interleukin-13 production (GO:0032736), positive regulation of interleukin-4 production (GO:0032753), positive regulation of interleukin-5 production (GO:0032754), response to vitamin A (GO:0033189), response to cytokine (GO:0034097), multicellular organism growth (GO:0035264), mRNA transcription by RNA polymerase II (GO:0042789), negative regulation of apoptotic process (GO:0043066), apoptotic cell clearance (GO:0043277), response to ethanol (GO:0045471), positive regulation of T-helper 2 cell differentiation (GO:0045630), positive regulation of neuron differentiation (GO:0045666), positive regulation of cell cycle (GO:0045787), negative regulation of DNA-templated transcription (GO:0045892), positive regulation of DNA-templated transcription (GO:0045893), positive regulation of transcription by RNA polymerase II (GO:0045944), regulation of synaptic plasticity (GO:0048167)

GO Molecular Function (28): mRNA regulatory element binding translation repressor activity (GO:0000900), RNA polymerase II transcription regulatory region sequence-specific DNA binding (GO:0000977), RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), DNA-binding transcription repressor activity (GO:0001217), transcription coactivator binding (GO:0001223), retinoic acid binding (GO:0001972), chromatin binding (GO:0003682), DNA-binding transcription factor activity (GO:0003700), nuclear receptor activity (GO:0004879), signaling receptor binding (GO:0005102), zinc ion binding (GO:0008270), enzyme binding (GO:0019899), protein domain specific binding (GO:0019904), chromatin DNA binding (GO:0031490), histone deacetylase binding (GO:0042826), protein kinase B binding (GO:0043422), retinoic acid-responsive element binding (GO:0044323), mRNA 5’-UTR binding (GO:0048027), protein kinase A binding (GO:0051018), alpha-actinin binding (GO:0051393), heterocyclic compound binding (GO:1901363), sequence-specific double-stranded DNA binding (GO:1990837), transcription cis-regulatory region binding (GO:0000976), DNA binding (GO:0003677), protein binding (GO:0005515), sequence-specific DNA binding (GO:0043565), metal ion binding (GO:0046872)

GO Cellular Component (13): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), transcription regulator complex (GO:0005667), nucleolus (GO:0005730), cytoplasm (GO:0005737), cytosol (GO:0005829), plasma membrane (GO:0005886), actin cytoskeleton (GO:0015629), dendrite (GO:0030425), protein-containing complex (GO:0032991), perinuclear region of cytoplasm (GO:0048471), RNA polymerase II transcription regulator complex (GO:0090575)

Reactome top-level categories

Rollup of top-6 pathways:

Category	Pathways
Generic Transcription Pathway	1
SUMO E3 ligases SUMOylate target proteins	1
Signaling by Nuclear Receptors	1
Activation of HOX genes during differentiation	1
Developmental Biology	1
Signaling by TGFBR3	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
protein binding	4
transcription cis-regulatory region binding	3
regulation of transcription by RNA polymerase II	2
negative regulation of DNA-templated transcription	2
gland development	2
developmental process involved in reproduction	2
cell population proliferation	2
regulation of cell population proliferation	2
mRNA binding	2
RNA polymerase II transcription regulatory region sequence-specific DNA binding	2
DNA-binding transcription factor activity	2
nuclear lumen	2
cytoplasm	2
transcription by RNA polymerase II	1
mesonephric tubule development	1
primary neural tube formation	1
tube closure	1
hepaticobiliary system development	1
columnar/cuboidal epithelial cell development	1
glandular epithelial cell differentiation	1
outflow tract morphogenesis	1
cardiac septum morphogenesis	1
endochondral bone growth	1
cartilage development involved in endochondral bone morphogenesis	1
connective tissue development	1
phosphorylation	1
protein modification process	1
gamete generation	1
cellular process involved in reproduction in multicellular organism	1
cell development	1
male gamete generation	1
multi-organism reproductive process	1
multi-multicellular organism process	1
positive regulation of cellular process	1
negative regulation of cellular process	1
pallium development	1
limbic system development	1
anatomical structure development	1
cellular developmental process	1

Protein interactions and networks

STRING

3282 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RARA	NCOR1	O75376	989
RARA	NCOR2	Q9Y618	987
RARA	RXRA	P19793	983
RARA	ZBTB16	Q05516	960
RARA	RARS1	P54136	942
RARA	NPM1	P06748	915
RARA	PML	P29590	904
RARA	PRAM1	Q96QH2	898
RARA	CTNNB1	P35222	875
RARA	RUNX1	Q01196	864
RARA	HDAC1	Q13547	830
RARA	NUMA1	Q14980	829
RARA	FOS	P01100	815
RARA	RUNX1T1	Q06455	813
RARA	CRABP2	P29373	812

IntAct

213 interactions, top by confidence:

A	B	Type	Score
RARA	RXRA	psi-mi:“MI:0407”(direct interaction)	0.950
RARA	RXRA	psi-mi:“MI:0915”(physical association)	0.950
RXRB	RARA	psi-mi:“MI:0915”(physical association)	0.950
RARA	RXRB	psi-mi:“MI:0915”(physical association)	0.950
RXRA	RARA	psi-mi:“MI:0915”(physical association)	0.950
RXRA	RARA	psi-mi:“MI:2364”(proximity)	0.950
RXRA	RARA	psi-mi:“MI:0407”(direct interaction)	0.950
RARA	RXRG	psi-mi:“MI:0915”(physical association)	0.940
RXRG	RARA	psi-mi:“MI:0915”(physical association)	0.940

BioGRID (390): RXRG (Two-hybrid), NRIP1 (Two-hybrid), TEKT4 (Two-hybrid), CREBBP (Affinity Capture-Western), RARA (Co-crystal Structure), RXRA (Reconstituted Complex), MED1 (Co-crystal Structure), RARA (Affinity Capture-Western), RARA (Two-hybrid), SNW1 (Affinity Capture-Western), SIRT1 (Affinity Capture-Western), RARA (Reconstituted Complex), RARA (Affinity Capture-Western), SQSTM1 (Affinity Capture-Western), ACTN4 (Affinity Capture-Western)

ESM2 similar proteins: A2T928, D3ZHS6, O42132, O75916, O88974, O93511, O97716, P03373, P10276, P10826, P10827, P11416, P13631, P18113, P18119, P18514, P18516, P18911, P22448, P22605, P28699, P37242, P49805, P51126, P57753, P63058, P63059, Q15047, Q1LUC3, Q28571, Q28C33, Q5FBR4, Q5RAP4, Q69ZT9, Q7ZTI3, Q80TJ7, Q90271, Q90966, Q91392, Q92831

Diamond homologs: A0JNE3, A2T928, A4IIG7, G5ECR9, G5EDJ0, O02151, O45666, O76202, O97716, P10276, P10588, P10826, P10827, P10828, P11416, P12813, P13056, P13631, P16376, P18117, P18514, P18515, P18516, P18911, P20153, P22448, P22449, P22605, P22736, P22829, P28699, P31396, P33242, P33244, P41828, P41830, P43354, P45447, P49116, P49117

SIGNOR signaling

32 interactions.

A	Effect	B	Mechanism
RARA	“down-regulates quantity by repression”	EGFR	“transcriptional regulation”
CDK7	unknown	RARA	phosphorylation
RARA	up-regulates	THRA	binding
THRA	up-regulates	RARA	binding
AKT	down-regulates	RARA	phosphorylation
RARA	up-regulates	RXRA	binding
RARA	up-regulates	RXRG	binding
RARA	“up-regulates quantity by expression”	RXRG	“transcriptional regulation”
RXRA	up-regulates	RARA	binding
RXRB	up-regulates	RARA	binding
RARA	“down-regulates quantity by repression”	CCNA1	“transcriptional regulation”
AKT1	down-regulates	RARA	phosphorylation
ASXL1	“up-regulates activity”	RARA	binding
NCOA1	“up-regulates quantity by expression”	RARA	“transcriptional regulation”
ASXL1	“up-regulates quantity by expression”	RARA	“transcriptional regulation”
“all-trans-retinoic acid”	“up-regulates activity”	RARA	“chemical activation”
“9-cis-retinoic acid”	“up-regulates activity”	RARA	“chemical activation”
KMT2E	“up-regulates activity”	RARA	binding
THR	“up-regulates activity”	RARA	binding
RARA	“up-regulates activity”	THR	binding
RARA	“up-regulates quantity by expression”	OXT	“transcriptional regulation”
TFIIH	unknown	RARA	phosphorylation
RARA	up-regulates	THR	binding
THR	up-regulates	RARA	binding
PRKACA	“down-regulates activity”	RARA	phosphorylation
CDK7	up-regulates	RARA	phosphorylation
RARA	down-regulates	CTNNB1
RARA	“down-regulates quantity by repression”	NR4A1	“transcriptional regulation”
NCOA2	up-regulates	RARA	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 69 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
RORA,B,C and NR1D1 (REV-ERBA) regulate gene expression	6	48.0×	6e-08
Nuclear Receptor transcription pathway	11	43.2×	3e-13
R-HSA-400253	6	40.7×	1e-07
Expression of BMAL (ARNTL), CLOCK, and NPAS2	7	40.2×	1e-08
Signaling by Retinoic Acid	5	40.0×	3e-06
NR1H2 and NR1H3-mediated signaling	5	38.6×	3e-06
Heme signaling	8	33.8×	4e-09
Epigenetic regulation of adipogenesis genes by MLL3 and MLL4 complexes	8	33.8×	4e-09

GO biological processes:

GO term	Partners	Fold	FDR
retinoic acid receptor signaling pathway	9	100.6×	5e-14
mRNA transcription by RNA polymerase II	6	34.2×	3e-06
positive regulation of miRNA transcription	5	25.1×	1e-04
regulation of circadian rhythm	5	22.4×	2e-04
rhythmic process	5	21.7×	2e-04
response to estradiol	6	20.5×	4e-05
cellular response to tumor necrosis factor	5	14.1×	1e-03
chromatin remodeling	7	8.8×	6e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	44
Likely benign	4
Benign	4

Top pathogenic / likely-pathogenic (0)

SpliceAI

2348 predictions. Top by Δscore:

Variant	Effect	Δscore
17:40348311:TCTA:T	acceptor_loss	1.0000
17:40348312:CTA:C	acceptor_loss	1.0000
17:40348313:TA:T	acceptor_loss	1.0000
17:40348314:A:AC	acceptor_loss	1.0000
17:40348314:A:AG	acceptor_gain	1.0000
17:40348315:G:GA	acceptor_gain	1.0000
17:40348315:G:GT	acceptor_loss	1.0000
17:40348315:GC:G	acceptor_gain	1.0000
17:40348315:GCC:G	acceptor_gain	1.0000
17:40348315:GCCA:G	acceptor_gain	1.0000
17:40349782:A:AG	acceptor_gain	1.0000
17:40349783:G:GG	acceptor_gain	1.0000
17:40349783:G:GT	acceptor_loss	1.0000
17:40349894:G:GT	donor_gain	1.0000
17:40349904:G:GT	donor_gain	1.0000
17:40349907:G:GG	donor_gain	1.0000
17:40349921:GGAGT:G	donor_gain	1.0000
17:40349922:GAGTG:G	donor_gain	1.0000
17:40349923:A:T	donor_gain	1.0000
17:40349924:GT:G	donor_gain	1.0000
17:40349926:G:GG	donor_gain	1.0000
17:40351907:CAGCT:C	acceptor_loss	1.0000
17:40351908:A:AG	acceptor_gain	1.0000
17:40351908:AGC:A	acceptor_loss	1.0000
17:40351908:AGCT:A	acceptor_gain	1.0000
17:40351909:G:GA	acceptor_gain	1.0000
17:40351909:GC:G	acceptor_gain	1.0000
17:40351909:GCT:G	acceptor_gain	1.0000
17:40351909:GCTG:G	acceptor_gain	1.0000
17:40351909:GCTGT:G	acceptor_gain	1.0000

AlphaMissense

3034 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:40348399:T:A	C88S	1.000
17:40348399:T:C	C88R	1.000
17:40348399:T:G	C88G	1.000
17:40348400:G:A	C88Y	1.000
17:40348400:G:C	C88S	1.000
17:40348400:G:T	C88F	1.000
17:40348401:C:G	C88W	1.000
17:40348406:T:A	V90D	1.000
17:40348408:T:A	C91S	1.000
17:40348408:T:C	C91R	1.000
17:40348408:T:G	C91G	1.000
17:40348409:G:A	C91Y	1.000
17:40348409:G:C	C91S	1.000
17:40348409:G:T	C91F	1.000
17:40348410:T:G	C91W	1.000
17:40348414:G:A	D93N	1.000
17:40348414:G:C	D93H	1.000
17:40348414:G:T	D93Y	1.000
17:40348415:A:C	D93A	1.000
17:40348415:A:G	D93G	1.000
17:40348415:A:T	D93V	1.000
17:40348421:C:T	S95F	1.000
17:40348423:T:C	S96P	1.000
17:40348424:C:T	S96L	1.000
17:40348426:G:A	G97S	1.000
17:40348426:G:C	G97R	1.000
17:40348426:G:T	G97C	1.000
17:40348427:G:A	G97D	1.000
17:40348427:G:T	G97V	1.000
17:40348429:T:G	Y98D	1.000

dbSNP variants (sampled 300 via entrez): RS1000053941 (17:40329541 A>G), RS1000135904 (17:40310030 T>C), RS1000188787 (17:40344103 C>T), RS1000290180 (17:40343578 A>C), RS1000293112 (17:40346972 G>A,T), RS1000295628 (17:40337555 C>A,T), RS1000343419 (17:40349780 C>T), RS1000405712 (17:40343935 G>A), RS1000413370 (17:40317073 A>C,G), RS1000470850 (17:40311670 C>T), RS1000510570 (17:40329804 T>C), RS1000528532 (17:40354574 G>T), RS1000627723 (17:40344903 C>T), RS1000698691 (17:40318313 G>A,T), RS1000886106 (17:40319178 G>A,C)

Disease associations

OMIM: gene MIM:180240 | disease phenotypes: MIM:156000, MIM:607174

GenCC curated gene-disease

Disease	Classification	Inheritance
craniosynostosis	Moderate	Autosomal dominant
multiple congenital anomalies/dysmorphic syndrome	Limited	Autosomal dominant
acute promyelocytic leukemia	No Known Disease Relationship	Autosomal dominant

Mondo (7): syndromic disease (MONDO:0002254), Meniere disease (MONDO:0007972), familial meningioma (MONDO:0011789), colorectal carcinoma (MONDO:0024331), multiple congenital anomalies/dysmorphic syndrome (MONDO:0019042), acute promyelocytic leukemia (MONDO:0012883), craniosynostosis (MONDO:0015469)

Orphanet (3): Orofacial clefting syndrome (Orphanet:139039), Familial multiple meningioma (Orphanet:263662), NON RARE IN EUROPE: Menière disease (Orphanet:45360)

HPO phenotypes

39 total (30 of 39 shown, HPO-id order):

HPO	Term
HP:0000212	Gingival overgrowth
HP:0000225	Gingival bleeding
HP:0000421	Epistaxis
HP:0000790	Hematuria
HP:0000967	Petechiae
HP:0000978	Bruising susceptibility
HP:0000979	Purpura
HP:0001324	Muscle weakness
HP:0001442	Typified by somatic mosaicism
HP:0001824	Weight loss
HP:0001873	Thrombocytopenia
HP:0001875	Decreased total neutrophil count
HP:0001876	Pancytopenia
HP:0001882	Decreased total leukocyte count
HP:0001892	Abnormal bleeding
HP:0001903	Anemia
HP:0001945	Fever
HP:0001974	Increased total leukocyte count
HP:0002027	Abdominal pain
HP:0002039	Anorexia
HP:0002321	Vertigo
HP:0002653	Bone pain
HP:0002716	Lymphadenopathy
HP:0002875	Exertional dyspnea
HP:0004836	Acute promyelocytic leukemia
HP:0005521	Disseminated intravascular coagulation
HP:0010280	Stomatitis
HP:0011900	Hypofibrinogenemia
HP:0012135	Abnormal granulocytopoietic cell morphology
HP:0012378	Fatigue

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST008916_85	Asthma	2.000000e-12

MeSH disease descriptors (5)

Descriptor	Name	Tree numbers
D003398	Craniosynostoses	C05.116.099.370.894.232; C05.660.207.240; C05.660.906.364; C16.131.621.207.240; C16.131.621.906.364
D015473	Leukemia, Promyelocytic, Acute	C04.557.337.539.275.700; C15.378.508.539.275.700
D008575	Meniere Disease	C09.218.568.217.500
D013577	Syndrome	C23.550.288.500
C537443	Meningioma, familial (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (6): CHEMBL2055 (SINGLE PROTEIN), CHEMBL2363069 (PROTEIN FAMILY), CHEMBL2363071 (PROTEIN FAMILY), CHEMBL2363072 (PROTEIN COMPLEX), CHEMBL3430883 (PROTEIN COMPLEX), CHEMBL5465238 (CHIMERIC PROTEIN)

Molecules with ChEMBL bioactivity

11 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 329,745 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1023	BEXAROTENE	4	40,951
CHEMBL1265	ADAPALENE	4	12,179
CHEMBL1657	TAZAROTENE	4	26,405
CHEMBL25202	TAMIBAROTENE	4	5,139
CHEMBL3707313	TRIFAROTENE	4	224
CHEMBL38	TRETINOIN	4	194,008
CHEMBL705	ALITRETINOIN	4	39,246
CHEMBL107430	NRX195183	2	138
CHEMBL191703	CONESSINE	2	437
CHEMBL383634	GLIQUIDONE	2	9,480
CHEMBL1232461	MOLIBRESIB	2	1,538

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

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: nhr — 1B. Retinoic acid receptors

Most potent curated ligand interactions (18 total), top 18:

Ligand	Action	Affinity	Parameter
[3H]9-cis-retinoic acid	Full agonist	9.6	pKd
Ro 40-6055	Agonist	9.52	pEC50
alitretinoin	Agonist	9.5	pKd
AGN193109	Inverse agonist	8.7	pIC50
BMS614	Antagonist	8.7	pIC50
BMS753	Agonist	8.7	pKi
BMS493	Inverse agonist	8.4	pIC50
AGN193836	Agonist	8.4	pKd
YCT-529	Antagonist	8.17	pIC50
tretinoin	Agonist	7.77	pEC50
BMS-189532	Antagonist	7.57	pKd
TTNPB	Agonist	7.44	pIC50
Ro 41-5253	Antagonist	7.22	pIC50
tazarotene	Agonist	7.2	pEC50
tamibarotene	Agonist	6.9	pIC50
trifarotene	Agonist	6.3	pEC50
adapalene	Agonist	5.96	pKi
CD666	Agonist	5.65	pKd

Binding affinities (BindingDB)

14 measured of 19 human assays (19 total across all organisms); most potent 14 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
9-cis retinoic acid	KD	0.3 nM
Ch 80	KD	0.4 nM
BMS 961	KI	1.5 nM
BMS614	KI	2.5 nM
4-[(E)-2-(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-propenyl]benzoic acid	EC50	5.5 nM	US-10188615: Alkoxy compounds for disease treatment
CD564	KD	118 nM
4-[(E)-2-(3-Adamantan-1-yl-4-hydroxy-phenyl)-propenyl]-benzoic acid	KI	1140 nM
CD666	KD	2240 nM
6-[3’-(1-adamantyl)-4’-hydroxyphenyl]-2-naphthalenecarboxylic acid	KI	6500 nM
BMS184394-S	KD	7500 nM
BMS184394	KD	7500 nM
BMS184394-R	KD	16000 nM
9-cis-retinoic acid (9cRA)	IC50	27100 nM
BMS753	IC50	40200 nM	US-9963439: Specific inhibitors of cytochrome P450 26 retinoic acid hydroxylase

ChEMBL bioactivities

433 potent at pChembl≥5 of 440 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.00	Ki	0.1	nM	TRETINOIN
9.74	EC50	0.18	nM	CHEMBL275311
9.52	EC50	0.3	nM	CHEMBL69367
9.35	IC50	0.45	nM	CHEMBL134375
9.22	EC50	0.6	nM	CHEMBL451835
9.11	IC50	0.78	nM	TRETINOIN
9.05	IC50	0.89	nM	TRETINOIN
9.00	EC50	1.01	nM	TRETINOIN
9.00	EC50	1	nM	TRETINOIN
9.00	AC50	1	nM	CHEMBL418570
9.00	EC50	1	nM	ALITRETINOIN
8.96	Ki	1.1	nM	CHEMBL89241
8.92	EC50	1.2	nM	CHEMBL1235644
8.82	IC50	1.5	nM	CHEMBL165629
8.74	Ki	1.8	nM	CHEMBL3815166
8.70	EC50	2	nM	CHEMBL69367
8.70	Kd	2	nM	CHEMBL326911
8.70	EC50	2	nM	CHEMBL275311
8.70	Kd	2	nM	CHEMBL358145
8.66	IC50	2.2	nM	CHEMBL133725
8.64	Kd	2.3	nM	TRETINOIN
8.62	IC50	2.4	nM	CHEMBL131850
8.55	Ki	2.8	nM	CHEMBL3814574
8.52	Kd	3	nM	NRX195183
8.52	Kd	3	nM	CHEMBL107054
8.51	Ki	3.1	nM	CHEMBL74331
8.48	Ki	3.3	nM	TRETINOIN
8.40	Kd	4	nM	CHEMBL439780
8.40	EC50	4	nM	CHEMBL98172
8.40	Kd	4	nM	CHEMBL3934863
8.40	EC50	4	nM	CHEMBL109581
8.40	EC50	4	nM	CHEMBL69367
8.40	EC50	4	nM	CHEMBL89241
8.36	Kd	4.38	nM	TRETINOIN
8.36	Kd	4.4	nM	CHEMBL317873
8.34	IC50	4.6	nM	CHEMBL5639513
8.30	EC50	5	nM	TRETINOIN
8.28	Ki	5.3	nM	CHEMBL36768
8.26	IC50	5.5	nM	CHEMBL162345
8.26	Kd	5.5	nM	CHEMBL165629
8.26	EC50	5.5	nM	CHEMBL5997757
8.22	EC50	6	nM	BEXAROTENE
8.21	Ki	6.2	nM	CHEMBL3813779
8.20	EC50	6.31	nM	TRETINOIN
8.19	IC50	6.5	nM	CHEMBL163530
8.19	Ki	6.5	nM	TAMIBAROTENE
8.15	Kd	7	nM	CHEMBL106527
8.15	EC50	7	nM	TRETINOIN
8.15	IC50	7	nM	ALITRETINOIN
8.11	Ki	7.7	nM	CHEMBL2385268

PubChem BioAssay actives

311 with measured affinity, of 1287 total; 50 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-[(E)-2-(5,5,8,8-tetramethyl-6,7-dihydronaphthalen-2-yl)prop-1-enyl]benzoic acid	1168702: Agonist activity at human RARalpha expressed in HEK293 cells by luciferase reporter gene assay	ec50	0.0002	uM
4-[(5,5,8,8-tetramethyl-6,7-dihydronaphthalene-2-carbonyl)amino]benzoic acid	396775: Activity at human RARalpha ligand binding domain expressed in COS7 cells co-transfected with Gal4-DBD assessed as transcriptional activation after 16 hrs by Gal4 response element-driven luciferase reporter gene assay	ec50	0.0003	uM
alitretinoin	1799183: Retinoid Competition Binding Assay from Article 10.1006/jmbi.2000.4032: “Structural basis for isotype selectivity of the human retinoic acid nuclear receptor.”	kd	0.0003	uM
4-[5-(5,5,8,8-tetramethyl-6,7-dihydronaphthalen-2-yl)-1H-pyrrol-2-yl]benzoic acid	200126: Binding affinity for Retinoic Acid Receptor alpha (RAR alpha)	ic50	0.0004	uM
tretinoin	1799183: Retinoid Competition Binding Assay from Article 10.1006/jmbi.2000.4032: “Structural basis for isotype selectivity of the human retinoic acid nuclear receptor.”	kd	0.0004	uM
4-[(E)-3-oxo-3-(5,5,8,8-tetramethyl-6,7-dihydronaphthalen-2-yl)prop-1-enyl]benzoic acid	1799183: Retinoid Competition Binding Assay from Article 10.1006/jmbi.2000.4032: “Structural basis for isotype selectivity of the human retinoic acid nuclear receptor.”	kd	0.0004	uM
4-[2-(5,5,8,8-tetramethyl-6,7-dihydronaphthalen-2-yl)ethynyl]benzoic acid	396775: Activity at human RARalpha ligand binding domain expressed in COS7 cells co-transfected with Gal4-DBD assessed as transcriptional activation after 16 hrs by Gal4 response element-driven luciferase reporter gene assay	ec50	0.0006	uM
4-[(5,5-dimethyl-8-quinolin-3-yl-6H-naphthalene-2-carbonyl)amino]benzoic acid	1799455: Competitive Assay from Article 10.1016/S1074-5521(99)80084-2: “Structural basis for engineering of retinoic acid receptor isotype-selective agonists and antagonists.”	ki	0.0010	uM
4-[(1,1,3,3-tetramethyl-2-oxoindene-5-carbonyl)amino]benzoic acid	1799455: Competitive Assay from Article 10.1016/S1074-5521(99)80084-2: “Structural basis for engineering of retinoic acid receptor isotype-selective agonists and antagonists.”	ki	0.0010	uM
(2E,4E,6E)-7-(3,5-ditert-butylphenyl)-3-methylocta-2,4,6-trienoic acid	198057: Inhibition of [3H]ATRA binding to Retinoic acid receptor RAR alpha	ki	0.0011	uM
4-[2,2-dimethyl-4-(4-methylphenyl)benzo[g]thiochromen-7-yl]benzoic acid	228580: Antagonistic activity against RAR alpha in transcriptional activation assay with 32 nM TTNPB	ic50	0.0015	uM
4-[5-(3-tert-butylphenyl)-1-(4-methylsulfonylphenyl)pyrazol-3-yl]benzoic acid	1306247: Displacement of [3H]-TTNPB from RARalpha/RXRalpha (unknown origin) expressed in baculovirus expression system by scintillation proximity assay	ki	0.0018	uM
2-fluoro-4-[(5,5,8,8-tetramethyl-6,7-dihydronaphthalene-2-carbonyl)amino]benzoic acid	35831: Binding affinity fo retinoic acid receptor RAR alpha	kd	0.0020	uM
4-[2-[5,5-dimethyl-8-(4-methylphenyl)-6H-naphthalen-2-yl]ethynyl]benzoic acid	198051: Binding constant for baculovirus-expressed Retinoic acid receptor RAR alpha	kd	0.0020	uM
4-[5-(5,5,8,8-tetramethyl-6,7-dihydroquinoxalin-2-yl)-1H-pyrrol-2-yl]benzoic acid	200127: Binding affinity for Retinoic Acid Receptor alpha (RAR alpha)	ic50	0.0022	uM
4-[5-(5,5,8,8-tetramethyl-6,7-dihydroquinoxalin-2-yl)thiophen-3-yl]benzoic acid	200127: Binding affinity for Retinoic Acid Receptor alpha (RAR alpha)	ic50	0.0024	uM
4-[1-(4-methylsulfonylphenyl)-5-(5,5,8,8-tetramethyl-6,7-dihydronaphthalen-2-yl)pyrazol-3-yl]benzoic acid	1306247: Displacement of [3H]-TTNPB from RARalpha/RXRalpha (unknown origin) expressed in baculovirus expression system by scintillation proximity assay	ki	0.0028	uM
2,6-difluoro-4-[(3-hydroxy-5,5,8,8-tetramethyl-6,7-dihydronaphthalene-2-carbonyl)amino]benzoic acid	35831: Binding affinity fo retinoic acid receptor RAR alpha	kd	0.0030	uM
4-[(4-chloro-3-hydroxy-5,5,8,8-tetramethyl-6,7-dihydronaphthalene-2-carbonyl)amino]-2,6-difluorobenzoic acid	35831: Binding affinity fo retinoic acid receptor RAR alpha	kd	0.0030	uM
(2E,4E,6Z)-3-methyl-7-(5,5,8,8-tetramethyl-3-propoxy-6,7-dihydronaphthalen-2-yl)octa-2,4,6-trienoic acid	200109: Transcriptional activation of Retinoic acid receptor RAR alpha	ec50	0.0040	uM
4-(3,5,5,8,8-pentamethyl-6,7-dihydronaphthalene-2-carbonyl)benzoic acid	198035: Transcriptional activation in CV-1 cells expressing Retinoic acid receptor RAR alpha	ec50	0.0040	uM
4-[(4-bromo-3-hydroxy-5,5,8,8-tetramethyl-6,7-dihydronaphthalene-2-carbonyl)amino]-2,6-difluorobenzoic acid	35831: Binding affinity fo retinoic acid receptor RAR alpha	kd	0.0040	uM
4-[(4-bromo-3-hydroxy-5,5,8,8-tetramethyl-6,7-dihydronaphthalene-2-carbonyl)amino]-2-fluorobenzoic acid	198046: Binding affinity for baculovirus-expressed Retinoic acid receptor RAR alpha	kd	0.0044	uM
4-[[2,2-dimethyl-4-(4-methylphenyl)chromene-6-carbonyl]amino]benzoic acid	2141845: Antagonist activity at recombinant human RAR-alpha expressed in mammalian cells in presence of 9-cis-RA by luciferase reporter gene based transactivation assay	ic50	0.0046	uM
4-(5,5,8,8-tetramethyl-6,7-dihydroanthracen-2-yl)benzoic acid	200139: Binding affinity to retinoic acid receptor alpha using [3H]CD 367 as radioligand	ki	0.0053	uM
4-[2,2-dimethyl-4-(4-methylphenyl)benzo[g]chromen-7-yl]benzoic acid	228580: Antagonistic activity against RAR alpha in transcriptional activation assay with 32 nM TTNPB	ic50	0.0055	uM
Bexarotene	198035: Transcriptional activation in CV-1 cells expressing Retinoic acid receptor RAR alpha	ec50	0.0060	uM
4-[5-(3-tert-butyl-5-methylphenyl)-1-(4-methylsulfonylphenyl)pyrazol-3-yl]benzoic acid	1306247: Displacement of [3H]-TTNPB from RARalpha/RXRalpha (unknown origin) expressed in baculovirus expression system by scintillation proximity assay	ki	0.0062	uM
4-[(5,5,8,8-tetramethyl-6,7-dihydronaphthalen-2-yl)carbamoyl]benzoic acid	200134: Agonistic activity towards retinoic acid receptor-alpha	ki	0.0065	uM
4-[2,2-dimethyl-4-(5-methylthiophen-2-yl)benzo[g]chromen-7-yl]benzoic acid	228580: Antagonistic activity against RAR alpha in transcriptional activation assay with 32 nM TTNPB	ic50	0.0065	uM
2,6-difluoro-4-[(5,5,8,8-tetramethyl-6,7-dihydronaphthalene-2-carbonyl)amino]benzoic acid	35831: Binding affinity fo retinoic acid receptor RAR alpha	kd	0.0070	uM
4-[(E)-2-(5,5-dimethyl-8-phenyl-6H-naphthalen-2-yl)ethenyl]benzoic acid	1306247: Displacement of [3H]-TTNPB from RARalpha/RXRalpha (unknown origin) expressed in baculovirus expression system by scintillation proximity assay	ki	0.0077	uM
4-[5-methyl-4-(5,5,8,8-tetramethyl-6,7-dihydronaphthalen-2-yl)-1,3-thiazol-2-yl]benzoic acid	1389198: Transactivation of GST-tagged RARalpha LBD (unknown origin) assessed as fluorescein-labelled coactivator peptide recruitment measured after 4 hrs by TR-FRET analysis	ec50	0.0082	uM
6-[2-(4,4-dimethyl-2,3-dihydrothiochromen-6-yl)ethynyl]pyridine-2-carboxylic acid	1380632: Agonist activity at GAL4 DNA-binding domain-tagged RARalpha (unknown origin) ligand-binding domain expressed in human HG5LN cells incubated for 18 hrs by luciferase reporter gene assay	ec50	0.0110	uM
4-[5,5-dimethyl-8-(4-methylphenyl)-6H-anthracen-2-yl]benzoic acid	228582: Binding affinity of [3H]- RA to baculovirus expressed human RAR alpha	kd	0.0130	uM
4-[2,2-dimethyl-4-(5-methylthiophen-2-yl)benzo[g]thiochromen-7-yl]benzoic acid	228582: Binding affinity of [3H]- RA to baculovirus expressed human RAR alpha	kd	0.0130	uM
(2E,4E,6Z)-7-(3-ethoxy-5,5,8,8-tetramethyl-6,7-dihydronaphthalen-2-yl)-3-methylocta-2,4,6-trienoic acid	200109: Transcriptional activation of Retinoic acid receptor RAR alpha	ec50	0.0140	uM
4-[5,5-dimethyl-8-(5-methylthiophen-2-yl)-6H-anthracen-2-yl]benzoic acid	228582: Binding affinity of [3H]- RA to baculovirus expressed human RAR alpha	kd	0.0150	uM
(2E,4E)-2,4-dimethyl-5-(6,6,9,9-tetramethyl-4-oxo-7,8-dihydrobenzo[g]chromen-3-yl)penta-2,4-dienoic acid	428028: Displacement of radioligand from RARalpha receptor	ic50	0.0150	uM
4-[4-(2-ethoxyethoxy)-5-methyl-1,3-thiazol-2-yl]benzoic acid	1389198: Transactivation of GST-tagged RARalpha LBD (unknown origin) assessed as fluorescein-labelled coactivator peptide recruitment measured after 4 hrs by TR-FRET analysis	ec50	0.0151	uM
4-[5-(5,5,8,8-tetramethyl-6,7-dihydroquinoxalin-2-yl)furan-3-yl]benzoic acid	200127: Binding affinity for Retinoic Acid Receptor alpha (RAR alpha)	ic50	0.0190	uM
Adapalene	1380632: Agonist activity at GAL4 DNA-binding domain-tagged RARalpha (unknown origin) ligand-binding domain expressed in human HG5LN cells incubated for 18 hrs by luciferase reporter gene assay	ec50	0.0220	uM
4-[(E)-2-(4,4-dimethyl-2,3-dihydrothiochromen-6-yl)prop-1-enyl]benzoic acid	166217: Effective concentration against RAR-alpha receptor	ec50	0.0270	uM
4-[[5,5-dimethyl-8-(4-methylphenyl)-6H-naphthalene-2-carbonyl]amino]benzoic acid	2141845: Antagonist activity at recombinant human RAR-alpha expressed in mammalian cells in presence of 9-cis-RA by luciferase reporter gene based transactivation assay	ic50	0.0290	uM
4-[(E)-3-(5,5,8,8-tetramethyl-6,7-dihydronaphthalen-2-yl)prop-1-enyl]benzoic acid	197921: Ability to inhibit TTNPB-induced transactivation at retinoic acid receptor alpha	ec50	0.0300	uM
4-[5-(4-phenyl-8-propan-2-ylquinolin-2-yl)-1H-pyrrol-2-yl]benzoic acid	198041: Antagonistic activity was evaluated in terms of inhibition of Retinoic acid receptor alpha transactivation by ATRA (50 nM)	ic50	0.0312	uM
4-[5-(5,5,8,8-tetramethyl-6,7-dihydroquinoxalin-2-yl)furan-2-yl]benzoic acid	200127: Binding affinity for Retinoic Acid Receptor alpha (RAR alpha)	ic50	0.0320	uM
4-[4-(2-methoxyethoxymethoxy)-3-(5,5,8,8-tetramethyl-6,7-dihydronaphthalen-2-yl)phenyl]benzoic acid	1380632: Agonist activity at GAL4 DNA-binding domain-tagged RARalpha (unknown origin) ligand-binding domain expressed in human HG5LN cells incubated for 18 hrs by luciferase reporter gene assay	ec50	0.0340	uM
4-[(E)-1-(5,5,8,8-tetramethyl-6,7-dihydronaphthalen-2-yl)prop-1-en-2-yl]benzoic acid	166217: Effective concentration against RAR-alpha receptor	ec50	0.0370	uM
4-[2-[8-(4-cyanophenyl)-5,5-dimethyl-6H-naphthalen-2-yl]ethynyl]benzoic acid	198045: Ability to displace 3H-retinoic acid (5 nM) from alpha retinoic acid receptor (alpha RAR) using transactivation assay	kd	0.0380	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Tretinoin	increases activity, affects binding, decreases secretion, increases sumoylation, affects reaction (+16 more)	62
Arsenic Trioxide	increases degradation, affects binding, increases activity, affects cotreatment, decreases reaction (+4 more)	14
Alitretinoin	decreases expression, increases expression, affects binding, increases activity, increases reaction	7
Am 580	decreases expression, decreases reaction, affects binding, increases activity, decreases activity (+1 more)	5
Ro 41-5253	decreases reaction, increases response to substance, affects binding, affects cotreatment, increases expression (+1 more)	5
Estradiol	decreases reaction, affects cotreatment, decreases expression, increases expression	5
bisphenol A	affects cotreatment, increases methylation, affects binding, decreases reaction, increases expression	4
Cadmium	decreases expression, increases abundance, increases expression, decreases reaction, affects methylation	4
sodium arsenite	decreases expression	3
4-(2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-propenyl)benzoic acid	affects binding, increases activity, affects cotreatment, increases expression	3
Vitamin A	affects cotreatment, increases expression	3
Zinc	affects cotreatment, increases expression	3
bisphenol F	increases expression, affects cotreatment	2
4-oxoretinoic acid	increases activity, increases expression	2
triphenyl phosphate	decreases reaction, increases expression, affects expression	2
arsenite	increases expression, increases methylation, decreases reaction	2
puerarin	increases reaction, increases expression, decreases expression	2
epigallocatechin gallate	increases expression	2
tamibarotene	decreases response to substance, affects binding, decreases reaction, affects cotreatment, increases expression (+1 more)	2
benzyloxycarbonylleucyl-leucyl-leucine aldehyde	decreases expression, decreases reaction, increases degradation, increases ubiquitination	2
bisphenol B	increases expression	2
bisphenol Z	increases expression	2
tetraarsenic tetrasulfide	affects binding, increases degradation, increases reaction, decreases reaction, increases expression	2
bisphenol S	decreases expression, decreases methylation, increases expression	2
(+)-JQ1 compound	decreases expression	2
Resveratrol	affects cotreatment, decreases expression, increases expression	2
Decitabine	affects cotreatment, increases expression, increases reaction	2
Zoledronic Acid	decreases expression	2
Fulvestrant	decreases reaction, increases expression, decreases expression, affects cotreatment, increases methylation	2
Vorinostat	decreases expression, increases expression, increases reaction, affects cotreatment	2

ChEMBL screening assays

368 unique, capped per target: 279 binding, 85 functional, 4 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1011984	Binding	Activity at human RARalpha ligand binding domain expressed in COS7 cells co-transfected with Gal4-DBD assessed as transcriptional activation after 16 hrs by Gal4 response element-driven luciferase reporter gene assay	Novel non-carboxylic acid retinoids: 1,2,4-oxadiazol-5-one derivatives. — Bioorg Med Chem Lett
CHEMBL1023990	Functional	Agonist activity at human RARalpha expressed in human HeLa cells assessed as relative luminescence units at >=10 uM by luciferase assay relative to control	New retinoid chemotypes: 9-cis-retinoic acid analogs with hydrophobic rings derived from terpenes as selective RAR agonists. — Bioorg Med Chem
CHEMBL3224186	ADMET	Inhibition of RAR alpha (unknown origin)	Overcoming retinoic acid receptor- based testicular toxicity in the optimisation of glucokinase activators — Medchemcomm

Cellosaurus cell lines

101 cell lines: 88 cancer cell line, 7 factor-dependent cell line, 3 embryonic stem cell, 2 spontaneously immortalized cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_0005	NB4	Cancer cell line	Female
CVCL_0041	Rh30	Cancer cell line	Male
CVCL_0092	NALM-6	Cancer cell line	Male
CVCL_0567	UF-1	Cancer cell line	Female
CVCL_0U51	NALM-6/SP-B	Cancer cell line	Male
CVCL_1807	AP-1060	Cancer cell line	Male
CVCL_4V57	NALM6/Clo	Cancer cell line	Male
CVCL_4W71	POLK F171A MSH-	Cancer cell line	Male
CVCL_4W72	POLK KO hetero MSH-	Cancer cell line	Male
CVCL_4W73	POLK KO homo MSH-	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00196768	PHASE4	UNKNOWN	Treatment Protocol for Relapsed Acute Promyelocytic Leukemia (APL) With Arsenic
NCT00408278	PHASE4	COMPLETED	Treatment of Newly Diagnosed Patients With Acute Promyelocytic Leukemia (PETHEMA LPA 2005)
NCT00465933	PHASE4	COMPLETED	Treatment of Acute Promyelocytic Leukemia With All-Trans Retinoic Acid (ATRA) and Idarubicin (AIDA)
NCT00504764	PHASE4	COMPLETED	Treatment of Relapsed Promyelocytic Leukemia With Arsenic Trioxide (ATO)
NCT01987297	PHASE4	UNKNOWN	Combined Retinoic Acid,Arsenic Trioxide and Chemo for Newly-diagnosed APL
NCT02020161	PHASE4	UNKNOWN	Clinical Guidelines for APL Treatment
NCT00722436	PHASE4	TERMINATED	Tranexamic Acid for Craniofacial Surgery
NCT02188576	PHASE4	COMPLETED	The Efficacy and Population Pharmacokinetics of Tranexamic Acid for Craniosynostosis Surgery
NCT01574313	PHASE4	COMPLETED	Effect of Stellate Ganglion Block on Meniere’s Disease
NCT02529475	PHASE4	TERMINATED	Evaluation of Inner Ear and Brain Structures With Contrast-enhanced MRI in Healthy Subjects (HYDROPS)
NCT04815187	PHASE4	ACTIVE_NOT_RECRUITING	Repurposed Use of Allergic Rhinitis and Allergic Asthma Drug to Reduce Vertigo and Hearing Loss in Meniere’s Disease
NCT04081701	PHASE4	RECRUITING	68-Ga DOTATATE PET/MRI in the Diagnosis and Management of Somatostatin Receptor Positive CNS Tumors.
NCT04386642	PHASE4	UNKNOWN	Tranexamic Acid Reduce Blood Loss in Meningioma Resection
NCT06377371	PHASE4	RECRUITING	Feasibility of Intraoperative Tracing of Meningioma Using [Cu64]DOTATATE
NCT01226303	PHASE3	UNKNOWN	Treatment Study for Children and Adolescents With Acute Promyelocitic Leukemia
NCT02688140	PHASE3	COMPLETED	Study for Patients With Newly Diagnosed, High-risk Acute Promyelocytic Leukemia
NCT02899169	PHASE3	UNKNOWN	Treatment of Non-high-risk Acute Promyelocytic Leukemia (APL) With Realgar-Indigo Naturalis Formula (RIF)
NCT04175587	PHASE3	UNKNOWN	Randomized,International Multi-center Clinical Trial of RIF Plus RA for Non-high-risk APL
NCT07296445	PHASE3	NOT_YET_RECRUITING	A Trial to Investigate Whether Oral Arsenic Trioxide Is Similar to Intravenous Arsenic Trioxide in Pharmacokinetics, Safety, and Efficacy (LATITUDE/SDKARS-301)
NCT07503730	PHASE3	RECRUITING	Early Use of Realgar-Indigo Naturalis Formula (RIF) Combined With All-trans Retinoic Acid (ATRA) for Treating Acute Promyelocytic Leukemia (APL).
NCT07504458	PHASE3	RECRUITING	Pivotal Open-label Phase 3 Clinical Study of QTX-2101 in Adult Patients With Acute Promyelocytic Leukemia
NCT03664674	PHASE3	COMPLETED	Phase 3 Study of OTO-104 in Subjects With Unilateral Meniere’s Disease
NCT04677972	PHASE3	COMPLETED	SPI-1005 for the Treatment of Meniere’s Disease
NCT05851508	PHASE3	RECRUITING	The Effecttiveness of Intratympanic Methylprednisolon Injections Compared to Placebo in the Treatment of Vertigo Attacks in Meniere’s Disease
NCT00517959	PHASE3	UNKNOWN	SCRT Versus Conventional RT in Children and Young Adults With Low Grade and Benign Brain Tumors
NCT01655927	PHASE3	UNKNOWN	Efficacy of Tranexamic Acid in Brain Tumor Resections
NCT03015701	PHASE3	COMPLETED	S9005 Mifepristone in Meningioma
NCT03558516	PHASE3	COMPLETED	Magnesium and Intraoperative Blood Loss in Meningioma Surgery
NCT04305470	PHASE3	COMPLETED	Gleolan for Visualization of Newly Diagnosed or Recurrent Meningioma
NCT00413166	PHASE2	COMPLETED	All-trans Retinoic Acid, and Arsenic +/- Idarubicin
NCT00520208	PHASE2	COMPLETED	Safety, Efficacy, & Pharmacokinetic Study of Tamibarotene to Treat Patients With Relapsed or Refractory APL
NCT00670150	PHASE2	WITHDRAWN	New Retinoid Agent Combined With Arsenic Trioxide for Untreated Acute Promyelocytic Leukemia
NCT00675870	PHASE2	UNKNOWN	Study of NRX 195183 Therapy for Patients With Relapsed or Refractory Acute Promyelocytic Leukemia
NCT00907582	PHASE2	TERMINATED	ASCT for Relapsed APL After Molecular Remission
NCT01064570	PHASE2	UNKNOWN	AIDA 2000 Guidelines
NCT01253070	PHASE2	COMPLETED	Sorafenib Tosylate and Chemotherapy in Treating Older Patients With Acute Myeloid Leukemia
NCT01404949	PHASE2	COMPLETED	Combined Tretinoin and Arsenic Trioxide for Patients With Newly Diagnosed Acute Promyelocytic Leukemia Followed by Risk-Adapted Postremission Therapy
NCT01409161	PHASE2	RECRUITING	Tretinoin and Arsenic Trioxide With or Without Gemtuzumab Ozogamicin in Treating Patients With Previously Untreated Acute Promyelocytic Leukemia
NCT03624270	PHASE2	UNKNOWN	Oral Arsenic Trioxide for Newly Diagnosed Acute Promyelocytic Leukaemia
NCT04687176	PHASE2	RECRUITING	Frontline Oral Arsenic Trioxide for APL