RARG

Summary

RARG (retinoic acid receptor gamma, HGNC:9866) is a protein-coding gene on chromosome 12q13.13, encoding Retinoic acid receptor gamma (P13631). Receptor for retinoic acid.

This gene encodes a retinoic acid receptor that belongs to the nuclear hormone receptor family. Retinoic acid receptors (RARs) act as ligand-dependent transcriptional regulators. When bound to ligands, RARs activate transcription by binding as heterodimers to the retinoic acid response elements (RARE) found in the promoter regions of the target genes. In their unbound form, RARs repress transcription of their target genes. RARs are involved in various biological processes, including limb bud development, skeletal growth, and matrix homeostasis. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 5916 — RefSeq curated summary.

At a glance

• GWAS associations: 4
• Clinical variants (ClinVar): 44 total — 1 likely-pathogenic
• Phenotypes (HPO): 1
• Druggable target: yes — 17 molecules with ChEMBL bioactivity
• Transcription factor: yes — 43 downstream targets (CollecTRI)
• MANE Select transcript: NM_000966

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9866
Approved symbol	RARG
Name	retinoic acid receptor gamma
Location	12q13.13
Locus type	gene with protein product
Status	Approved
Aliases	RARC, NR1B3, RARgamma, RAR-gamma
Ensembl gene	ENSG00000172819
Ensembl biotype	protein_coding
OMIM	180190
Entrez	5916

Gene structure

Transcript identifiers

Ensembl transcripts: 28 — 17 protein_coding, 7 protein_coding_CDS_not_defined, 4 retained_intron

ENST00000338561, ENST00000394426, ENST00000425354, ENST00000543726, ENST00000543762, ENST00000546377, ENST00000546717, ENST00000548284, ENST00000548317, ENST00000549859, ENST00000550265, ENST00000550350, ENST00000550362, ENST00000550721, ENST00000551158, ENST00000551501, ENST00000551580, ENST00000552901, ENST00000870211, ENST00000870212, ENST00000870213, ENST00000870214, ENST00000870215, ENST00000870216, ENST00000870217, ENST00000959620, ENST00000959621, ENST00000959622

RefSeq mRNA: 5 — MANE Select: NM_000966 NM_000966, NM_001042728, NM_001243730, NM_001243731, NM_001243732

CCDS: CCDS41790, CCDS58236, CCDS58237, CCDS8850

Canonical transcript exons

ENST00000425354 — 10 exons

Exon	Start	End
ENSE00001354350	53210569	53211863
ENSE00001368414	53231169	53231235
ENSE00001380039	53227362	53227687
ENSE00001518440	53231974	53232209
ENSE00003498093	53213085	53213243
ENSE00003566869	53214059	53214235
ENSE00003597358	53215646	53215794
ENSE00003620311	53213496	53213700
ENSE00003635700	53214446	53214606
ENSE00003637589	53215293	53215434

Expression profiles

Bgee: expression breadth ubiquitous, 199 present calls, max score 98.46.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 13.8001 / max 144.9108, expressed in 1639 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
131218	6.8231	1358
131222	3.9743	1084
131219	1.0552	694
131217	0.7123	472
131221	0.4808	289
131220	0.4394	197
131216	0.3151	172

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
lower esophagus mucosa	UBERON:0035834	98.46	gold quality
skin of leg	UBERON:0001511	97.27	gold quality
skin of abdomen	UBERON:0001416	97.07	gold quality
esophagus mucosa	UBERON:0002469	96.97	gold quality
stromal cell of endometrium	CL:0002255	95.25	gold quality
zone of skin	UBERON:0000014	94.61	gold quality
ectocervix	UBERON:0012249	94.31	gold quality
endocervix	UBERON:0000458	94.05	gold quality
esophagus	UBERON:0001043	92.77	gold quality
right coronary artery	UBERON:0001625	92.48	gold quality
vagina	UBERON:0000996	92.33	gold quality
right uterine tube	UBERON:0001302	92.31	gold quality
apex of heart	UBERON:0002098	92.23	gold quality
tibial nerve	UBERON:0001323	91.18	gold quality
minor salivary gland	UBERON:0001830	90.89	gold quality
right lobe of thyroid gland	UBERON:0001119	90.69	gold quality
descending thoracic aorta	UBERON:0002345	90.63	gold quality
ascending aorta	UBERON:0001496	90.56	gold quality
mucosa of stomach	UBERON:0001199	90.53	gold quality
thoracic aorta	UBERON:0001515	90.47	gold quality
body of uterus	UBERON:0009853	90.35	gold quality
left uterine tube	UBERON:0001303	89.99	gold quality
tongue squamous epithelium	UBERON:0006919	89.79	silver quality
aorta	UBERON:0000947	89.75	gold quality
left coronary artery	UBERON:0001626	89.74	gold quality
left lobe of thyroid gland	UBERON:0001120	89.62	gold quality
mouth mucosa	UBERON:0003729	89.59	gold quality
saliva-secreting gland	UBERON:0001044	89.46	gold quality
popliteal artery	UBERON:0002250	89.41	gold quality
tibial artery	UBERON:0007610	89.38	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	8.61

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

43 targets.

Target	Regulation
ABCA1	Activation
ACAN	Unknown
BGLAP	Activation
CAT
CNR1	Unknown
CRABP2
CYP19A1	Unknown
CYP26A1	Unknown
DLEU7
DUSP1	Unknown
EGFR	Unknown
FGFR1
FOLR2
FOXC1
GPRC5A
GREB1
HAS2	Unknown
HOXA1
ICAM1	Activation
IVL
KDM1A
KRT5	Repression
KRT88P
LAMB1
LRAT
ME3
MEIS1
MMP11
NANOG	Repression
PAM

JASPAR motifs

Motif	Name	Family
MA1553.1	RARG	Thyroid hormone receptor-related factors (NR1)
MA1553.2	RARG	Thyroid hormone receptor-related factors (NR1)

JASPAR matrix evidence (PMIDs): PMID:1738600

Upstream regulators (CollecTRI, top): CTNNB1, F2RL1, JUN, NR3C1, RARA, RARB, SP1

miRNA regulators (miRDB)

119 targeting RARG, 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-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-507	99.97	70.11	1915
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-512-3P	99.97	67.35	1049
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-557	99.96	70.01	1640
HSA-MIR-96-5P	99.95	72.80	2140
HSA-MIR-545-3P	99.95	70.74	2783
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-450B-5P	99.92	71.48	3175
HSA-MIR-12133	99.92	71.82	2006
HSA-MIR-1271-5P	99.91	71.99	1972
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057
HSA-MIR-605-3P	99.88	69.22	1833
HSA-MIR-182-5P	99.87	74.03	2589
HSA-MIR-4779	99.86	66.50	1583
HSA-MIR-221-5P	99.86	65.45	1052

Literature-anchored findings (GeneRIF, showing 40)

• Retinoid signaling is attenuated by retinoic acid-induced proteasome-mediated degradation of RARG in human keratocytes. (PMID:11855864)
• Retinoids cause apoptosis in pancreatic cancer cells via activation of RAR-gamma and altered expression of Bcl-2/Bax. (PMID:12189556)
• The 1.4 A resolution crystal structure of the ligand binding domain of the retinoic acid receptor RARgamma complexed with the retinoid SR11254 reveals several types of C-H…O hydrogen bonds (PMID:12220491)
• Present throughout the epithelium with minimal nuclear accumulation. Increased in basal and luminal epithelial nuclei in glands with benign prostatic hyperplasia. (PMID:12399530)
• RARgamma interact only weakly with SMRT. (PMID:12554770)
• RAR beta and RAR gamma receptors appear to adopt a constitutively closed helix 12 conformation in the absence of hormone that may approximate the conformation of RAR alpha when bound to hormone agonist. (PMID:12665583)
• In a 9-cis retinoic acid-dependent fashion in cells in vitro, retinoic acid receptor isoform gamma 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)
• Tazarotene is a prodrug selective for RARbeta/gamma, thereby motivating interest in determining whether tazarotene might activate putative tumor suppressor activity. (PMID:15383624)
• phosphorylation of the AF-1 domain controls RARgamma-mediated transcription through triggering the dissociation of vinexin beta (PMID:15734736)
• Biological properties of the other RAR isoforms (RARbeta and RARgamma), through the generation pf fusion protein isoforms in acutte promyelocytic leukemia. (PMID:17252005)
• study elucidated a nongenomic extranuclear signal mediated by the RAR-SRC interaction that is negatively regulated by CSK and is required for RA-induced neuronal differentiation (PMID:17325034)
• analysis to determine directly whether PML-RAR, like PML-RAR, is able to induce APL (PMID:18685608)
• The first 2250 bp of the HAS2 promoter contain three response elements (REs) for the transcription factor CREB1 as well as two REs for the nuclear receptor RAR (PMID:19416972)
• the subcellular localization of RARgamma is regulated by complex interactions among ligand binding, receptor phosphorylation, and receptor dimerizations (PMID:19416983)
• Study found that RARalpha/RARgamma exhibit extensive colocalization of their genomic binding regions with ERalpha in the vicinity of genes that are antagonistically regulated by estrogen and RA. (PMID:19563758)
• TNIP1 interacts with liganded RARalpha and RARgamma but acts as a corepressor of their activity. (PMID:19732752)
• Data show significant associations between SNPs in RARA, RARB, TOP2B and RARG, RXRA, TLR3, TRIM5 and RIG-I genes and rubella virus-specific cytokine immune responses. (PMID:19902255)
• PARgamma expressions are decreased in PBMC and SWAT of obese subjects in weight gain. (PMID:20387030)
• Retinoic acid receptor gamma 2 could specifically interact with vitamin D response elements, either in the presence or absence of the vitamin D receptor. (PMID:20420906)
• Microbiota are required for the generation of both IL-17-positive and Foxp3-positive, retinoic acid-related orphan receptor gamma-positive transgenic T cell subsets in the intestinal lamina propria. (PMID:21178008)
• One variant in the RARA gene (rs12051734), three variants in the RARB gene (rs6799734, rs12630816, rs17016462), and one variant in the RARG gene (rs3741434) were found to be statistically significant at p < 0.05 as risk factors for meningomyelocele. (PMID:21254357)
• results suggest that a RARgamma-dependent functional crosstalk is present between the retinoic acid and BMP2 signaling to induce osteogenic transdifferentiation in myoblastic C2C12 cells (PMID:21401418)
• findings demonstrate that signaling through RARs has critical roles in molecular reprogramming and that the synergistic interaction between Rarg and Lrh1 directs reprogramming toward ground-state pluripotency (PMID:21990348)
• Evidence that the retinoic acid receptor gamma plays a major role in the regulation of the human prostatic transglutaminase gene. (PMID:22362749)
• Low RARgamma expression is associated with advanced gastric cancer. (PMID:22901127)
• RARgamma in concert with ATRA regulates protein levels of CDK1 and its subcellular localization. (PMID:23518499)
• RARG plays an important role in the proliferation, metastasis, and chemoresistance of cholangiocarcinoma through simultaneous activation of the Akt/NF-kappaB and Wnt/beta-catenin pathways. (PMID:23798555)
• The current status of knowledge indicates that there might be inter- or overlapping actions between PPARg and RARs, and there might be an association of PPARg/RARs(RARa, RARb, and RARg) with renal diseases (PMID:24050824)
• deregulation of the retinoid/rexinoid signaling pathway has a major role and may represent a potential therapeutic target for NUP98-RARG-mediated transformation (PMID:25510432)
• A nonsynonymous variant in RARG is highly associated with anthracycline-induced cardiotoxicity in childhood cancers. (PMID:26237429)
• Loss of RARG expression is associated with Colorectal Tumorigenesis and Metastasis. (PMID:27325643)
• Results show that RARgamma expression is significantly upregulated in human hepatocellular carcinoma (HCC) tissues and demonstrate that RARgamma could promote HCC invasion and metastasis by regulating E-cadherin reduction. (PMID:27756432)
• RARgamma might serve as a potential therapeutic target for chemoresistant colorectal cancer patients. (PMID:28272990)
• Study reports that retinoic acid receptor-gamma (RARgamma) is a negative regulator of p53 signaling and thus extend the oncogenic potential of RARgamma to a new role in controlling the balance between AKT and p53. (PMID:28336971)
• Our study is the first to report that treatment with a RARgamma specific agonist augments cellular adhesion to alpha5beta1 integrin substrates, increases cell surface levels of the beta1 integrin subunit, and dampens cellular proliferation in a time and concentration dependent manner in a human erythroleukemia cell line (PMID:28552962)
• Dual small interfering RNA (siRNA) silencing of RARalpha and RARgamma reversed RA blockade of P4-induced CK5. Using promoter deletion analysis, we identified a region 1.1 kb upstream of the CK5 transcriptional start site that is necessary for P4 activation and contains a putative progesterone response element (PRE (PMID:28692043)
• the cytoplasmic retinoic acid receptor gamma (RARgamma) controls receptor-interacting protein kinase 1 (RIP1)-initiated cell death when cellular inhibitor of apoptosis (cIAP) activity is blocked. (PMID:28871172)
• RARA and RARG gene downregulation associated with EZH2 mutation in acute promyelocytic-like morphology leukemia (PMID:29530751)
• A novel CPSF6-RARG fusion transcript in acute myeloid leukemia. (PMID:29568099)

Cross-species orthologs

186 orthologs

Organism	Symbol	Gene ID
danio_rerio	rarga	ENSDARG00000034117
danio_rerio	rargb	ENSDARG00000054003
mus_musculus	Rarg	ENSMUSG00000001288
rattus_norvegicus	Rarg	ENSRNOG00000012499
drosophila_melanogaster	Hr96	FBGN0015240
caenorhabditis_elegans		WBGENE00001062
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		WBGENE00004786
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), RARA (ENSG00000131759), PPARG (ENSG00000132170), NR1I3 (ENSG00000143257), RORC (ENSG00000143365), NR1I2 (ENSG00000144852), THRB (ENSG00000151090), NR1D2 (ENSG00000174738), PPARA (ENSG00000186951), RORB (ENSG00000198963)

Protein

Protein identifiers

Retinoic acid receptor gamma — P13631 (reviewed: P13631)

Alternative names: Nuclear receptor subfamily 1 group B member 3

All UniProt accessions (6): P13631, A8K3H3, F1D8P1, H3BMH6, H3BMK1, H3BMY6

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 RAR/RXR 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, acts mainly as an activator of gene expression due to weak binding to corepressors. Required for limb bud development. In concert with RARA or RARB, required for skeletal growth, matrix homeostasis and growth plate function.

Subunit / interactions. Homodimer. Heterodimer with a RXR molecule. Binds DNA preferentially as a RAR/RXR heterodimer. Forms a complex with PUS1 and the SRA1 RNA in the nucleus.

Subcellular location. Nucleus. Cytoplasm.

Tissue specificity. Expressed in aortic endothelial cells (at protein level).

Domain organisation. Composed of three domains: a modulating N-terminal domain, a DNA-binding domain and a C-terminal ligand-binding domain.

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

Isoforms (4)

UniProt ID	Names	Canonical?
P13631-1	1	yes
P13631-2	2
P13631-3	3
P13631-4	4

RefSeq proteins (5): NP_000957, NP_001036193, NP_001230659, NP_001230660, NP_001230661 (=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 (42 total): helix 13, sequence conflict 5, region of interest 5, splice variant 3, strand 3, compositionally biased region 2, cross-link 2, sequence variant 2, zinc finger region 2, chain 1, domain 1, modified residue 1, DNA-binding region 1, turn 1

Structure

Experimental structures (PDB)

11 structures.

PDB	Method	Resolution (Å)
1FCY	X-RAY DIFFRACTION	1.3
1FCZ	X-RAY DIFFRACTION	1.38
1FD0	X-RAY DIFFRACTION	1.38
1FCX	X-RAY DIFFRACTION	1.47
1EXA	X-RAY DIFFRACTION	1.59
1EXX	X-RAY DIFFRACTION	1.67
5M24	X-RAY DIFFRACTION	1.69
6FX0	X-RAY DIFFRACTION	1.9
2LBD	X-RAY DIFFRACTION	2.06
3LBD	X-RAY DIFFRACTION	2.4
4LBD	X-RAY DIFFRACTION	2.5

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P13631-F1	79.23	0.62

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 (3): 34, 172, 401

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-383280	Nuclear Receptor transcription pathway
R-HSA-5362517	Signaling by Retinoic Acid
R-HSA-5617472	Activation of anterior HOX genes in hindbrain development during early embryogenesis

MSigDB gene sets: 387 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, AHRARNT_01, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, RNGTGGGC_UNKNOWN, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_GLAND_MORPHOGENESIS, GOBP_CARTILAGE_DEVELOPMENT, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, GOBP_PROSTATE_GLAND_MORPHOGENESIS, GOBP_REGULATION_OF_CARTILAGE_DEVELOPMENT, GOBP_RESPONSE_TO_PEPTIDE, GOBP_EPITHELIAL_CELL_DEVELOPMENT, GOBP_HINDLIMB_MORPHOGENESIS, GOBP_GROWTH

GO Biological Process (46): negative regulation of transcription by RNA polymerase II (GO:0000122), neural tube closure (GO:0001843), glandular epithelial cell development (GO:0002068), growth plate cartilage chondrocyte growth (GO:0003430), apoptotic process (GO:0006915), positive regulation of cell population proliferation (GO:0008284), negative regulation of cell population proliferation (GO:0008285), regulation of cell size (GO:0008361), anterior/posterior pattern specification (GO:0009952), positive regulation of gene expression (GO:0010628), cell differentiation (GO:0030154), embryonic camera-type eye development (GO:0031076), regulation of myelination (GO:0031641), negative regulation of chondrocyte differentiation (GO:0032331), response to retinoic acid (GO:0032526), embryonic hindlimb morphogenesis (GO:0035116), multicellular organism growth (GO:0035264), positive regulation of apoptotic process (GO:0043065), positive regulation of programmed cell death (GO:0043068), regulation of myeloid cell differentiation (GO:0045637), positive regulation of transcription by RNA polymerase II (GO:0045944), embryonic eye morphogenesis (GO:0048048), retinoic acid receptor signaling pathway (GO:0048384), canonical Wnt signaling pathway (GO:0060070), face development (GO:0060324), trachea cartilage development (GO:0060534), prostate gland epithelium morphogenesis (GO:0060740), Harderian gland development (GO:0070384), cellular response to retinoic acid (GO:0071300), stem cell proliferation (GO:0072089), cellular response to leukemia inhibitory factor (GO:1990830), negative regulation of stem cell proliferation (GO:2000647), chondrocyte development (GO:0002063), growth plate cartilage development (GO:0003417), regulation of DNA-templated transcription (GO:0006355), cell population proliferation (GO:0008283), regulation of gene expression (GO:0010468), programmed cell death (GO:0012501), negative regulation of cell differentiation (GO:0045596), reproductive structure development (GO:0048608)

GO Molecular Function (12): 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 (GO:0003677), chromatin binding (GO:0003682), DNA-binding transcription factor activity (GO:0003700), nuclear receptor activity (GO:0004879), zinc ion binding (GO:0008270), nuclear retinoid X receptor binding (GO:0046965), sequence-specific double-stranded DNA binding (GO:1990837), protein binding (GO:0005515), sequence-specific DNA binding (GO:0043565), metal ion binding (GO:0046872)

GO Cellular Component (7): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), transcription regulator complex (GO:0005667), cytoplasm (GO:0005737), membrane (GO:0016020), RNA polymerase II transcription regulator complex (GO:0090575)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Generic Transcription Pathway	1
Signaling by Nuclear Receptors	1
Activation of HOX genes during differentiation	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
regulation of transcription by RNA polymerase II	2
programmed cell death	2
cell population proliferation	2
regulation of cell population proliferation	2
positive regulation of cellular process	2
RNA polymerase II transcription regulatory region sequence-specific DNA binding	2
binding	2
transcription by RNA polymerase II	1
negative regulation of DNA-templated transcription	1
primary neural tube formation	1
tube closure	1
columnar/cuboidal epithelial cell development	1
glandular epithelial cell differentiation	1
chondrocyte hypertrophy	1
growth plate cartilage chondrocyte development	1
developmental growth involved in morphogenesis	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
negative regulation of cellular process	1
regulation of cellular component size	1
regionalization	1
gene expression	1
regulation of gene expression	1
positive regulation of macromolecule biosynthetic process	1
cellular developmental process	1
camera-type eye development	1
embryonic organ development	1
myelination	1
regulation of cellular process	1
regulation of nervous system development	1
chondrocyte differentiation	1
regulation of chondrocyte differentiation	1
negative regulation of cell differentiation	1
negative regulation of cartilage development	1
response to lipid	1
response to oxygen-containing compound	1
embryonic limb morphogenesis	1
hindlimb morphogenesis	1
multicellular organismal process	1

Protein interactions and networks

STRING

1528 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RARG	RARS1	P54136	968
RARG	CRABP2	P29373	881
RARG	RARB	P10826	824
RARG	SRA1	Q9HD15	818
RARG	RXRA	P19793	777
RARG	CYP26A1	O43174	728
RARG	PLAAT4	Q9UL19	692
RARG	RBP1	P09455	655
RARG	CCAR1	Q8IX12	647
RARG	PLAAT3	P53816	642
RARG	PLAAT1	Q9HDD0	635
RARG	ALDH1A2	O94788	620
RARG	RARA	P10276	620
RARG	CYP26B1	Q9NR63	619
RARG	RBP2	P50120	618

IntAct

56 interactions, top by confidence:

A	B	Type	Score
RARG	RXRB	psi-mi:“MI:0915”(physical association)	0.740
RARG	RXRG	psi-mi:“MI:0915”(physical association)	0.560
MYF5	RARG	psi-mi:“MI:0915”(physical association)	0.560
RARG	BBS4	psi-mi:“MI:0915”(physical association)	0.560
RARG	PRKAR1B	psi-mi:“MI:0915”(physical association)	0.560
RARG	RARA	psi-mi:“MI:0914”(association)	0.530
RARA	FOS	psi-mi:“MI:0914”(association)	0.460
RARG	ZNF423	psi-mi:“MI:0915”(physical association)	0.400
SORBS3	RARG	psi-mi:“MI:0915”(physical association)	0.400
RARG	SORBS3	psi-mi:“MI:0915”(physical association)	0.400
	RARG	psi-mi:“MI:0915”(physical association)	0.370
IL31	RARG	psi-mi:“MI:0915”(physical association)	0.370
MRPL12	RARG	psi-mi:“MI:0915”(physical association)	0.370
RARG	SPHK1	psi-mi:“MI:0915”(physical association)	0.370
RARG	MTMR6	psi-mi:“MI:0915”(physical association)	0.370
IL24	RARG	psi-mi:“MI:0915”(physical association)	0.370
RARG	OIP5	psi-mi:“MI:0915”(physical association)	0.370
RARG	LSR	psi-mi:“MI:0915”(physical association)	0.370
RARG	ZNF576	psi-mi:“MI:0915”(physical association)	0.370
RHPN2	RARG	psi-mi:“MI:0915”(physical association)	0.370
ACY3	RARG	psi-mi:“MI:0915”(physical association)	0.370
Sorbs3	RARG	psi-mi:“MI:0915”(physical association)	0.370
RARG		psi-mi:“MI:0914”(association)	0.350
ESR1	FOS	psi-mi:“MI:0914”(association)	0.350

BioGRID (60): RARG (Reconstituted Complex), RARG (Reconstituted Complex), RARG (Reconstituted Complex), PSMC5 (Two-hybrid), RARA (Affinity Capture-MS), PNMAL1 (Affinity Capture-MS), RXRB (Affinity Capture-MS), ZPLD1 (Affinity Capture-MS), KCNJ6 (Affinity Capture-MS), RBL2 (Affinity Capture-MS), RARG (Affinity Capture-Western), YAP1 (Affinity Capture-Western), RARG (Reconstituted Complex), RARG (Two-hybrid), RARG (Two-hybrid)

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

25 interactions.

A	Effect	B	Mechanism
RARG	up-regulates	THRA	binding
THRA	up-regulates	RARG	binding
RARG	up-regulates	RXRA	binding
RARG	up-regulates	RXRB	binding
RXRA	up-regulates	RARG	binding
RXRB	up-regulates	RARG	binding
F2RL1	“down-regulates quantity by repression”	RARG	“transcriptional regulation”
“all-trans-retinoic acid”	“up-regulates activity”	RARG	“chemical activation”
adapalene	“up-regulates activity”	RARG	“chemical activation”
“9-cis-retinoic acid”	“up-regulates activity”	RARG	“chemical activation”
THR	“up-regulates activity”	RARG	binding
RARG	“up-regulates activity”	THR	binding
RARG	up-regulates	THR	binding
THR	up-regulates	RARG	binding
AKT1	“up-regulates activity”	RARG	phosphorylation
tazarotene	“up-regulates activity”	RARG	“chemical activation”
“4-{[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)carbonyl]amino}benzoic acid”	“up-regulates activity”	RARG	“chemical activation”
CDK7	“up-regulates activity”	RARG	phosphorylation
POU5F1	“up-regulates quantity”	RARG
“CAK complex”	“up-regulates activity”	RARG	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	1
Uncertain significance	26
Likely benign	1
Benign	1

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
4686674	NM_000966.6(RARG):c.1237C>T (p.Arg413Ter)	Likely pathogenic

SpliceAI

1792 predictions. Top by Δscore:

Variant	Effect	Δscore
12:53211859:AGCTC:A	acceptor_gain	1.0000
12:53211860:GCTC:G	acceptor_gain	1.0000
12:53211861:CTC:C	acceptor_gain	1.0000
12:53211861:CTCC:C	acceptor_gain	1.0000
12:53211862:TC:T	acceptor_gain	1.0000
12:53211862:TCCT:T	acceptor_gain	1.0000
12:53211863:CC:C	acceptor_gain	1.0000
12:53211864:C:CC	acceptor_gain	1.0000
12:53211867:CAA:C	acceptor_gain	1.0000
12:53211869:A:AC	acceptor_gain	1.0000
12:53213080:CTCA:C	donor_loss	1.0000
12:53213083:A:AC	donor_gain	1.0000
12:53213083:AC:A	donor_gain	1.0000
12:53213083:ACC:A	donor_gain	1.0000
12:53213084:C:CT	donor_gain	1.0000
12:53213084:CC:C	donor_gain	1.0000
12:53213084:CCC:C	donor_gain	1.0000
12:53213084:CCCT:C	donor_gain	1.0000
12:53213084:CCCTT:C	donor_gain	1.0000
12:53213123:AGCAT:A	donor_gain	1.0000
12:53213240:CGGT:C	acceptor_gain	1.0000
12:53213241:GGT:G	acceptor_gain	1.0000
12:53213244:C:CC	acceptor_gain	1.0000
12:53213497:T:TA	donor_gain	1.0000
12:53214055:TTAC:T	donor_loss	1.0000
12:53214057:A:AC	donor_gain	1.0000
12:53214057:AC:A	donor_gain	1.0000
12:53214058:C:CT	donor_gain	1.0000
12:53214058:CC:C	donor_gain	1.0000
12:53214058:CCAGG:C	donor_gain	1.0000

AlphaMissense

2984 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:53211794:A:G	L416P	1.000
12:53211797:A:G	M415T	1.000
12:53211809:A:G	L411S	1.000
12:53211842:A:G	L400P	1.000
12:53213085:C:G	G393R	1.000
12:53213085:C:T	G393R	1.000
12:53213102:C:G	R387P	1.000
12:53213105:A:G	L386P	1.000
12:53213105:A:T	L386H	1.000
12:53213123:A:G	L380P	1.000
12:53213180:A:G	L361P	1.000
12:53213507:A:G	L336P	1.000
12:53213507:A:T	L336H	1.000
12:53213509:G:C	C335W	1.000
12:53213511:A:G	C335R	1.000
12:53213516:G:T	A333D	1.000
12:53213517:C:G	A333P	1.000
12:53213522:A:G	L331P	1.000
12:53213525:A:G	L330P	1.000
12:53213528:C:T	G329E	1.000
12:53213529:C:A	G329W	1.000
12:53213529:C:G	G329R	1.000
12:53213529:C:T	G329R	1.000
12:53213561:A:G	L318P	1.000
12:53213570:G:T	A315D	1.000
12:53213578:A:C	F312L	1.000
12:53213578:A:T	F312L	1.000
12:53213579:A:G	F312S	1.000
12:53213580:A:G	F312L	1.000
12:53213600:C:T	G305E	1.000

dbSNP variants (sampled 300 via entrez): RS1000086011 (12:53222232 A>T), RS1000213677 (12:53217223 G>A,C), RS1000586203 (12:53226860 C>T), RS1000619101 (12:53226569 C>G), RS1000727660 (12:53233377 G>A), RS1000988490 (12:53221857 G>C), RS1001144037 (12:53224726 T>C), RS1001157584 (12:53220706 G>A,T), RS1001484247 (12:53220976 G>C), RS1001548892 (12:53210687 C>A,T), RS1001552174 (12:53222307 G>A,C), RS1001567382 (12:53217742 C>A,T), RS1001723838 (12:53216746 T>TTGCA), RS1002054092 (12:53215193 G>A), RS1002158391 (12:53223530 C>A,G,T)

Disease associations

OMIM: gene MIM:180190 | disease phenotypes: MIM:604229, MIM:226985

GenCC curated gene-disease

Mondo (2): Peters anomaly (MONDO:0011414), epithelial squamous dysplasia, keratinizing desquamative, of urinary tract (MONDO:0009193)

Orphanet (1): Peters anomaly (Orphanet:708)

HPO phenotypes

1 total (1 of 1 shown, HPO-id order):

HPO	Term
HP:0000659	Peters anomaly

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST003062_1	Anthracycline-induced cardiotoxicity in childhood cancer	6.000000e-08
GCST003062_2	Anthracycline-induced cardiotoxicity in childhood cancer	8.000000e-08
GCST008595_118	Cognitive ability, years of educational attainment or schizophrenia (pleiotropy)	1.000000e-10
GCST010573_7	Cardiorespiratory fitness (800m run time)	2.000000e-07

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0005257	response to anthracycline-based chemotherapy
EFO:1001482	cardiotoxicity
EFO:0004337	intelligence
EFO:0004784	self reported educational attainment
EFO:0004328	exercise test

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
C565584	Epithelial Squamous Dysplasia, Keratinizing Desquamative, of Urinary Tract (supp.)
C537884	Peters anomaly (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (4): CHEMBL2003 (SINGLE PROTEIN), CHEMBL2363069 (PROTEIN FAMILY), CHEMBL2363071 (PROTEIN FAMILY), CHEMBL3885633 (PROTEIN COMPLEX)

Molecules with ChEMBL bioactivity

17 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 727,776 (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
CHEMBL1082	AMOXICILLIN	4	113,048
CHEMBL112	ACETAMINOPHEN	4	157,242
CHEMBL1265	ADAPALENE	4	12,179
CHEMBL1657	TAZAROTENE	4	26,405
CHEMBL1946170	REGORAFENIB	4	12,678
CHEMBL2103772	RACECADOTRIL	4	1,787
CHEMBL25202	TAMIBAROTENE	4	5,139
CHEMBL3707313	TRIFAROTENE	4	224
CHEMBL38	TRETINOIN	4	194,008
CHEMBL408	TROGLITAZONE	4	38,856
CHEMBL495	ALPROSTADIL	4	13,450
CHEMBL705	ALITRETINOIN	4	39,246
CHEMBL715	OLANZAPINE	4	40,057
CHEMBL843	ROSIGLITAZONE MALEATE	4	22,589
CHEMBL191703	CONESSINE	2	437
CHEMBL383634	GLIQUIDONE	2	9,480

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

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs2229774	Toxicity	3	anthracyclines and related substances;daunorubicin;doxorubicin	Cardiotoxicity;Neoplasms

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs2229774	RARG	3	6.25	1	anthracyclines and related substances;daunorubicin;doxorubicin

PharmGKB dosing guidelines

1 guidelines.

Source	Drug	Guideline	Dosing?	Recommendation?
CPNDS	daunorubicin;doxorubicin	Annotation of CPNDS Guideline for daunorubicin, doxorubicin and RARG, SLC28A3, UGT1A6		yes

GtoPdb / IUPHAR curated pharmacology

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

Target class: nhr — 1B. Retinoic acid receptors

Most potent curated ligand interactions (16 total), top 16:

Ligand	Action	Affinity	Parameter
tretinoin	Agonist	9.6	pKd
[3H]9-cis-retinoic acid	Full agonist	9.2	pKd
alitretinoin	Agonist	9.0	pKd
AGN193109	Antagonist	8.5	pIC50
trifarotene	Agonist	8.11	pEC50
Ro 40-6055	Agonist	7.89	pEC50
TTNPB	Agonist	7.82	pIC50
tazarotene	Agonist	7.4	pEC50
CD666	Agonist	7.17	pKd
AHPN	Agonist	7.11	pKi
CD2665	Antagonist	7.1	pIC50
BMS493	Antagonist	7.0	pIC50
adapalene	Agonist	6.89	pKi
BMS270394	Agonist	6.3	pIC50
tamibarotene	Agonist	6.23	pEC50
YCT-529	Antagonist	5.48	pIC50

Binding affinities (BindingDB)

13 measured of 14 human assays (14 total across all organisms); most potent 13 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
6-[3-Adamantan-1-yl-4-(2,3-dihydroxy-propoxy)-phenyl]-naphthalene-2-carboxylic acid	KI	151 nM
CD666	KD	2240 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

482 potent at pChembl≥5 of 489 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.40	Ki	0.04	nM	TRETINOIN
10.19	EC50	0.065	nM	CHEMBL5997757
9.92	Kd	0.12	nM	CHEMBL3939687
9.70	Kd	0.2	nM	TRETINOIN
9.70	EC50	0.2	nM	TRETINOIN
9.66	EC50	0.22	nM	CHEMBL4210595
9.60	Kd	0.25	nM	CHEMBL3936922
9.60	Kd	0.25	nM	CHEMBL3945228
9.60	Kd	0.25	nM	CHEMBL3907274
9.57	Ki	0.27	nM	CHEMBL3814574
9.52	Kd	0.3	nM	TRETINOIN
9.47	EC50	0.34	nM	CHEMBL89241
9.40	EC50	0.4	nM	CHEMBL285179
9.40	EC50	0.4	nM	CHEMBL12585
9.30	IC50	0.5	nM	CHEMBL165629
9.30	Kd	0.5	nM	CHEMBL3957342
9.30	Kd	0.5	nM	CHEMBL3901588
9.30	Kd	0.5	nM	CHEMBL3931870
9.30	EC50	0.5	nM	TRETINOIN
9.30	IC50	0.5	nM	TRETINOIN
9.30	Ki	0.5	nM	TRETINOIN
9.28	EC50	0.53	nM	CHEMBL5947674
9.22	Ki	0.6	nM	TRETINOIN
9.22	EC50	0.6	nM	CHEMBL451835
9.21	IC50	0.62	nM	TRETINOIN
9.15	EC50	0.7	nM	TRETINOIN
9.15	Ki	0.7	nM	TRETINOIN
9.10	Kd	0.8	nM	ALITRETINOIN
9.05	EC50	0.9	nM	CHEMBL1235644
9.04	EC50	0.92	nM	CHEMBL4205733
9.00	Kd	1	nM	CHEMBL3953756
9.00	EC50	1	nM	TRETINOIN
9.00	AC50	1	nM	CHEMBL25088
9.00	EC50	1	nM	CHEMBL275311
9.00	Ki	1	nM	ALITRETINOIN
8.96	Ki	1.1	nM	CHEMBL3814815
8.96	Ki	1.1	nM	CHEMBL3813779
8.96	Ki	1.1	nM	CHEMBL3815166
8.89	Kd	1.3	nM	CHEMBL82716
8.85	Ki	1.4	nM	CHEMBL3813975
8.85	EC50	1.4	nM	CHEMBL4202830
8.85	EC50	1.4	nM	CHEMBL441231
8.80	Ki	1.6	nM	CHEMBL3813965
8.72	EC50	1.9	nM	CHEMBL3939687
8.72	Ki	1.9	nM	CHEMBL89241
8.70	IC50	2	nM	CHEMBL162345
8.70	IC50	2	nM	CHEMBL162393
8.70	IC50	2	nM	CHEMBL165417
8.70	Kd	2	nM	CHEMBL3960035
8.70	Kd	2	nM	CHEMBL3891815

PubChem BioAssay actives

337 with measured affinity, of 1060 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
tretinoin	198732: Agonistic activity towards retinoic acid receptor-gamma	ki	<0.0001	uM
4-[4-(3-hydroxypropoxy)-3-(5,5,8,8-tetramethyl-6,7-dihydronaphthalen-2-yl)phenyl]benzoic acid	1380631: Agonist activity at GAL4 DNA-binding domain-tagged RARgamma (unknown origin) ligand-binding domain expressed in human HG5LN cells incubated for 18 hrs by luciferase reporter gene assay	ec50	0.0002	uM
4-[1-(4-methylsulfonylphenyl)-5-(5,5,8,8-tetramethyl-6,7-dihydronaphthalen-2-yl)pyrazol-3-yl]benzoic acid	1306249: Displacement of [3H]-TTNPB from RARgamma/RXRalpha (unknown origin) expressed in baculovirus expression system by scintillation proximity assay	ki	0.0003	uM
(2E,4E,6E)-7-(3,5-ditert-butylphenyl)-3-methylocta-2,4,6-trienoic acid	198902: Transcriptional activation in CV-1 cells expressing Retinoic acid receptor RAR gamma	ec50	0.0003	uM
4-[2,2-dimethyl-4-(4-methylphenyl)benzo[g]thiochromen-7-yl]benzoic acid	228588: Antagonistic activity against RAR gamma in transcriptional activation assay with 3.2 nM TTNPB	ic50	0.0005	uM
4-[2-(5,5,8,8-tetramethyl-6,7-dihydronaphthalen-2-yl)ethynyl]benzoic acid	392142: Activity at human RARgamma 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-[(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	0.0006	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	0.0008	uM
4-[4-(4-hydroxybutoxy)-3-(5,5,8,8-tetramethyl-6,7-dihydronaphthalen-2-yl)phenyl]benzoic acid	1380631: Agonist activity at GAL4 DNA-binding domain-tagged RARgamma (unknown origin) ligand-binding domain expressed in human HG5LN cells incubated for 18 hrs by luciferase reporter gene assay	ec50	0.0009	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
4-[5-(3-tert-butylphenyl)-1-(4-methylsulfonylphenyl)pyrazol-3-yl]benzoic acid	1306249: Displacement of [3H]-TTNPB from RARgamma/RXRalpha (unknown origin) expressed in baculovirus expression system by scintillation proximity assay	ki	0.0011	uM
4-[5-(3-tert-butyl-5-methylphenyl)-1-(4-methylsulfonylphenyl)pyrazol-3-yl]benzoic acid	1306249: Displacement of [3H]-TTNPB from RARgamma/RXRalpha (unknown origin) expressed in baculovirus expression system by scintillation proximity assay	ki	0.0011	uM
4-[5-(3,5-ditert-butylphenyl)-1-[4-(4-methylpiperazine-1-carbonyl)phenyl]pyrazol-3-yl]benzoic acid	1306249: Displacement of [3H]-TTNPB from RARgamma/RXRalpha (unknown origin) expressed in baculovirus expression system by scintillation proximity assay	ki	0.0011	uM
6-[1-(5,5,8,8-tetramethyl-6,7-dihydronaphthalen-2-yl)ethenyl]naphthalene-2-carboxylic acid	198728: Apparent binding constant against Retinoic acid receptor gamma in HeLa cell GAl-4 transactivation assay	kd	0.0013	uM
4-[4-(2-hydroxyethyl)-3-(5,5,8,8-tetramethyl-6,7-dihydronaphthalen-2-yl)phenyl]benzoic acid	1380631: Agonist activity at GAL4 DNA-binding domain-tagged RARgamma (unknown origin) ligand-binding domain expressed in human HG5LN cells incubated for 18 hrs by luciferase reporter gene assay	ec50	0.0014	uM
4-[1-(4-carbamoylphenyl)-5-(3,5-ditert-butylphenyl)pyrazol-3-yl]benzoic acid	1306249: Displacement of [3H]-TTNPB from RARgamma/RXRalpha (unknown origin) expressed in baculovirus expression system by scintillation proximity assay	ki	0.0014	uM
3-fluoro-4-[[(2R)-2-hydroxy-2-(5,5,8,8-tetramethyl-6,7-dihydronaphthalen-2-yl)acetyl]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	0.0015	uM
4-[5-(3-tert-butyl-5-propan-2-ylphenyl)-1-(4-methylsulfonylphenyl)pyrazol-3-yl]benzoic acid	1306249: Displacement of [3H]-TTNPB from RARgamma/RXRalpha (unknown origin) expressed in baculovirus expression system by scintillation proximity assay	ki	0.0016	uM
4-[3-[3-tert-butyl-4-(diethylamino)phenyl]-4-(3-hydroxypropoxy)phenyl]benzoic acid	1380631: Agonist activity at GAL4 DNA-binding domain-tagged RARgamma (unknown origin) ligand-binding domain expressed in human HG5LN cells incubated for 18 hrs by luciferase reporter gene assay	ec50	0.0019	uM
4-[5,5-dimethyl-8-(4-methylphenyl)-6H-anthracen-2-yl]benzoic acid	228588: Antagonistic activity against RAR gamma in transcriptional activation assay with 3.2 nM TTNPB	ic50	0.0020	uM
4-[5,5-dimethyl-8-(5-methylthiophen-2-yl)-6H-anthracen-2-yl]benzoic acid	228588: Antagonistic activity against RAR gamma in transcriptional activation assay with 3.2 nM TTNPB	ic50	0.0020	uM
4-[5-(5,5,8,8-tetramethyl-6,7-dihydroquinoxalin-2-yl)thiophen-3-yl]benzoic acid	198726: Binding affinity for Retinoic Acid Receptor gamma (RAR gamma)	ic50	0.0020	uM
4-(5,5,8,8-tetramethyl-6,7-dihydroanthracen-2-yl)benzoic acid	198738: Binding affinity to retinoic acid receptor (RAR) gamma using [3H]CD 367 as radioligand	ki	0.0020	uM
4-[4-methoxy-3-(5,5,8,8-tetramethyl-6,7-dihydronaphthalen-2-yl)phenyl]benzoic acid	1380631: Agonist activity at GAL4 DNA-binding domain-tagged RARgamma (unknown origin) ligand-binding domain expressed in human HG5LN cells incubated for 18 hrs by luciferase reporter gene assay	ec50	0.0020	uM
4-[(E)-2-(5,5,8,8-tetramethyl-6,7-dihydronaphthalen-2-yl)prop-1-enyl]benzoic acid	199391: Binding affinity against retinoic Acid gamma receptors co-transfected into CV-1 cells	ec50	0.0020	uM
4-[2,2-dimethyl-4-(4-methylphenyl)benzo[g]chromen-7-yl]benzoic acid	228588: Antagonistic activity against RAR gamma in transcriptional activation assay with 3.2 nM TTNPB	ic50	0.0020	uM
4-[3-(3-tert-butyl-4-pyrrolidin-1-ylphenyl)-4-(3-hydroxypropoxy)phenyl]benzoic acid	1380631: Agonist activity at GAL4 DNA-binding domain-tagged RARgamma (unknown origin) ligand-binding domain expressed in human HG5LN cells incubated for 18 hrs by luciferase reporter gene assay	ec50	0.0021	uM
4-[5-(3,5-ditert-butylphenyl)-1-[4-(dimethylcarbamoyl)phenyl]pyrazol-3-yl]benzoic acid	1306249: Displacement of [3H]-TTNPB from RARgamma/RXRalpha (unknown origin) expressed in baculovirus expression system by scintillation proximity assay	ki	0.0022	uM
4-[5-(3,5-ditert-butylphenyl)-1-[4-(morpholine-4-carbonyl)phenyl]pyrazol-3-yl]benzoic acid	1306249: Displacement of [3H]-TTNPB from RARgamma/RXRalpha (unknown origin) expressed in baculovirus expression system by scintillation proximity assay	ki	0.0023	uM
4-[2-[5,5-dimethyl-8-(4-methylphenyl)-6H-naphthalen-2-yl]ethynyl]benzoic acid	199042: Antagonist activity of TTNPB (10 nM) function at retinoic acid receptor gamma	ic50	0.0030	uM
6-(5,5,8,8-tetramethyl-6,7-dihydronaphthalene-2-carbonyl)naphthalene-2-carboxylic 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	0.0030	uM
4-[(E)-4-[2-(4-ethylphenyl)-6,6-dimethylcyclohexen-1-yl]but-3-en-1-ynyl]benzoic acid	199042: Antagonist activity of TTNPB (10 nM) function at retinoic acid receptor gamma	ic50	0.0030	uM
Adapalene	1380631: Agonist activity at GAL4 DNA-binding domain-tagged RARgamma (unknown origin) ligand-binding domain expressed in human HG5LN cells incubated for 18 hrs by luciferase reporter gene assay	ec50	0.0031	uM
6-[(Z)-N-hydroxy-C-(5,5,8,8-tetramethyl-6,7-dihydronaphthalen-2-yl)carbonimidoyl]naphthalene-2-carboxylic acid	198728: Apparent binding constant against Retinoic acid receptor gamma in HeLa cell GAl-4 transactivation assay	kd	0.0033	uM
4-[4-(5,5,8,8-tetramethyl-6,7-dihydroquinoxalin-2-yl)-1,3-thiazol-2-yl]benzoic acid	198726: Binding affinity for Retinoic Acid Receptor gamma (RAR gamma)	ic50	0.0036	uM
4-[3-[3-tert-butyl-4-(diethylamino)phenyl]-4-(2-hydroxyethoxy)phenyl]benzoic acid	1380631: Agonist activity at GAL4 DNA-binding domain-tagged RARgamma (unknown origin) ligand-binding domain expressed in human HG5LN cells incubated for 18 hrs by luciferase reporter gene assay	ec50	0.0036	uM
4-[(E)-4-[3,3-dimethyl-6-(4-methylphenyl)cyclohexa-1,5-dien-1-yl]but-3-en-1-ynyl]benzoic acid	199050: Binding affinity towards retinoic acid receptor gamma was determined using [3H]ATRA (5 nM) as radioligand	kd	0.0040	uM
4-[(E)-3-(5,5,8,8-tetramethyl-6,7-dihydronaphthalen-2-yl)prop-1-enyl]benzoic acid	198898: Ability to inhibit TTNPB-induced transactivation at retinoic acid receptor gamma	ec50	0.0040	uM
4-[2,2-dimethyl-4-(5-methylthiophen-2-yl)benzo[g]chromen-7-yl]benzoic acid	228588: Antagonistic activity against RAR gamma in transcriptional activation assay with 3.2 nM TTNPB	ic50	0.0040	uM
4-[5-(3,5-ditert-butylphenyl)-1-[4-(dimethylsulfamoyl)phenyl]pyrazol-3-yl]benzoic acid	1306249: Displacement of [3H]-TTNPB from RARgamma/RXRalpha (unknown origin) expressed in baculovirus expression system by scintillation proximity assay	ki	0.0041	uM
4-[4-(hydroxymethyl)-3-(5,5,8,8-tetramethyl-6,7-dihydronaphthalen-2-yl)phenyl]benzoic acid	1380631: Agonist activity at GAL4 DNA-binding domain-tagged RARgamma (unknown origin) ligand-binding domain expressed in human HG5LN cells incubated for 18 hrs by luciferase reporter gene assay	ec50	0.0044	uM
4-[5-(3,5-ditert-butylphenyl)-1-(4-methylsulfonylphenyl)pyrazol-3-yl]benzoic acid	1306249: Displacement of [3H]-TTNPB from RARgamma/RXRalpha (unknown origin) expressed in baculovirus expression system by scintillation proximity assay	ki	0.0044	uM
4-[5-(5,5,8,8-tetramethyl-6,7-dihydroquinoxalin-2-yl)furan-2-yl]benzoic acid	198726: Binding affinity for Retinoic Acid Receptor gamma (RAR gamma)	ic50	0.0046	uM
4-[3-[3-tert-butyl-4-(diethylamino)phenyl]-4-(4-hydroxybutoxy)phenyl]benzoic acid	1380631: Agonist activity at GAL4 DNA-binding domain-tagged RARgamma (unknown origin) ligand-binding domain expressed in human HG5LN cells incubated for 18 hrs by luciferase reporter gene assay	ec50	0.0047	uM
4-[(E)-4-[2-(4-tert-butylphenyl)-6,6-dimethylcyclohexen-1-yl]but-3-en-1-ynyl]benzoic acid	199050: Binding affinity towards retinoic acid receptor gamma was determined using [3H]ATRA (5 nM) as radioligand	kd	0.0050	uM
4-[(E)-4-[6,6-dimethyl-2-(4-methylphenyl)cyclohexen-1-yl]but-3-en-1-ynyl]benzoic acid	199042: Antagonist activity of TTNPB (10 nM) function at retinoic acid receptor gamma	ic50	0.0050	uM
4-[4-(2-methoxyethoxymethoxy)-3-(5,5,8,8-tetramethyl-6,7-dihydronaphthalen-2-yl)phenyl]benzoic acid	1380631: Agonist activity at GAL4 DNA-binding domain-tagged RARgamma (unknown origin) ligand-binding domain expressed in human HG5LN cells incubated for 18 hrs by luciferase reporter gene assay	ec50	0.0060	uM
4-[4-(2-methoxyethoxymethoxy)-3-(5,5,8,8-tetramethyl-6,7-dihydronaphthalen-2-yl)phenyl]-2-methylbenzoic acid	1380631: Agonist activity at GAL4 DNA-binding domain-tagged RARgamma (unknown origin) ligand-binding domain expressed in human HG5LN cells incubated for 18 hrs by luciferase reporter gene assay	ec50	0.0074	uM
6-[2,2-difluoro-1-(5,5,8,8-tetramethyl-6,7-dihydronaphthalen-2-yl)ethenyl]naphthalene-2-carboxylic acid	198728: Apparent binding constant against Retinoic acid receptor gamma in HeLa cell GAl-4 transactivation assay	kd	0.0075	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Tretinoin	increases reaction, affects response to substance, increases response to substance, decreases expression, decreases reaction (+5 more)	26
Alitretinoin	decreases expression, increases expression, affects binding, increases activity	6
sodium arsenite	decreases expression, increases abundance, increases expression	5
CD2665	increases expression, decreases activity, increases activity, decreases reaction	3
bisphenol A	decreases expression, increases expression, affects cotreatment	3
4-(2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-propenyl)benzoic acid	affects binding, increases activity	3
4-oxoretinoic acid	increases activity, affects binding	2
triphenyl phosphate	increases expression, affects expression, decreases reaction	2
Decitabine	increases expression, affects cotreatment	2
Benzo(a)pyrene	decreases expression, increases expression	2
Dieldrin	increases activity, increases expression	2
Endrin	increases activity, increases expression	2
Estradiol	affects cotreatment, decreases expression	2
Smoke	decreases expression	2
Tetrachlorodibenzodioxin	increases expression	2
aristolochic acid I	increases expression	1
GSK-J4	decreases expression	1
quinomethionate	affects expression	1
glycidyl methacrylate	decreases expression	1
tributyltin	increases activity, affects binding	1
trichostatin A	increases reaction, affects binding, decreases reaction	1
beta-lapachone	decreases expression, increases expression	1
afimoxifene	affects response to substance	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
enilconazole	increases activity	1
4-hydroxyretinoic acid	increases activity	1
potassium chromate(VI)	decreases expression	1
methacrylaldehyde	affects cotreatment, decreases expression	1
S-(1,2-dichlorovinyl)cysteine	increases expression, affects cotreatment, decreases expression, affects response to substance	1
4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-anthracenyl)benzoic acid	affects binding, decreases reaction	1

ChEMBL screening assays

255 unique, capped per target: 182 binding, 72 functional, 1 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1022117	Binding	Activity at RARgamma expressed in mouse NIH3T3 cells by R-SAT assay relative to Am-580	Design, synthesis, and structure-activity analysis of isoform-selective retinoic acid receptor beta ligands. — J Med Chem
CHEMBL1023992	Functional	Agonist activity at human RARgamma 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
CHEMBL3224188	ADMET	Inhibition of RAR gamma (unknown origin)	Overcoming retinoic acid receptor- based testicular toxicity in the optimisation of glucokinase activators — Medchemcomm

Cellosaurus cell lines

6 cell lines: 3 embryonic stem cell, 2 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_A5S9	SEES3-1V human RARG, clone1	Embryonic stem cell	Male
CVCL_A5T0	SEES3-1V human RARG, clone2	Embryonic stem cell	Male
CVCL_A5T1	SEES3-1V human RARG, clone3	Embryonic stem cell	Male
CVCL_LF52	GeneBLAzer RARgamma-UAS-bla HEK 293T	Transformed cell line	Female
CVCL_TI49	HAP1 RARG (-) 1	Cancer cell line	Male
CVCL_TI50	HAP1 RARG (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford