RORA

gene

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Also known as RZRAROR1ROR2ROR3NR1F1ROR-alphaRORalphaRORa1RORα

Summary

RORA (RAR related orphan receptor A, HGNC:10258) is a protein-coding gene on chromosome 15q22.2, encoding Nuclear receptor ROR-alpha (P35398). Nuclear receptor that binds DNA as a monomer to ROR response elements (RORE) containing a single core motif half-site 5’-AGGTCA-3’ preceded by a short A-T-rich sequence.

The protein encoded by this gene is a member of the NR1 subfamily of nuclear hormone receptors. It can bind as a monomer or as a homodimer to hormone response elements upstream of several genes to enhance the expression of those genes. The encoded protein has been shown to interact with NM23-2, a nucleoside diphosphate kinase involved in organogenesis and differentiation, as well as with NM23-1, the product of a tumor metastasis suppressor candidate gene. Also, it has been shown to aid in the transcriptional regulation of some genes involved in circadian rhythm. Four transcript variants encoding different isoforms have been described for this gene.

Source: NCBI Gene 6095 — RefSeq curated summary.

At a glance

Gene–disease (curated): intellectual developmental disorder with or without epilepsy or cerebellar ataxia (Strong, GenCC) — +3 more curated relationships
GWAS associations: 103
Clinical variants (ClinVar): 546 total — 16 pathogenic, 24 likely-pathogenic
Phenotypes (HPO): 32
Druggable target: yes — 2 molecules with ChEMBL bioactivity
Transcription factor: yes — 96 downstream targets (CollecTRI)
MANE Select transcript: NM_134261

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10258
Approved symbol	RORA
Name	RAR related orphan receptor A
Location	15q22.2
Locus type	gene with protein product
Status	Approved
Aliases	RZRA, ROR1, ROR2, ROR3, NR1F1, ROR-alpha, RORalpha, RORa1, RORα
Ensembl gene	ENSG00000069667
Ensembl biotype	protein_coding
OMIM	600825
Entrez	6095

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 6 protein_coding, 4 protein_coding_CDS_not_defined, 3 retained_intron, 1 nonsense_mediated_decay

ENST00000261523, ENST00000309157, ENST00000335670, ENST00000449337, ENST00000551975, ENST00000557822, ENST00000558234, ENST00000558904, ENST00000559145, ENST00000559343, ENST00000559587, ENST00000560004, ENST00000560300, ENST00000561093

RefSeq mRNA: 4 — MANE Select: NM_134261 NM_002943, NM_134260, NM_134261, NM_134262

CCDS: CCDS10177, CCDS10178, CCDS10179, CCDS45271

Canonical transcript exons

ENST00000335670 — 11 exons

Exon	Start	End
ENSE00000391550	60503535	60503667
ENSE00000691379	60502760	60502867
ENSE00000885024	60499892	60500004
ENSE00000885025	60500959	60501069
ENSE00001032962	60505508	60505629
ENSE00001141437	60488284	60497619
ENSE00001323632	61229053	61229302
ENSE00003559420	60678657	60678686
ENSE00003609182	60511226	60511621
ENSE00003635782	60531766	60531851
ENSE00003659420	60514616	60514757

Expression profiles

Bgee: expression breadth ubiquitous, 284 present calls, max score 99.46.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 23.4954 / max 640.1186, expressed in 1566 samples.

FANTOM5 promoters (9 alternative TSS)

Promoter ID	TPM avg	Samples expressed
150335	15.8149	1257
150354	3.0764	949
150336	2.5693	852
150356	1.1495	227
150355	0.6101	220
150337	0.1097	39
150357	0.1070	54
150324	0.0515	17
150326	0.0070	4

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
upper leg skin	UBERON:0004262	99.46	gold quality
lateral nuclear group of thalamus	UBERON:0002736	99.10	gold quality
skin of hip	UBERON:0001554	99.03	gold quality
nipple	UBERON:0002030	98.12	gold quality
mammalian vulva	UBERON:0000997	97.02	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	96.99	gold quality
biceps brachii	UBERON:0001507	96.85	gold quality
adrenal tissue	UBERON:0018303	96.81	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	96.44	gold quality
upper arm skin	UBERON:0004263	96.42	gold quality
tibia	UBERON:0000979	96.41	gold quality
calcaneal tendon	UBERON:0003701	96.41	gold quality
penis	UBERON:0000989	96.23	gold quality
skin of abdomen	UBERON:0001416	96.15	gold quality
zone of skin	UBERON:0000014	96.06	gold quality
skin of leg	UBERON:0001511	95.83	gold quality
tendon of biceps brachii	UBERON:0008188	95.61	gold quality
tendon	UBERON:0000043	95.21	gold quality
saphenous vein	UBERON:0007318	95.15	gold quality
gingiva	UBERON:0001828	94.37	gold quality
synovial joint	UBERON:0002217	94.04	gold quality
gingival epithelium	UBERON:0001949	93.70	gold quality
oral cavity	UBERON:0000167	93.69	gold quality
Brodmann (1909) area 23	UBERON:0013554	92.98	gold quality
caput epididymis	UBERON:0004358	92.92	gold quality
cauda epididymis	UBERON:0004360	92.89	gold quality
postcentral gyrus	UBERON:0002581	92.72	gold quality
endothelial cell	CL:0000115	92.60	gold quality
epithelium of nasopharynx	UBERON:0001951	92.53	gold quality
nasopharynx	UBERON:0001728	92.51	gold quality

Single-cell (SCXA)

Detected in 20 experiment(s), a significant marker in 17.

Experiment	Marker?	Max mean expression
E-HCAD-35	yes	4823.94
E-GEOD-180759	yes	4528.01
E-HCAD-25	yes	3530.91
E-MTAB-11268	yes	3017.45
E-CURD-46	yes	1223.47
E-MTAB-9221	yes	678.53
E-CURD-88	yes	617.74
E-GEOD-149689	yes	358.41
E-HCAD-4	yes	82.58
E-CURD-122	yes	34.54
E-MTAB-8410	yes	22.97
E-CURD-119	yes	22.74
E-MTAB-7316	yes	20.83
E-MTAB-8142	yes	15.49
E-MTAB-6701	yes	9.07

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

96 targets.

Target	Regulation
ADAM2
AFP	Unknown
AGRP
ALOX5
APOA1
APOA4
APOA5	Unknown
APOC3	Unknown
ARG1
ARR3
BGLAP
BHLHE40
BHLHE41
BMAL1	Unknown
CAV3	Activation
CCR6	Unknown
CD79A
CEBPA	Repression
CHRNA3
CPT1B	Activation
CREBBP
CS
CYP19A1	Activation
CYP2C19
CYP2C8	Activation
CYP2C9
CYP7B1	Activation
CYP8B1	Activation
DMP1	Activation
DRD3	Unknown

JASPAR motifs

Motif	Name	Family
MA0071.1	RORA	Thyroid hormone receptor-related factors (NR1)
MA0072.1	RORA	Thyroid hormone receptor-related factors (NR1)
MA0072.2	RORA	Thyroid hormone receptor-related factors (NR1)

JASPAR matrix evidence (PMIDs): PMID:7926749

Upstream regulators (CollecTRI, top): AR, ARNT, CEBPB, ESR1, FOXN1, HIF1A, RORA, RORC, SP1, SP3, STAT3

miRNA regulators (miRDB)

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

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-1277-5P	100.00	73.95	5056
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-6758-5P	100.00	66.21	1470
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-3163	100.00	77.23	8605
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-3646	100.00	73.56	5283

Literature-anchored findings (GeneRIF, showing 40)

ROR(alpha) and Reverb(alpha) are expressed with a similar tissue distribution and are both induced during the differentiation of rat L6 myoblastic cells (PMID:12114512)
ROR alpha activation induces decreased expression of alpha v beta 3 integrin and increased expression of beta 4 integrin subunit (PMID:12168086)
adenoviral overexpression of hRORalpha1 in HepG2 cells led to enhanced hRev-erbalpha mRNA accumulation, further confirming the physiological importance of RORalpha1 in the regulation of Rev-erbalpha expression (PMID:12377782)
higher binding affinity of cholesterol sulfate translates into an increased transcriptional activity of RORalpha so cholesterol sulfate could play a crucial role in the regulation of RORalpha in vivo. (PMID:14722075)
study demonstrates that overexpression of RORalpha1 and RORalpha4 inhibits TNF-alpha induced expression of VCAM-1 and ICAM-1 in human umbilical vein endothelial cells by inhibiting the NF-B signaling pathway (PMID:14741380)
the hypoxia-responsive region of the RORalpha4 promoter is composed of the HRE and GC-rich sequences and the transcriptional activation under hypoxia is conferred through the cooperation of HIF-1 with Sp1/Sp3 (PMID:14742449)
expression of Rev-erbalpha was upregulated by RORalpha1 but that upregulation was attenuated by Rev-erbalpha itself in A7r5 VSMCs. (PMID:15013753)
15d-PGJ2 induced RORalpha1 and RORalpha4 expression and inhibited TNF-alpha-induced vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) expression in human umbilical vein endothelial cells (PMID:15662020)
results suggest a novel mechanism whereby RORalpha modulates lipid metabolism and implies RORalpha as a potential target for the treatment of dyslipidemia and atherosclerosis (PMID:15781255)
RORalpha1 and RORalpha4 as transcriptional activators of human APOA5 gene expression (PMID:15790933)
We hypothesise that the obesity in this family is caused by (i) haploinsufficiency for RORa1 or, (ii) a gain of function mechanism mediated by the RORa1-UNC5C fusion gene. (PMID:15886715)
RORalpha1 provides neuroprotection by increasing the expression of the antioxidant proteins glutathione peroxidase 1 and peroxiredoxin 6, leading to a reduction in the accumulation of stress-induced reactive oxygen species. (PMID:16539693)
Results from RT-PCR, western blotting and confocal microscopy demonstrated that the MT1, MT2 and RORalpha1 melatonin receptors are expressed in the human term placental tissues and in choriocarcinoma cell lines JEG-3 and BeWo. (PMID:16632463)
Extracellular signal-regulated kinase-2 phosphorylates RORalpha4 in vitro (PMID:17512500)
Report transcriptional activation of HIF-1 by RORalpha and discuss its role in hypoxia signaling. (PMID:18658046)
RORalpha is SUMOylated by both SUMO-1 and SUMO-2. (PMID:19041634)
a possible role for RORA, a receptor for cholesterol, in the pathophysiology of age-related macular degeneration (PMID:19786043)
RORalpha and RORgamma are ligand-regulated members of the NR superfamily and may serve as sensors for 7-oxygenated sterols. (PMID:19965867)
RORalpha mediates transrepression of the Wnt/beta-catenin target genes. (PMID:20122401)
RORalpha and RORgamma display an overlapping ligand preference with another class of oxysterol nuclear receptors, the liver X receptors (LXRalpha [NR1H3] and LXRbeta [NR1H2]). (PMID:20211758)
a clear link between RORalpha, a key regulator of the mammalian clock, and FGF21, an important hormone regulating glucose and lipid homeostasis. (PMID:20332535)
decreased expression of RORA and BCL-2 proteins in the autistic brain (PMID:20375269)
No significant differences were found in the hMel-1B and RORa receptors in patients with adolescent idiopathic scoliosis compared with controls (PMID:20733416)
Data demonstrate that NPAS2 is also a RORalpha and REV-ERBalpha target gene. (PMID:20817722)
8 is REV-ERBalpha is a member of the nuclear receptor superfamily that functions as a receptor for the porphoryin heme. SR8278, is identified as a synthetic antagonist of the nuclear heme receptor REV-ERB. (PMID:21043485)
Common variants and haplotypes within the RORA gene appear to act synergistically with the ARMS2 A69S polymorphism to increase risk of neovascular age-related macular degeneration. (PMID:21060049)
RORA has the potential to be under both negative and positive feedback regulation by male and female hormones, respectively, through one of its transcriptional targets, aromatase; This further suggests a mechanism for introducing sex bias in autism. (PMID:21359227)
RORalpha1 is involved in human osteoblast metabolism by stimulating osteoblast marker expression and inhibiting inflammatory responses. (PMID:21480365)
The regulation of RORalpha activity by PKA as well as CaMK-IV provides a new link in the signalling network that regulates metabolic processes such as glycogen and lipid metabolism. (PMID:21514275)
These results open new routes on the roles of RORalpha in glucose metabolism and carcinogenesis within cells of hepatic origin. (PMID:21818335)
distinct ROBO1 variants may influence the risk of wet and dry AMD, and the effects of ROBO1 on AMD risk may be modulated by RORA variants. (PMID:21998696)
retinoic acid-related orphan receptor alpha significantly activated the human NR1D1 promoter (PMID:22024429)
RORA expression was downregulated in colorectal adenocarcinomas compared to normal controls and correlated with time to disease progression (PMID:22104449)
showed that transcription of SEMA3F is directly regulated by RORalpha (PMID:22350413)
Citrate synthase (CS) is a direct RORalpha target gene and one mechanism by which RORalpha regulates lipid metabolism is via regulation of CS expression. (PMID:22485150)
We demonstrate that treatment of cancer cells with a newly described synthetic ROR agonist, SR1078, leads to p53 stabilization and induction of apoptosis. (PMID:22509368)
Genetic variants of RORA associate with depressive disorder and bipolar disorder. (PMID:22538398)
Rora expression was induced by cigarette smoke in mice and cell culture. Rora-deficient mice were protected from smoke induced airspace enlargement. DNA damage may contribute to pathogenesis of emphysema and Rora has a role in responses to genotoxicity. (PMID:22744720)
found an association at genome-wide levels of significance between PTSD and the retinoic acid orphan receptor alpha. receptor A (RORA) gene (PMID:22869035)
study to evaluate the gene expression of RORalpha and RORgammat and their potential role in acute-on-chronic hepatitis B liver failure (ACHBLF); mRNA level of RORgammat was positively correlated with model of end-stage liver disease (MELD) score, but there was no correlation of RORalpha and MELD score (PMID:23043388)

Cross-species orthologs

188 orthologs

Organism	Symbol	Gene ID
danio_rerio	roraa	ENSDARG00000031768
mus_musculus	Rora	ENSMUSG00000032238
rattus_norvegicus	Rora	ENSRNOG00000077683
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	nhr-23	WBGENE00003622
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), RARB (ENSG00000077092), VDR (ENSG00000111424), PPARD (ENSG00000112033), THRA (ENSG00000126351), NR1D1 (ENSG00000126368), NR1H2 (ENSG00000131408), RARA (ENSG00000131759), PPARG (ENSG00000132170), NR1I3 (ENSG00000143257), RORC (ENSG00000143365), NR1I2 (ENSG00000144852), THRB (ENSG00000151090), RARG (ENSG00000172819), NR1D2 (ENSG00000174738), PPARA (ENSG00000186951), RORB (ENSG00000198963)

Protein

Protein identifiers

Nuclear receptor ROR-alpha — P35398 (reviewed: P35398)

Alternative names: Nuclear receptor RZR-alpha, Nuclear receptor subfamily 1 group F member 1, RAR-related orphan receptor A, Retinoid-related orphan receptor-alpha

All UniProt accessions (6): P35398, A0A087X2G0, A0A0C4DFP5, A0A0C4DG53, H0YII6, H0YLS5

UniProt curated annotations — full annotation on UniProt →

Function. Nuclear receptor that binds DNA as a monomer to ROR response elements (RORE) containing a single core motif half-site 5’-AGGTCA-3’ preceded by a short A-T-rich sequence. Key regulator of embryonic development, cellular differentiation, immunity, circadian rhythm as well as lipid, steroid, xenobiotics and glucose metabolism. Considered to have intrinsic transcriptional activity, have some natural ligands like oxysterols that act as agonists (25-hydroxycholesterol) or inverse agonists (7-oxygenated sterols), enhancing or repressing the transcriptional activity, respectively. Recruits distinct combinations of cofactors to target genes regulatory regions to modulate their transcriptional expression, depending on the tissue, time and promoter contexts. Regulates genes involved in photoreceptor development including OPN1SW, OPN1SM and ARR3 and skeletal muscle development with MYOD1. Required for proper cerebellum development. Regulates SHH gene expression, among others, to induce granule cells proliferation as well as expression of genes involved in calcium-mediated signal transduction. Regulates the circadian expression of several clock genes, including CLOCK, BMAL1, NPAS2 and CRY1. Competes with NR1D1 for binding to their shared DNA response element on some clock genes such as BMAL1, CRY1 and NR1D1 itself, resulting in NR1D1-mediated repression or RORA-mediated activation of clock genes expression, leading to the circadian pattern of clock genes expression. Therefore influences the period length and stability of the clock. Regulates genes involved in lipid metabolism such as apolipoproteins APOA1, APOA5, APOC3 and PPARG. In liver, has specific and redundant functions with RORC as positive or negative modulator of expression of genes encoding phase I and phase II proteins involved in the metabolism of lipids, steroids and xenobiotics, such as CYP7B1 and SULT2A1. Induces a rhythmic expression of some of these genes. In addition, interplays functionally with NR1H2 and NR1H3 for the regulation of genes involved in cholesterol metabolism. Also involved in the regulation of hepatic glucose metabolism through the modulation of G6PC1 and PCK1. In adipose tissue, plays a role as negative regulator of adipocyte differentiation, probably acting through dual mechanisms. May suppress CEBPB-dependent adipogenesis through direct interaction and PPARG-dependent adipogenesis through competition for DNA-binding. Downstream of IL6 and TGFB and synergistically with RORC isoform 2, is implicated in the lineage specification of uncommitted CD4(+) T-helper (T(H)) cells into T(H)17 cells, antagonizing the T(H)1 program. Probably regulates IL17 and IL17F expression on T(H) by binding to the essential enhancer conserved non-coding sequence 2 (CNS2) in the IL17-IL17F locus. Involved in hypoxia signaling by interacting with and activating the transcriptional activity of HIF1A. May inhibit cell growth in response to cellular stress. May exert an anti-inflammatory role by inducing CHUK expression and inhibiting NF-kappa-B signaling.

Subunit / interactions. Monomer. Interacts (via the DNA-binding domain) with HIF1A; the interaction enhances HIF1A transcription under hypoxia through increasing protein stability. Interacts with CEBPB; the interaction disrupts the interaction CEBPB:EP300. Interacts with the coactivators NCOA2, PPARGC1A (via LXXLL motif), EP300 and MED1. Interacts with the corepressor NCOR1. Interacts with MAGED1 and CTNNB1. Interacts with CRY1 and PER2. Interacts (via AF-2 motif) with PROX1. Interacts with NRIP1. Isoform 4 interacts (via AF-2 motif) with isoform 1 of FOXP3 (via LXXLL motif).

Subcellular location. Nucleus.

Tissue specificity. Widely expressed in a number of tissues. Expressed in both regulatory T-cells (Treg) and effector T-cells (Teff). Isoform 4: Highly expressed in the central nervous system, including in the cerebellum.

Post-translational modifications. Phosphorylation by conventional PKCs in neurons inhibits transcriptional activity. Phosphorylated on Thr-183 by MAPK1/ERK1 in vitro. Sumoylated by SENP1 and SENP2. Sumoylation, promoted by PIAS2, PIAS3, PIAS4 but not PIAS1, enhances the transcriptional activity. Desumoylated by SENP1. Ubiquitinated, leading to its degradation by the proteasome. Proteasomal degradation is required for efficient transcriptional activity and is prevented by HR. Monomethylated at Lys-38 by EZH2, this creates a degron recognized by a DCX (DDB1-DCAF1/VPRBP-CUL4A-RBX1) E3 ubiquitin ligase complex.

Disease relevance. Intellectual developmental disorder with or without epilepsy or cerebellar ataxia (IDDECA) [MIM:618060] An autosomal dominant neurodevelopmental disorder that manifests with variable features of mild-to-severe intellectual disability, developmental delay, autism spectrum disorder, cerebellar ataxia and epilepsy. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The AF-2 (activation function-2) motif is required for recruiting coregulators containing LXXLL motifs.

Induction. Induced by oxidative stress and DNA damage. Isoform 4 is induced by hypoxia (through transactivation by HIF1A and SP1), but not isoform 1.

Miscellaneous. Produced by alternative promoter usage. Region from 23 to 71 inhibits DNA-binding and transactivation activity. Produced by alternative splicing. Produced by alternative promoter usage.

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

Isoforms (4)

UniProt ID	Names	Canonical?
P35398-2	1, Alpha-1	yes
P35398-1	2, Alpha-2
P35398-3	3, Alpha-3
P35398-4	4, Alpha-4

RefSeq proteins (4): NP_002934, NP_599022, NP_599023, NP_599024 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000536	Nucl_hrmn_rcpt_lig-bd	Domain
IPR001628	Znf_hrmn_rcpt	Domain
IPR001723	Nuclear_hrmn_rcpt	Family
IPR003079	ROR_rcpt	Family
IPR013088	Znf_NHR/GATA	Homologous_superfamily
IPR035500	NHR-like_dom_sf	Homologous_superfamily
IPR044101	NR_DBD_ROR	Domain

Pfam: PF00104, PF00105

UniProt features (67 total): mutagenesis site 21, helix 13, sequence variant 8, turn 4, splice variant 3, sequence conflict 3, modified residue 2, zinc finger region 2, region of interest 2, strand 2, compositionally biased region 2, chain 1, domain 1, cross-link 1, DNA-binding region 1, short sequence motif 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
1N83	X-RAY DIFFRACTION	1.63
4S15	X-RAY DIFFRACTION	1.9
1S0X	X-RAY DIFFRACTION	2.2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P35398-F1	76.40	0.57

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): 38, 183, 240

Mutagenesis-validated functional residues (21):

Position	Phenotype
183	greatly increased transcriptional activity. decrease in repression by nr1d1.
183	some increase in transcriptional activity. no change in repression by nr1d1.
183	attenuates transcriptional activity.
183	some increase in transcriptional activity.
240	loss of sumoylation.
288	less effect on transcriptional activity with cholesterol sulfate as substrate as compared to cholesterol as substrate.
323	about 60% loss of transcriptional activity.
330	about 80% loss of transcriptional activity.
335	strongly decreases interaction with ncoa2 and med1.
339	complete loss of transcriptional activity; when associated with a-507.
357	increased transcriptional activity. no effect on protein degradation.
361	small reduction in transcriptional activity. no protein degradation.
364	greatly reduced transcriptional activity. protects from protein degradation.
371	almost total loss of transcriptional activity.
399	slight loss of transcriptional activity.
441	no effect on sumoylation.
484	almost total loss of transcriptional activity.
507	complete loss of transcriptional activity; when associated with a-339.
507	about 40% loss of transcriptional activity.
509	abolishes transcriptional activity. protects from protein degradation.
510–511	decreases interaction with ncoa2. loss of interaction with foxp3.

Function

Pathways and Gene Ontology

Reactome pathways

27 pathways

ID	Pathway
R-HSA-1989781	PPARA activates gene expression
R-HSA-383280	Nuclear Receptor transcription pathway
R-HSA-4090294	SUMOylation of intracellular receptors
R-HSA-6785807	Interleukin-4 and Interleukin-13 signaling
R-HSA-9707616	Heme signaling
R-HSA-9931509	Expression of BMAL (ARNTL), CLOCK, and NPAS2
R-HSA-9931510	Phosphorylated BMAL1:CLOCK (ARNTL:CLOCK) activates expression of core clock genes
R-HSA-9933387	RORA,B,C and NR1D1 (REV-ERBA) regulate gene expression
R-HSA-9931512	Phosphorylation of CLOCK, acetylation of BMAL1 (ARNTL) at target gene promoters
R-HSA-9931521	The CRY:PER:kinase complex represses transactivation by the BMAL:CLOCK (ARNTL:CLOCK) complex
R-HSA-1280215	Cytokine Signaling in Immune system
R-HSA-1368082
R-HSA-1430728	Metabolism
R-HSA-168256	Immune System
R-HSA-212436	Generic Transcription Pathway
R-HSA-2262752	Cellular responses to stress
R-HSA-2990846	SUMOylation
R-HSA-3108232	SUMO E3 ligases SUMOylate target proteins
R-HSA-392499	Metabolism of proteins
R-HSA-400206	Regulation of lipid metabolism by PPARalpha
R-HSA-400253
R-HSA-449147	Signaling by Interleukins
R-HSA-556833	Metabolism of lipids
R-HSA-597592	Post-translational protein modification
R-HSA-73857	RNA Polymerase II Transcription
R-HSA-74160	Gene expression (Transcription)
R-HSA-8953897	Cellular responses to stimuli

MSigDB gene sets: 1529 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_MCMV_INFECTION_UP, GSE45365_NK_CELL_VS_CD8A_DC_MCMV_INFECTION_UP, GOBP_CIRCADIAN_RHYTHM, GOBP_REGULATION_OF_CELL_ACTIVATION, RNGTGGGC_UNKNOWN, GOBP_ACYLGLYCEROL_HOMEOSTASIS, GOBP_HINDBRAIN_DEVELOPMENT, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, GOBP_REGULATION_OF_FAT_CELL_DIFFERENTIATION, FREAC2_01, GOBP_METENCEPHALON_DEVELOPMENT, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, MODULE_571, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM

GO Biological Process (33): angiogenesis (GO:0001525), regulation of DNA-templated transcription (GO:0006355), regulation of transcription by RNA polymerase II (GO:0006357), xenobiotic metabolic process (GO:0006805), nitric oxide biosynthetic process (GO:0006809), regulation of smoothened signaling pathway (GO:0008589), positive regulation of vascular endothelial growth factor production (GO:0010575), regulation of glucose metabolic process (GO:0010906), regulation of steroid metabolic process (GO:0019218), cerebellar Purkinje cell differentiation (GO:0021702), cerebellar granule cell precursor proliferation (GO:0021930), intracellular receptor signaling pathway (GO:0030522), circadian regulation of gene expression (GO:0032922), cellular response to sterol (GO:0036315), cholesterol homeostasis (GO:0042632), muscle cell differentiation (GO:0042692), positive regulation of circadian rhythm (GO:0042753), regulation of macrophage activation (GO:0043030), negative regulation of canonical NF-kappaB signal transduction (GO:0043124), negative regulation of fat cell differentiation (GO:0045599), positive regulation of DNA-templated transcription (GO:0045893), positive regulation of transcription by RNA polymerase II (GO:0045944), cGMP metabolic process (GO:0046068), negative regulation of inflammatory response (GO:0050728), triglyceride homeostasis (GO:0070328), cellular response to interleukin-1 (GO:0071347), cellular response to tumor necrosis factor (GO:0071356), cellular response to hypoxia (GO:0071456), T-helper 17 cell differentiation (GO:0072539), circadian rhythm (GO:0007623), regulation of gene expression (GO:0010468), regulation of circadian rhythm (GO:0042752), rhythmic process (GO:0048511)

GO Molecular Function (16): 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), transcription coregulator binding (GO:0001221), transcription corepressor binding (GO:0001222), transcription coactivator binding (GO:0001223), DNA binding (GO:0003677), DNA-binding transcription factor activity (GO:0003700), nuclear receptor activity (GO:0004879), beta-catenin binding (GO:0008013), oxysterol binding (GO:0008142), zinc ion binding (GO:0008270), sequence-specific DNA binding (GO:0043565), ligand-modulated transcription factor activity (GO:0098531), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (4): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), nucleolus (GO:0005730)

Reactome top-level categories

Rollup of top-12 pathways:

Category	Pathways
Circadian clock	5
Regulation of lipid metabolism by PPARalpha	1
Generic Transcription Pathway	1
SUMO E3 ligases SUMOylate target proteins	1
Signaling by Interleukins	1
Cellular responses to stress	1
Immune System	1
RNA Polymerase II Transcription	1
Cellular responses to stimuli	1
Post-translational protein modification	1
SUMOylation	1
Metabolism of lipids	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regulation of gene expression	2
regulation of DNA-templated transcription	2
circadian rhythm	2
transcription cis-regulatory region binding	2
RNA polymerase II transcription regulatory region sequence-specific DNA binding	2
DNA-binding transcription factor activity	2
transcription coregulator binding	2
cellular anatomical structure	2
nuclear lumen	2
blood vessel morphogenesis	1
anatomical structure formation involved in morphogenesis	1
DNA-templated transcription	1
regulation of RNA biosynthetic process	1
transcription by RNA polymerase II	1
metabolic process	1
cellular response to xenobiotic stimulus	1
biosynthetic process	1
nitric oxide metabolic process	1
smoothened signaling pathway	1
regulation of signal transduction	1
positive regulation of cytokine production	1
vascular endothelial growth factor production	1
regulation of vascular endothelial growth factor production	1
glucose metabolic process	1
regulation of carbohydrate metabolic process	1
regulation of small molecule metabolic process	1
steroid metabolic process	1
regulation of lipid metabolic process	1
cell differentiation in hindbrain	1
cerebellar Purkinje cell layer formation	1
central nervous system neuron differentiation	1
cell proliferation in external granule layer	1
intracellular signal transduction	1
response to sterol	1
cellular response to lipid	1
cellular response to oxygen-containing compound	1
sterol homeostasis	1
cell differentiation	1
muscle structure development	1
regulation of circadian rhythm	1

Protein interactions and networks

STRING

0 interactions, top by confidence (×1000):

IntAct

18 interactions, top by confidence:

A	B	Type	Score
RORA	GFAP	psi-mi:“MI:0915”(physical association)	0.560
GFAP	RORA	psi-mi:“MI:0915”(physical association)	0.560
PSMC5	RORA	psi-mi:“MI:0915”(physical association)	0.550
RORA	NR0B1	psi-mi:“MI:0915”(physical association)	0.510
RORA	NCOA1	psi-mi:“MI:0407”(direct interaction)	0.440
RORA	FOXP3	psi-mi:“MI:0915”(physical association)	0.370
IFNA8	RORA	psi-mi:“MI:0915”(physical association)	0.370
IL17F	RORA	psi-mi:“MI:0915”(physical association)	0.370
IL25	RORA	psi-mi:“MI:0915”(physical association)	0.370
	RORA	psi-mi:“MI:0915”(physical association)	0.370
RORA		psi-mi:“MI:0914”(association)	0.350
Csnk1e	RORA	psi-mi:“MI:0915”(physical association)	0.000
Bhlhe41	RORA	psi-mi:“MI:0915”(physical association)	0.000
LMO3	RORA	psi-mi:“MI:0915”(physical association)	0.000
NR0B1	RORA	psi-mi:“MI:0915”(physical association)	0.000
PSMC5	RORA	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (50): RORA (Two-hybrid), RORA (Two-hybrid), RORA (Two-hybrid), RORA (Two-hybrid), RORA (Two-hybrid), PSMC5 (Two-hybrid), Nme2 (Two-hybrid), Nme2 (Reconstituted Complex), HIF1A (Reconstituted Complex), SP1 (Reconstituted Complex), RORA (Two-hybrid), EP300 (Reconstituted Complex), RORA (Reconstituted Complex), RORA (Affinity Capture-MS), RORA (Affinity Capture-MS)

ESM2 similar proteins: A0JNE3, A0P8Z4, O00482, O42101, P06211, P06212, P13056, P19785, P28701, P28705, P35398, P37238, P45448, P48443, P49116, P49117, P49867, P51128, P51129, P51448, P55094, P57783, P70033, P79926, P81559, Q04913, Q0GFF6, Q0VC20, Q15406, Q26622, Q28CK1, Q505F1, Q5BJR8, Q5RCZ5, Q5REL6, Q64249, Q66J63, Q66JK1, Q6GN21, Q8VIJ4

Diamond homologs: A0JNE3, A0P8Z4, A2T928, A4IIG7, F1QJF4, F1QLY4, O01639, O09018, O18924, O18971, O35507, O62807, O77245, O88275, P10276, P10589, P10826, P11416, P13055, P13056, P13631, P16375, P16376, P17671, P18514, P18515, P18516, P18911, P22448, P22605, P24468, P28699, P31396, P33244, P35398, P37231, P37233, P37238, P41828, P41829

SIGNOR signaling

15 interactions.

A	Effect	B	Mechanism
MAPK1	down-regulates	RORA	phosphorylation
PRKCA	unknown	RORA	phosphorylation
RORA	“down-regulates activity”	NR1D1	binding
RORA	“up-regulates quantity by expression”	NPAS2	“transcriptional regulation”
RORA	“up-regulates quantity by expression”	ARNTL	“transcriptional regulation”
RORA	“up-regulates quantity by expression”	CAV3	“transcriptional regulation”
RORA	“up-regulates quantity by expression”	CPT1B	“transcriptional regulation”
RORA	“up-regulates quantity by expression”	SHH	“transcriptional regulation”
RORA	“up-regulates quantity by expression”	ITPR1	“transcriptional regulation”
RORA	“up-regulates quantity by expression”	PCP4	“transcriptional regulation”
RORA	“up-regulates quantity by expression”	PCP2	“transcriptional regulation”
RORA	“up-regulates quantity by expression”	SLC1A6	“transcriptional regulation”
RORA	“up-regulates quantity by expression”	NLGN1	“transcriptional regulation”
RORA	“up-regulates quantity by expression”	NTRK2	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	16
Likely pathogenic	24
Uncertain significance	328
Likely benign	90
Benign	28

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1254934	NM_134261.3(RORA):c.351_354del (p.Asp118fs)	Pathogenic
1300412	NM_134261.3(RORA):c.439C>T (p.Arg147Ter)	Pathogenic
2304091	NM_134261.3(RORA):c.1268_1291delinsAT (p.Phe423fs)	Pathogenic
2307580	NM_134261.3(RORA):c.184A>T (p.Lys62Ter)	Pathogenic
2442252	NM_134261.3(RORA):c.1069A>T (p.Lys357Ter)	Pathogenic
2572286	NM_134261.3(RORA):c.424+1G>A	Pathogenic
2578526	NM_134261.3(RORA):c.505C>T (p.Gln169Ter)	Pathogenic
3024237	NM_134261.3(RORA):c.499C>T (p.Gln167Ter)	Pathogenic
3359018	NM_134261.3(RORA):c.731dup (p.Cys245fs)	Pathogenic
3600692	NM_134261.3(RORA):c.283-2A>G	Pathogenic
4529682	NM_134261.3(RORA):c.520C>T (p.Gln174Ter)	Pathogenic
4686787	NM_134261.3(RORA):c.355C>T (p.Arg119Ter)	Pathogenic
549841	NM_134261.3(RORA):c.804_805del (p.Ser269fs)	Pathogenic
549843	NM_134261.3(RORA):c.275G>C (p.Gly92Ala)	Pathogenic
59971	GRCh38/hg38 1p32.1-31.1(chr1:59632500-76730877)x1	Pathogenic
807672	NM_134261.3(RORA):c.867_876dup (p.Glu293fs)	Pathogenic
1064858	NM_134261.3(RORA):c.900G>A (p.Trp300Ter)	Likely pathogenic
1251925	NM_134261.3(RORA):c.821-1G>C	Likely pathogenic
2429099	NM_134261.3(RORA):c.203T>A (p.Ile68Asn)	Likely pathogenic
2501285	NM_134261.3(RORA):c.1304G>A (p.Trp435Ter)	Likely pathogenic
2672163	NM_134261.3(RORA):c.698_719dup (p.Lys240_Pro241insSerTer)	Likely pathogenic
3235694	NM_134261.3(RORA):c.274G>A (p.Gly92Ser)	Likely pathogenic
3236192	NM_134261.3(RORA):c.1345del (p.Ile449fs)	Likely pathogenic
3342822	NM_134261.3(RORA):c.1013C>A (p.Ala338Asp)	Likely pathogenic
3373026	NM_134261.3(RORA):c.251A>C (p.His84Pro)	Likely pathogenic
3775344	NM_134261.3(RORA):c.196+51421T>A	Likely pathogenic
3897844	NM_134261.3(RORA):c.559_566del (p.Asn187fs)	Likely pathogenic
3947184	NM_134261.3(RORA):c.370C>T (p.Arg124Cys)	Likely pathogenic
4076384	NM_134261.3(RORA):c.999del (p.Gln332_Tyr333insTer)	Likely pathogenic
4277261	NM_134261.3(RORA):c.1075+2del	Likely pathogenic

SpliceAI

7786 predictions. Top by Δscore:

Variant	Effect	Δscore
15:60497616:TTAA:T	acceptor_gain	1.0000
15:60499887:CTCA:C	donor_loss	1.0000
15:60499888:TCA:T	donor_loss	1.0000
15:60499889:CA:C	donor_loss	1.0000
15:60499890:A:AC	donor_gain	1.0000
15:60499890:AC:A	donor_gain	1.0000
15:60499890:ACC:A	donor_loss	1.0000
15:60499891:C:CA	donor_loss	1.0000
15:60499891:C:CC	donor_gain	1.0000
15:60499891:CC:C	donor_gain	1.0000
15:60499891:CCT:C	donor_gain	1.0000
15:60500001:CGAT:C	acceptor_gain	1.0000
15:60500003:ATC:A	acceptor_loss	1.0000
15:60500004:TCTA:T	acceptor_loss	1.0000
15:60500005:C:CC	acceptor_gain	1.0000
15:60500005:CTAA:C	acceptor_loss	1.0000
15:60500006:T:C	acceptor_loss	1.0000
15:60500010:C:CT	acceptor_gain	1.0000
15:60500953:TCTTA:T	donor_loss	1.0000
15:60500954:CTTA:C	donor_loss	1.0000
15:60500955:TTACC:T	donor_loss	1.0000
15:60500956:TA:T	donor_loss	1.0000
15:60500957:A:AG	donor_loss	1.0000
15:60500958:C:T	donor_loss	1.0000
15:60500958:CCTG:C	donor_gain	1.0000
15:60501066:CAAC:C	acceptor_gain	1.0000
15:60501067:AAC:A	acceptor_gain	1.0000
15:60501068:ACC:A	acceptor_loss	1.0000
15:60501069:CCT:C	acceptor_loss	1.0000
15:60501070:C:CC	acceptor_gain	1.0000

AlphaMissense

3453 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
15:60497502:C:T	E509K	1.000
15:60497510:A:G	L506S	1.000
15:60497555:A:G	F491S	1.000
15:60497564:A:G	L488P	1.000
15:60499941:A:G	L453P	1.000
15:60500970:A:G	L428P	1.000
15:60500979:G:T	A425E	1.000
15:60502867:C:T	G359D	1.000
15:60503535:C:G	G359R	1.000
15:60503539:T:A	K357N	1.000
15:60503539:T:G	K357N	1.000
15:60503540:T:A	K357I	1.000
15:60503543:A:C	L356R	1.000
15:60503543:A:G	L356P	1.000
15:60503543:A:T	L356Q	1.000
15:60503546:A:G	L355P	1.000
15:60503546:A:T	L355H	1.000
15:60503552:A:C	I353S	1.000
15:60503552:A:G	I353T	1.000
15:60503552:A:T	I353N	1.000
15:60503554:T:A	Q352H	1.000
15:60503554:T:G	Q352H	1.000
15:60503555:T:G	Q352P	1.000
15:60503558:T:A	D351V	1.000
15:60503559:C:A	D351Y	1.000
15:60503559:C:G	D351H	1.000
15:60503570:A:G	L347P	1.000
15:60503578:A:C	F344L	1.000
15:60503578:A:T	F344L	1.000
15:60503579:A:G	F344S	1.000

dbSNP variants (sampled 300 via entrez): RS1000007014 (15:60582807 G>A), RS1000009252 (15:60914148 C>T), RS1000012529 (15:61213992 C>G,T), RS1000020050 (15:61026411 T>C), RS1000025727 (15:60540879 A>C), RS1000026257 (15:60947802 C>T), RS1000029490 (15:61174916 A>G), RS1000030371 (15:60545608 G>C), RS1000030760 (15:61093964 C>T), RS1000034774 (15:61201416 A>G), RS1000038346 (15:61052361 G>C), RS1000043054 (15:60943539 G>A), RS1000048261 (15:61213791 G>A,C), RS1000049923 (15:60671692 A>G), RS1000050739 (15:60628696 T>A)

Disease associations

OMIM: gene MIM:600825 | disease phenotypes: MIM:617654, MIM:618060, MIM:162200

GenCC curated gene-disease

Disease	Classification	Inheritance
intellectual developmental disorder with or without epilepsy or cerebellar ataxia	Strong	Autosomal dominant
hearing loss, autosomal recessive 108	Moderate	Autosomal recessive
hearing loss, autosomal recessive	Supportive	Autosomal recessive
nonsyndromic genetic hearing loss	Limited	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
nonsyndromic genetic hearing loss	Limited	AR

Mondo (6): hearing loss, autosomal recessive 108 (MONDO:0033200), intellectual developmental disorder with or without epilepsy or cerebellar ataxia (MONDO:0060745), neurodevelopmental disorder (MONDO:0700092), neurofibromatosis type 1 (MONDO:0018975), nonsyndromic genetic hearing loss (MONDO:0019497), hearing loss, autosomal recessive (MONDO:0019588)

Orphanet (1): Neurofibromatosis type 1 (Orphanet:636)

HPO phenotypes

32 total (30 of 32 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000028	Cryptorchidism
HP:0000126	Hydronephrosis
HP:0000486	Strabismus
HP:0000540	Hypermetropia
HP:0000565	Esotropia
HP:0000612	Iris coloboma
HP:0000639	Nystagmus
HP:0000646	Amblyopia
HP:0000657	Oculomotor apraxia
HP:0000729	Autistic behavior
HP:0000750	Delayed speech and language development
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001263	Global developmental delay
HP:0001270	Motor delay
HP:0001290	Generalized hypotonia
HP:0001321	Cerebellar hypoplasia
HP:0001337	Tremor
HP:0002079	Hypoplasia of the corpus callosum
HP:0002311	Incoordination
HP:0003298	Spina bifida occulta
HP:0003593	Infantile onset
HP:0006879	Pontocerebellar atrophy
HP:0007256	Abnormal pyramidal sign
HP:0008527	Congenital sensorineural hearing impairment
HP:0012076	Borderline personality disorder
HP:0012450	Chronic constipation

GWAS associations

103 associations (top):

Study	Trait	p-value
GCST000509_4	Response to citalopram treatment	8.000000e-06
GCST000779_2	Depression (quantitative trait)	6.000000e-07
GCST000804_10	Asthma	1.000000e-07
GCST000880_1	Menarche (age at onset)	8.000000e-07
GCST000892_11	Total ventricular volume (Alzheimer’s disease interaction)	3.000000e-06
GCST000965_3	C-reactive protein levels	4.000000e-09
GCST001277_16	Liver enzyme levels (gamma-glutamyl transferase)	7.000000e-20
GCST001307_4	Gamma glutamyl transferase levels	2.000000e-08
GCST001444_39	Pulmonary function decline	2.000000e-06
GCST001521_23	Subcutaneous adipose tissue	7.000000e-07
GCST001757_9	Schizophrenia	4.000000e-06
GCST001816_4	Breast cancer (prognosis)	4.000000e-06
GCST001973_12	Menarche (age at onset)	2.000000e-06
GCST001973_6	Menarche (age at onset)	2.000000e-06
GCST002541_102	Menarche (age at onset)	2.000000e-13
GCST002928_25	Nickel levels	7.000000e-06
GCST002991_6	Pancreatic cancer	7.000000e-06
GCST003678_3	C-reactive protein levels or total cholesterol levels (pleiotropy)	3.000000e-10
GCST003679_16	C-reactive protein levels or LDL-cholesterol levels (pleiotropy)	2.000000e-12
GCST003987_15	Asthma	4.000000e-11
GCST004904_178	Body mass index	4.000000e-10
GCST005038_90	Allergic disease (asthma, hay fever or eczema)	9.000000e-13
GCST005212_29	Asthma	1.000000e-09
GCST005580_78	Intraocular pressure	1.000000e-11
GCST005580_83	Intraocular pressure	3.000000e-11
GCST005714_2	Cerebrospinal fluid beta-site APP cleaving enzyme levels	6.000000e-06
GCST005934_4	Neuropathic pain in head and neck cancer	1.000000e-08
GCST005986_20	Blood urea nitrogen levels	1.000000e-15
GCST006408_11	Allergic sensitization	7.000000e-08
GCST006409_14	Allergic rhinitis	6.000000e-13

EFO canonical traits (35, from GWAS)

EFO ID	Trait name
EFO:0004703	age at menarche
EFO:0004458	C-reactive protein measurement
EFO:0004532	serum gamma-glutamyl transferase measurement
EFO:0004314	forced expiratory volume
EFO:0004574	total cholesterol measurement
EFO:0004611	low density lipoprotein cholesterol measurement
EFO:0004340	body mass index
EFO:0004695	intraocular pressure measurement
EFO:0009179	beta-secretase 1 measurement
EFO:0005762	neuropathic pain
EFO:0005298	allergic sensitization measurement
EFO:0009363	chronic central serous retinopathy
EFO:0009751	facial asymmetry measurement
EFO:0004847	age at onset
EFO:1002011	adult onset asthma
EFO:0009941	Inhalant adrenergic use measurement
EFO:0009942	Glucocorticoid use measurement
EFO:0008039	BMI-adjusted hip circumference
EFO:0004344	birth weight
EFO:0005939	parental genotype effect measurement
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0004530	triglyceride measurement
EFO:0004614	apolipoprotein A 1 measurement
EFO:0004346	neuroimaging measurement
EFO:0004840	cortical thickness
EFO:0010091	tea consumption measurement
EFO:0006781	coffee consumption measurement
EFO:0004842	eosinophil count
EFO:0007991	eosinophil percentage of leukocytes
EFO:0004348	hematocrit

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D065886	Neurodevelopmental Disorders	F03.625
D009456	Neurofibromatosis 1	C04.557.580.600.580.590.650; C04.700.631.650; C10.562.600.500; C10.574.500.549.400; C10.668.829.675; C16.320.400.560.400; C16.320.700.633.650
C564609	Deafness, Autosomal Recessive (supp.)
C580334	Nonsyndromic Deafness (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5868 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

2 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 194,757 (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
CHEMBL38	TRETINOIN	4	194,008
CHEMBL4472508	CINTIRORGON	1	749

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

PharmGKB clinical annotations

2 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs4774388	Efficacy	3	interferon beta-1a	Multiple Sclerosis
rs809736	Efficacy	3	citalopram	Major Depressive Disorder

PharmGKB variants

2 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs809736	RORA	3	0.00	1	citalopram
rs4774388	RORA	3	2.25	1	interferon beta-1a

GtoPdb / IUPHAR curated pharmacology

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

Target class: nhr — 1F. Retinoic acid-related orphans

Most potent curated ligand interactions (3 total), top 3:

Ligand	Action	Affinity	Parameter
T0901317	Inverse agonist	6.88	pKi
SR1001	Inverse agonist	6.76	pKi
CD2314	Agonist	5.42	pKd

Binding affinities (BindingDB)

472 measured of 575 human assays (594 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
MLS000056567	EC50	0.0113 nM
BMCL181297 Compound 5A	IC50	40 nM
3-[3-(4-tert-butylphenyl)-1,2,4-oxadiazol-5-yl]-N-ethyl-propanamide	IC50	45.8 nM
3-[3-(4-tert-butylphenyl)-1,2,4-oxadiazol-5-yl]propanamide	IC50	47.9 nM
3-[3-(4-tert-butylphenyl)-1,2,4-oxadiazol-5-yl]-N-methyl-propanamide	IC50	52 nM
1-Ethyl-6-methyl-3-thiophen-2-yl-1H-pyrimido[5,4-e][1,2,4]triazine-5,7-dione	IC50	72.2 nM
PODOFILOX	IC50	81 nM
MLS000056239	IC50	106 nM
2-methyl-6-phenyl-3-(1-pyrrolyl)-4-thieno[2,3-d]pyrimidinone	EC50	112 nM
MLS000064750	IC50	113 nM
2-({[2-(4-ethoxyphenyl)-5-methyl-1,3-oxazol-4-yl]methyl}thio)-N-(2-furylmethyl)acetamide	IC50	140 nM
5-bromanyl-N-(pyridin-4-ylmethyl)thiophene-2-sulfonamide	IC50	185 nM
(2-phenyl-1,3-thiazol-4-yl)methyl 1-methylpyrrole-2-carboxylate	EC50	221 nM
3-[(4-ethoxyphenoxy)methyl]benzoic acid	IC50	225 nM
1-azepanyl-[4-(5-phenyl-1,3,4-oxadiazol-2-yl)phenyl]methanone	EC50	282 nM
3-[(2-chloro-4-methylol-phenoxy)methyl]benzoic acid	IC50	288 nM
2-(1-propyl-4-pyridinylidene)indene-1,3-dione	IC50	296 nM
MLS000077996	EC50	317 nM
2-[(1-bicyclo[2.2.1]hept-2-yl-1H-tetrazol-5-yl)thio]-N-4-quinolinylacetamide	IC50	353 nM
7-amino-3-phenyl-6-pyrazolo[1,5-a]pyrimidinecarboxylic acid ethyl ester	EC50	356 nM
3-[(4-methoxyphenoxy)methyl]benzoic acid	IC50	370 nM
4-acetyl-N-(2,3-dihydro-1,4-benzodioxin-6-yl)-3,5-dimethyl-1H-pyrrole-2-carboxamide	EC50	400 nM
5-(4-butylcyclohexyl)-3-(2-pyridinyl)-1,2,4-oxadiazole	EC50	403 nM
MLS000100813	IC50	409 nM
2-(2-chlorophenyl)-5-(4-chlorophenyl)-1,3,4-oxadiazole	EC50	431 nM
MLS000048173	EC50	446 nM
3alpha,16,17,18-tetrahydroxyaphidicolone	IC50	464 nM
MLS000062478	EC50	480 nM
2-CHLORO-2’-DEOXYADENOSINE	IC50	487 nM
(Z)-4-(4-ethoxyphenyl)-3-buten-2-one oxime	EC50	491 nM
2-[2-[[3-(4-chlorophenyl)-5-methyl-7-pyrazolo[1,5-a]pyrimidinyl]amino]ethoxy]ethanol	EC50	536 nM
3-[(2-chloranylphenoxy)methyl]benzoic acid	IC50	538 nM
MLS000036584	EC50	556 nM
8-methyl-2-phenyl-imidazo[1,2-a]pyridine	EC50	563 nM
3-[2-(3,5-dimethoxyphenyl)-5,7-dimethyl-6-pyrazolo[1,5-a]pyrimidinyl]propanoic acid	IC50	570 nM
2-[2-[[1-(4-chlorophenyl)-4-pyrazolo[3,4-d]pyrimidinyl]amino]ethoxy]ethanol	EC50	595 nM
MLS000039439	EC50	596 nM
2-[2-(2,5-dimethyl-1-prop-2-enyl-pyrrol-3-yl)-2-oxidanylidene-ethyl]sulfanyl-1H-quinazolin-4-one	EC50	609 nM
1-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-(4-quinazolinyloxy)ethanone	EC50	615 nM
5-(cyclopropylamino)-2-(4-ethoxyphenyl)-1,3-oxazole-4-carbonitrile	EC50	624 nM
3-(2-keto-1-methyl-propoxy)-4-methyl-7,8,9,10-tetrahydrobenzo[c]chromen-6-one	EC50	628 nM
4-[4-[(3-cyano-5,6-dihydro-4H-cyclopenta[b]thiophen-2-yl)carbamoyl]phenyl]sulfonylpiperazine-1-carboxylic acid ethyl ester	EC50	636 nM
(6-fluoro-1,3-benzothiazol-2-yl)-(4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl)amine	EC50	639 nM
2-[5-(2-naphthyl)-1,2,4-oxadiazol-3-yl]pyridine	IC50	644 nM
MLS000053249	EC50	653 nM
2,6-Dimethyl-benzo[1,2-b;4,5-b’]difuran-3,7-dicarboxylic acid bis-(2-dimethylamino-ethyl) ester	IC50	656 nM
4-[[4-(hydroximinomethyl)-2-methoxy-phenoxy]methyl]benzoic acid	IC50	670 nM
6-[4-(3-chlorophenyl)-1-piperazinyl]-3-cyclohexyl-1H-pyrimidine-2,4-dione	IC50	675 nM
4,6-bis(bromanyl)-2-(4-methoxyphenyl)-1,3-benzoxazol-5-amine	EC50	693 nM
4-[4-[2-(4-chloranylphenoxy)ethyl]piperazin-1-yl]thieno[2,3-d]pyrimidine	IC50	711 nM

ChEMBL bioactivities

113 potent at pChembl≥5 of 149 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.92	Ki	12	nM	CHEMBL497207
7.92	Ki	12	nM	CHEMBL497834
7.92	Ki	12	nM	7-OXOCHOLESTEROL
7.54	EC50	29	nM	CHEMBL3314003
7.07	EC50	86	nM	CHEMBL3617295
6.96	IC50	110	nM	CHEMBL4225808
6.88	Ki	132	nM	T091317
6.76	Ki	172	nM	CHEMBL3094388
6.70	IC50	199.5	nM	TRETINOIN
6.70	EC50	200	nM	CHEMBL3617309
6.66	Ki	220	nM	CHEMBL3218916
6.55	EC50	280	nM	CHEMBL3617297
6.41	EC50	390	nM	CHEMBL3596591
6.32	EC50	480	nM	CHEMBL3218916
6.30	IC50	501.2	nM	CHEMBL4562895
6.30	IC50	500	nM	CHEMBL3218916
6.22	IC50	600	nM	CHEMBL4163193
6.16	Ki	698	nM	CHEMBL5902122
6.05	IC50	900	nM	CHEMBL3094388
5.98	Ki	1048	nM	CHEMBL5855413
5.96	EC50	1100	nM	CHEMBL3598049
5.92	EC50	1200	nM	CHEMBL3598044
5.89	IC50	1300	nM	CHEMBL3121750
5.89	EC50	1300	nM	CHEMBL3598070
5.85	EC50	1400	nM	CHEMBL3598048
5.82	EC50	1500	nM	CHEMBL3598052
5.80	EC50	1600	nM	CHEMBL3598047
5.80	IC50	1585	nM	CHEMBL4551507
5.80	IC50	1600	nM	CHEMBL5618909
5.78	IC50	1680	nM	CHEMBL261115
5.76	IC50	1740	nM	CHEMBL4465197
5.75	EC50	1800	nM	CHEMBL3598074
5.72	EC50	1900	nM	CHEMBL3598051
5.70	IC50	2000	nM	T091317
5.70	EC50	2000	nM	CHEMBL3598053
5.70	IC50	1995	nM	CHEMBL4458320
5.68	EC50	2100	nM	CHEMBL3598050
5.66	EC50	2200	nM	CHEMBL3598077
5.64	IC50	2310	nM	CHEMBL1735739
5.62	EC50	2400	nM	CHEMBL3263710
5.61	IC50	2470	nM	CHEMBL1718444
5.60	IC50	2512	nM	CHEMBL4463668
5.58	IC50	2600	nM	T091317
5.55	EC50	2800	nM	CHEMBL3263696
5.53	EC50	2925	nM	CINTIRORGON
5.51	Ki	3111	nM	CHEMBL5089797
5.49	IC50	3220	nM	CHEMBL261114
5.49	Ki	3271	nM	CHEMBL5932023
5.46	Ki	3461	nM	CHEMBL5903358
5.42	EC50	3800	nM	CHEMBL3263714

PubChem BioAssay actives

90 with measured affinity, of 562 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
2-chloro-6-fluoro-N-[1-(4-fluorophenyl)sulfonyl-3,4-dihydro-2H-quinolin-7-yl]benzamide	1247815: Inverse agonist activity at GAL4-fused human RORa expressed in HEK293 cells assessed as suppression of basal transcriptional activity after 20 hrs by dual-glo luciferase reporter gene assay	ec50	0.0290	uM
2,6-difluoro-N-[1-(4-fluorophenyl)sulfonyl-3,4-dihydro-2H-quinolin-7-yl]benzamide	1247815: Inverse agonist activity at GAL4-fused human RORa expressed in HEK293 cells assessed as suppression of basal transcriptional activity after 20 hrs by dual-glo luciferase reporter gene assay	ec50	0.0860	uM
N-[5-(2-chlorobenzoyl)-4-(2-chlorophenyl)-1,3-thiazol-2-yl]-2-(4-ethylsulfonylphenyl)acetamide	1390735: Inverse agonist activity at GAL4-DNA binding domain-fused human RORalpha ligand binding domain expressed in HEK293T cells incubated for 20 hrs by luciferase reporter gene assay	ic50	0.1100	uM
N-[4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl]-N-(2,2,2-trifluoroethyl)benzenesulfonamide	1177722: Binding affinity to RORa (unknown origin) by radioligand binding assay	ki	0.1320	uM
N-[5-[[4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl]sulfamoyl]-4-methyl-1,3-thiazol-2-yl]acetamide	1177724: Binding affinity to RORa-LBD (unknown origin) by radioligand binding assay	ki	0.1720	uM
tretinoin	1168690: Inverse agonist activity at RORalpha (unknown origin) by M1H assay	ic50	0.1995	uM
2-chloro-N-[1-(4-fluorophenyl)sulfonyl-3,4-dihydro-2H-quinolin-7-yl]benzamide	1247815: Inverse agonist activity at GAL4-fused human RORa expressed in HEK293 cells assessed as suppression of basal transcriptional activity after 20 hrs by dual-glo luciferase reporter gene assay	ec50	0.2000	uM
2,6-difluoro-N-[1-(4-fluorophenyl)sulfonyl-2,3-dihydroindol-6-yl]benzamide	1247815: Inverse agonist activity at GAL4-fused human RORa expressed in HEK293 cells assessed as suppression of basal transcriptional activity after 20 hrs by dual-glo luciferase reporter gene assay	ec50	0.2800	uM
4-chloro-3-[1-(2-chloro-6-fluorobenzoyl)-3,4-dihydro-2H-quinolin-6-yl]benzamide	1295293: Inverse agonist activity at human ROR-alpha transfected in HEK293T cells by Gal4 luciferase reporter gene assay	ec50	0.3900	uM
(2R)-2-acetamido-2-(4-ethylsulfonylphenyl)-N-[4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl]acetamide	1510657: Agonist activity at human His6-tcs-RORalpha LBD assessed as PGC1alpha peptide (130 to 154 residues) recruitment incubated for 1 hr by FRET assay	ic50	0.5012	uM
2-acetamido-N-[4-[5-cyano-2-(2,2,2-trifluoroethoxy)-3-pyridinyl]thiophen-2-yl]-2-(4-ethylsulfonylphenyl)acetamide	1357030: Inverse agonist activity at His6-tcs-human RORalpha LBD assessed as inhibition of biotinylated PGC1alpha (130 to 154 residues) peptide recruitment incubated for 1 hr by HTRF-FRET assay	ic50	0.6000	uM
N-[4-(3-acetamido-1-propan-2-ylpyrazol-5-yl)-2-piperidin-1-ylphenyl]-2-chloro-6-fluoro-N-(trideuteriomethyl)benzamide	1237147: Inverse agonist activity at RORalpha (unknown origin)	ec50	1.1000	uM
N-[4-(3-acetamido-1-propan-2-ylpyrazol-5-yl)-2-(cyclobutylmethoxy)phenyl]-2-chloro-6-fluoro-N-(trideuteriomethyl)benzamide	1237147: Inverse agonist activity at RORalpha (unknown origin)	ec50	1.2000	uM
N-[4-(3-acetamido-1-cyclopentylpyrazol-5-yl)-2-(3-azabicyclo[3.1.0]hexan-3-yl)phenyl]-2-chloro-6-fluoro-N-(trideuteriomethyl)benzamide	1237147: Inverse agonist activity at RORalpha (unknown origin)	ec50	1.3000	uM
1,1,4,4-tetramethyl-N-phenyl-2,3-dihydro-1,4-benzodisiline-6-carboxamide	1072616: Inverse agonist activity at human RORalpha expressed in HEK293 cells after 18 hrs by luciferase reporter gene assay	ic50	1.3000	uM
N-[4-(3-acetamido-1-propan-2-ylpyrazol-5-yl)-2-pyrrolidin-1-ylphenyl]-2-chloro-6-fluoro-N-(trideuteriomethyl)benzamide	1237147: Inverse agonist activity at RORalpha (unknown origin)	ec50	1.4000	uM
N-[4-(3-acetamido-1-propan-2-ylpyrazol-5-yl)-2-(3-azabicyclo[3.1.0]hexan-3-yl)phenyl]-2,6-dichloro-N-(trideuteriomethyl)benzamide	1237147: Inverse agonist activity at RORalpha (unknown origin)	ec50	1.5000	uM
2-amino-2-(4-ethylsulfonylphenyl)-N-[4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl]acetamide	1510657: Agonist activity at human His6-tcs-RORalpha LBD assessed as PGC1alpha peptide (130 to 154 residues) recruitment incubated for 1 hr by FRET assay	ic50	1.5849	uM
N-[4-(3-acetamido-1-propan-2-ylpyrazol-5-yl)-2-(3-azabicyclo[3.1.0]hexan-3-yl)phenyl]-2-chloro-6-fluoro-N-(trideuteriomethyl)benzamide	1237147: Inverse agonist activity at RORalpha (unknown origin)	ec50	1.6000	uM
2-(2-chlorophenyl)-N-[3-(2-methyl-4-pyridinyl)-5-(trifluoromethyl)phenyl]acetamide	2130371: Inhibition of ROR-alpha (unknown origin) expressed in HEK293T cells co-transfected with RL/Gal4-VP16 incubated for 16 hrs by Dual-Glo Luciferase assay	ic50	1.6000	uM
ethyl 2-[2-[2-[(4-fluorophenyl)methylamino]-2-oxoethyl]-1-oxoisoquinolin-5-yl]oxypropanoate	329655: Inhibition of GAL4-tagged RORalpha by luciferase assay	ic50	1.6800	uM
N-[4-[2-fluoro-4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl]phenyl]heptanamide	1595545: Inverse agonist activity at Gal4-fused RORalpha LBD (unknown origin) expressed in 293T cells measured after 24 hrs by dual-luciferase reporter gene assay	ic50	1.7400	uM
N-[4-[3-acetamido-1-(cyclopropylmethyl)pyrazol-5-yl]-2-(3-azabicyclo[3.1.0]hexan-3-yl)phenyl]-2-chloro-6-fluoro-N-(trideuteriomethyl)benzamide	1237147: Inverse agonist activity at RORalpha (unknown origin)	ec50	1.8000	uM
N-[4-(3-acetamido-1-propan-2-ylpyrazol-5-yl)-2-(3-azabicyclo[3.1.0]hexan-3-yl)phenyl]-2-chloro-6-fluoro-N-methylbenzamide	1237147: Inverse agonist activity at RORalpha (unknown origin)	ec50	1.9000	uM
2-(4-ethylsulfonylphenyl)-N-[4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl]-2-[(2-phenylacetyl)amino]acetamide	1510657: Agonist activity at human His6-tcs-RORalpha LBD assessed as PGC1alpha peptide (130 to 154 residues) recruitment incubated for 1 hr by FRET assay	ic50	1.9953	uM
N-[4-(3-acetamido-1-propan-2-ylpyrazol-5-yl)-2-(3-azabicyclo[3.1.0]hexan-3-yl)phenyl]-2-fluoro-6-methyl-N-(trideuteriomethyl)benzamide	1237147: Inverse agonist activity at RORalpha (unknown origin)	ec50	2.0000	uM
N-[4-(3-acetamido-1-propan-2-ylpyrazol-5-yl)-2-phenylphenyl]-2-chloro-6-fluoro-N-(trideuteriomethyl)benzamide	1237147: Inverse agonist activity at RORalpha (unknown origin)	ec50	2.1000	uM
N-[5-(2-acetamido-4-propan-2-yl-1,3-thiazol-5-yl)-3-piperidin-1-yl-2-pyridinyl]-2-chloro-6-fluoro-N-methylbenzamide	1237147: Inverse agonist activity at RORalpha (unknown origin)	ec50	2.2000	uM
N-(2-methylpropyl)-N-[[4-(4-methylsulfonylphenyl)phenyl]methyl]-1-phenylmethanesulfonamide	1139098: Inverse agonist activity at human GAL4-fused RORa expressed in HEK293 cells after 5 hrs by luciferase reporter gene based transcriptional assay	ec50	2.4000	uM
2-acetamido-2-(4-ethylsulfonylphenyl)-N-[4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl]acetamide	1510657: Agonist activity at human His6-tcs-RORalpha LBD assessed as PGC1alpha peptide (130 to 154 residues) recruitment incubated for 1 hr by FRET assay	ic50	2.5119	uM
N-(2-methylpropyl)-N-[[5-(4-methylsulfonylphenyl)thiophen-2-yl]methyl]-1-phenylmethanesulfonamide	1139098: Inverse agonist activity at human GAL4-fused RORa expressed in HEK293 cells after 5 hrs by luciferase reporter gene based transcriptional assay	ec50	2.8000	uM
3-[(2S)-6-[3-(difluoromethoxy)-5-fluorophenyl]-4-[3-(trifluoromethyl)phenyl]sulfonyl-2,3-dihydro-1,4-benzoxazin-2-yl]-2,2-dimethylpropanoic acid	2022738: Agonist activity at human Gal4-fused RORalpha expressed in HEK293T cells assessed as luciferase activity incubated for 16 to 20 hrs by Luciferase reporter gene assay	ec50	2.9250	uM
ethyl 2-[2-[2-(benzylamino)-2-oxoethyl]-1-oxoisoquinolin-5-yl]oxypropanoate	329655: Inhibition of GAL4-tagged RORalpha by luciferase assay	ic50	3.2200	uM
N-[[4-[4-(methanesulfonamido)phenyl]phenyl]methyl]-N-(2-methylpropyl)-1-phenylmethanesulfonamide	1139098: Inverse agonist activity at human GAL4-fused RORa expressed in HEK293 cells after 5 hrs by luciferase reporter gene based transcriptional assay	ec50	3.8000	uM
4-[1-[2-chloro-6-(trifluoromethyl)benzoyl]-6-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[[(4R)-4-[(3S,8S,9S,10R,13R,14S,17R)-3-hydroxy-10,13-dimethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl]pentanoyl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethylcarbamoyl]indazol-3-yl]benzoic acid	2133286: Inverse agonist activity at human his 6 tagged RORalpha LBD incubated for 60 mins by TR-FRET assay	ic50	4.0000	uM
4-[(3aR,9bR)-9b-(4-fluorophenyl)sulfonyl-7-[[2-fluoro-6-(trifluoromethyl)phenyl]methoxy]-2,3a,4,5-tetrahydro-1H-benzo[e]indole-3-carbonyl]-4-methylcyclohexane-1-carboxylic acid	1668290: Agonist activity at Gal4-fused RORalpha (unknown origin)	ec50	4.2000	uM
N-(2-methylpropyl)-N-[[5-(3-methylsulfonylphenyl)thiophen-2-yl]methyl]-1-phenylmethanesulfonamide	1139098: Inverse agonist activity at human GAL4-fused RORa expressed in HEK293 cells after 5 hrs by luciferase reporter gene based transcriptional assay	ec50	4.2000	uM
ethyl 6-methyl-2-oxo-4-(4-phenylmethoxyphenyl)-3,4-dihydro-1H-pyrimidine-5-carboxylate	748366: Partial agonist activity at GST-fussed RORalpha (unknown origin) assessed as recruitment of TIF2-BAP protein after overnight incubation by pull down assay	ec50	4.3000	uM
N-(2-methylpropyl)-4-[(1-methylsulfonylpiperidin-4-yl)amino]-N-[[2-(trifluoromethyl)phenyl]methyl]benzenesulfonamide	1173407: Inverse agonist activity at GAL4-fused human RORa expressed in HEK293T cells assessed as suppression of basal transcriptional activity after 20 hrs by dual-glo luciferase reporter gene assay	ec50	4.4000	uM
N-ethyl-N-[4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl]benzenesulfonamide	1059098: Inverse agonist activity at GAL4-fused human RORa expressed in HEK293T cells assessed as suppression of basal transcriptional activity after 20 hrs by dual-glo luciferase reporter gene assay	ec50	5.0000	uM
5-butyl-2-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-9-methoxyphenanthridin-6-one	1139695: Inverse agonist activity at human ROR-alpha1 expressed in HEK293 cells after 16 hrs by luciferase reporter gene assay	ic50	5.3000	uM
1-[4-[3-fluoro-4-[[(3S,6R)-3-methyl-1,1-dioxo-6-phenylthiazinan-2-yl]methyl]phenyl]piperazin-1-yl]ethanone	1637553: Inverse agonist activity at GAL4-fused human RORa expressed in HEK293 cells assessed as activation of basal transcriptional activity by dual-glo luciferase reporter gene assay	ec50	5.4000	uM
ethyl 4-[2-chloro-4-[(2-chlorophenyl)methoxy]-5-methoxyphenyl]-6-methyl-2-oxo-3,4-dihydro-1H-pyrimidine-5-carboxylate	748366: Partial agonist activity at GST-fussed RORalpha (unknown origin) assessed as recruitment of TIF2-BAP protein after overnight incubation by pull down assay	ec50	5.5000	uM
5-butyl-2-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-9-(trifluoromethyl)phenanthridin-6-one	1139695: Inverse agonist activity at human ROR-alpha1 expressed in HEK293 cells after 16 hrs by luciferase reporter gene assay	ic50	5.5000	uM
5-butyl-9-chloro-2-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenanthridin-6-one	1139695: Inverse agonist activity at human ROR-alpha1 expressed in HEK293 cells after 16 hrs by luciferase reporter gene assay	ic50	5.6000	uM
(4S)-4-benzyl-3-(3-cyclopentylpropyl)-1-[4-[(5S)-2-propyl-4,5-dihydro-1H-imidazol-5-yl]butyl]imidazolidine-2-thione	1439654: Antagonist activity at human Gal4-fused DBD RORalpha LBD (Pro-211-end) expressed in TRex-CHOK1 cells after 20 hrs by luciferase reporter gene assay	ic50	5.8000	uM
[(1S,2R,5S,6S,7S,9R,11S,12S,15R,16S)-15-[(1S)-1-[(2R)-5-(hydroxymethyl)-4-methyl-6-oxo-2,3-dihydropyran-2-yl]ethyl]-5-methoxy-2,16-dimethyl-3-oxo-8-oxapentacyclo[9.7.0.02,7.07,9.012,16]octadecan-6-yl] 5-[(3aS,4S,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoate	1768119: Binding affinity to RORalpha (unknown origin) by surface plasmon resonance (SPR) sensor assay	kd	5.9000	uM
(4S)-4-benzyl-1-[4-[(5S)-2-(2-cyclopentylethyl)-4,5-dihydro-1H-imidazol-5-yl]butyl]-3-(2-phenylethyl)imidazolidine-2-thione	1439654: Antagonist activity at human Gal4-fused DBD RORalpha LBD (Pro-211-end) expressed in TRex-CHOK1 cells after 20 hrs by luciferase reporter gene assay	ic50	6.0000	uM
4-fluoro-N-[4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl]-N-(2,2,2-trifluoroethyl)benzenesulfonamide	1059098: Inverse agonist activity at GAL4-fused human RORa expressed in HEK293T cells assessed as suppression of basal transcriptional activity after 20 hrs by dual-glo luciferase reporter gene assay	ec50	6.0000	uM
2-(5,5-dibutylbenzo[b][1]benzosilol-2-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol	1230161: Inverse agonist activity at human ROR-alpha1 transfected in HEK293 cells after 16 hrs by luciferase reporter gene assay	ic50	6.2000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression, decreases expression, decreases methylation	9
Benzo(a)pyrene	affects methylation, decreases expression, decreases methylation, increases expression	6
sodium arsenite	increases expression, increases methylation, decreases expression	4
Tobacco Smoke Pollution	increases methylation, decreases expression, increases expression	4
Aflatoxin B1	affects expression, decreases expression, decreases methylation	4
Estradiol	affects expression, affects binding, increases reaction, decreases expression, increases expression	3
Cadmium Chloride	decreases expression, increases expression	3
bisphenol A	affects localization, increases expression, affects cotreatment, affects methylation	2
cobaltous chloride	decreases reaction, increases expression	2
Decitabine	decreases expression, decreases reaction, increases expression	2
aristolochic acid I	decreases expression	1
GSK-J4	increases expression	1
Esketamine	increases expression	1
sotorasib	decreases expression, affects cotreatment	1
testosterone enanthate	increases expression	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
pirinixic acid	increases activity, affects binding, decreases expression	1
deoxynivalenol	increases expression	1
25-hydroxycholesterol	affects binding	1
trichostatin A	increases expression	1
3,4-dichloroaniline	increases expression	1
photomirex	affects binding	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
zinc chloride	decreases reaction, increases expression	1
3-phenoxybenzoic acid	affects binding	1
nickel chloride	increases expression	1
benzo(e)pyrene	affects methylation	1
flucythrinate	affects binding	1
aflatoxin B2	increases methylation	1

ChEMBL screening assays

115 unique, capped per target: 111 binding, 3 functional, 1 unclassified

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1738630	Unclassified	PUBCHEM_BIOASSAY: Late stage results from the probe development effort to identify novel modulators of the Retinoic acid receptor-related Orphan Receptors (ROR). (Class of assay: screening) [Related pubchem assays (depositor defined):AID213	PubChem BioAssay data set
CHEMBL1961834	Binding	Effect on RORA(NR1F1) dependent reporter activity in HEK293 cells at 20 uM	Regulation of circadian behaviour and metabolism by synthetic REV-ERB agonists. — Nature
CHEMBL5723471	Functional	Affinity On-target Cellular interaction: (Reporter gene assay (HEK293T cells)) EUB0001157a RORA	Affinity On-target Cellular Literature for EUbOPEN Chemogenomic Library

Cellosaurus cell lines

1 cell lines: 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D9QV	Ubigene HEK293 RORA KO	Transformed cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT02909959	PHASE2	COMPLETED	Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
NCT06081348	PHASE2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06352372	PHASE2	COMPLETED	Safety and Efficacy of tPBM for Epileptiform Activity in Autism
NCT00503191	PHASE1	COMPLETED	NeuroModulation Technique Treatment of Autism
NCT04475848	PHASE1	COMPLETED	A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants
NCT06300398	PHASE1	COMPLETED	IAMA-6 Oral Dose Study in Healthy Adults
NCT01802190	Not specified	TERMINATED	Prevalence of POU4F3 and SLC17A8 Mutations
NCT01783041	PHASE2/PHASE3	COMPLETED	Effect of Early L-Carnitine Supplementation on Neurodevelopmental Outcomes in Very Preterm Infants
NCT05767385	PHASE2/PHASE3	RECRUITING	Fetal Cerebrovascular Autoregulation in Congenital Heart Disease and Association With Neonatal Neurobehavior
NCT05675098	EARLY_PHASE1	NOT_YET_RECRUITING	Central Nervous System Stimulants and Physical Function in Children With Cerebral Palsy
NCT00783783	Not specified	COMPLETED	CYP2D6 Pharmacogenetics in Risperidone-Treated Children
NCT01778504	Not specified	RECRUITING	Studying Childhood-onset Behavioral, Psychiatric, and Developmental Disorders
NCT01850784	Not specified	UNKNOWN	High Energy Formula Feeding in Infants With Congenital Heart Disease
NCT01922791	Not specified	COMPLETED	Nutrition and Pregnancy Intervention Study
NCT01942525	Not specified	UNKNOWN	Influence of Intrauterine Growth Restriction on Amplitude-integrated EEG in Preterm Infants
NCT02003170	Not specified	COMPLETED	Etiology and Early Diagnosis of Neurodevelopmental Disorders
NCT02118649	Not specified	ACTIVE_NOT_RECRUITING	Enhancing Behavior and Brain Response to Visual Targets Using a Computer Game
NCT02557191	Not specified	TERMINATED	Biomarkers, Neurodevelopment and Preterm Infants
NCT02690675	Not specified	COMPLETED	Iron Supplement Effect on Child Development
NCT02694003	Not specified	COMPLETED	Better Nights, Better Days for Children With Neurodevelopment Disorders
NCT02792894	Not specified	COMPLETED	Family Networks (FaNs) for Children With Developmental Disorders and Delays
NCT02871674	Not specified	UNKNOWN	Good Night Project: Behavioural Sleep Interventions for Children With ADHD: A Randomised Controlled Trial
NCT02887157	Not specified	COMPLETED	Analyzing Retinal Microanatomy in ROP
NCT02898298	Not specified	COMPLETED	Positive Emotion Regulation Training in Children, Adolescents and Young Adults With and Without Developmental Disorder
NCT02912780	Not specified	UNKNOWN	Introduction of Microsystems in a Level 3 Neonatal Intensive Care Unit
NCT03023293	Not specified	COMPLETED	n-3 PUFAs, Irisin and Maternal Glucose Metabolism From Pregnancy to Postpartum
NCT03023644	Not specified	COMPLETED	Improving Neurodevelopmental Outcomes in Children With Congenital Heart Disease: An Intervention Study
NCT03032991	Not specified	UNKNOWN	Early Biomarkers of Neurodevelopment in Offspring of Diabetic Mothers
NCT03088189	Not specified	TERMINATED	Effect of Parental Peri-conceptional Vitamin B12 Supplementation on Infant Neurocognitive Development in Offspring
NCT03096028	Not specified	COMPLETED	Developmental Origins of Mental Health Disorders
NCT03148782	Not specified	COMPLETED	Brain Plasticity Underlying Acquisition of New Organizational Skills in Children-R61 Phase
NCT03172104	Not specified	COMPLETED	Neurobehavioural Development of Infants Born <30 Weeks Gestational Age Between Birth and Five Years of Age
NCT03222375	Not specified	RECRUITING	SQUED™ Series 28.1 Home-use and Treatment of Autowave Reverberator of Autism
NCT03229928	Not specified	COMPLETED	Clinical Testing of a Real-Time Behavior Measurement Tool: Measuring Outcomes for CHAnge

Associated diseases: hearing loss, autosomal recessive 108, intellectual developmental disorder with or without epilepsy or cerebellar ataxia, nonsyndromic genetic hearing loss, hearing loss, autosomal recessive
Disease cohort memberships (association, not causation — diseases whose associated-gene cohort lists this gene; a subset are also under Associated diseases): allergic disease, allergic rhinitis, alopecia, Alzheimer disease, asthma, bacterial meningitis, breast carcinoma, cataract, childhood onset asthma, eosinophilic esophagitis, exocrine pancreatic carcinoma, hearing loss, autosomal recessive, hearing loss, autosomal recessive 108, intellectual developmental disorder with or without epilepsy or cerebellar ataxia, keratoconus, major depressive disorder, multiple sclerosis, neurofibromatosis type 1, nonsyndromic genetic hearing loss, open-angle glaucoma