ESRRG

Summary

ESRRG (estrogen related receptor gamma, HGNC:3474) is a protein-coding gene on chromosome 1q41, encoding Estrogen-related receptor gamma (P62508). Orphan receptor that acts as a transcription activator in the absence of bound ligand.

This gene encodes a member of the estrogen receptor-related receptor (ESRR) family, which belongs to the nuclear hormone receptor superfamily. All members of the ESRR family share an almost identical DNA binding domain, which is composed of two C4-type zinc finger motifs. The ESRR members are orphan nuclear receptors; they bind to the estrogen response element and steroidogenic factor 1 response element, and activate genes controlled by both response elements in the absence of any ligands. The ESRR family is closely related to the estrogen receptor (ER) family. They share target genes, co-regulators and promoters, and by targeting the same set of genes, the ESRRs seem to interfere with the ER-mediated estrogen response in various ways. It has been reported that the family member encoded by this gene functions as a transcriptional activator of DNA cytosine-5-methyltransferases 1 (Dnmt1) expression by direct binding to its response elements in the DNMT1 promoters, modulates cell proliferation and estrogen signaling in breast cancer, and negatively regulates bone morphogenetic protein 2-induced osteoblast differentiation and bone formation. Multiple alternatively spliced transcript variants have been identified, which mainly differ at the 5’ end and some of which encode protein isoforms differing in the N-terminal region.

Source: NCBI Gene 2104 — RefSeq curated summary.

At a glance

• GWAS associations: 37 (top 3% of genes corpus-wide)
• Clinical variants (ClinVar): 67 total — 4 pathogenic, 5 likely-pathogenic
• Regional missense constraint (gnomAD): 2 of 5 regions constrained (≈25% of expected missense variation)
• GTEx eGene: eQTL in 14 tissues, sQTL in 0 (q < 0.05)
• Drug target: yes — 1 curated mechanism-of-action drug; 2 molecules with ChEMBL bioactivity
• Constraint (gnomAD): pLI 0.99 (loss-of-function intolerant), LOEUF 0.46 (moderately constrained)
• Transcription factor: yes — 30 downstream targets (CollecTRI)
• MANE Select transcript: NM_001438
• Notable: 67 clinical variants but no curated precision-oncology (CIViC) evidence yet

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3474
Approved symbol	ESRRG
Name	estrogen related receptor gamma
Location	1q41
Locus type	gene with protein product
Status	Approved
Aliases	NR3B3, ERRg, ERR-gamma
Ensembl gene	ENSG00000196482
Ensembl biotype	protein_coding
OMIM	602969
Entrez	2104

Gene structure

Transcript identifiers

Ensembl transcripts: 28 — 22 protein_coding, 6 protein_coding_CDS_not_defined

MANE Select: ENST00000408911

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 12, TSL 2: 1, TSL 3: 1, TSL 4: 4, TSL 5: 6

ENST00000408911, ENST00000359162, ENST00000360012, ENST00000361395, ENST00000361525, ENST00000366937, ENST00000366938, ENST00000366940, ENST00000391890, ENST00000459825, ENST00000459955, ENST00000463665, ENST00000469486, ENST00000469913, ENST00000471371, ENST00000475275, ENST00000477799, ENST00000481543, ENST00000487276, ENST00000488947, ENST00000493603, ENST00000493748, ENST00000586199, ENST00000616180, ENST00000673908, ENST00001042525, ENST00001042526, ENST00001145429

RefSeq mRNA: 20 — MANE Select: NM_001438 NM_001134285, NM_001243505, NM_001243506, NM_001243507, NM_001243509, NM_001243510, NM_001243511, NM_001243512, NM_001243513, NM_001243514, NM_001243515, NM_001243518, NM_001243519, NM_001350122, NM_001350123, NM_001350124, NM_001350125, NM_001438, NM_206594, NM_206595

CCDS: CCDS1517, CCDS41468, CCDS58060, CCDS58061

Canonical transcript exons

ENST00000408911 — 7 exons

Exon	Start	End
ENSE00001409682	216503251	216507183
ENSE00001586839	216564219	216564380
ENSE00001626361	216650973	216651089
ENSE00003570231	216677076	216677491
ENSE00003648022	216723244	216723429
ENSE00003682678	216567988	216568098
ENSE00003787984	216519152	216519421

Expression profiles

Bgee: expression breadth ubiquitous, 250 present calls, max score 97.91.

FANTOM5 (CAGE): breadth broad, TPM avg 3.8021 / max 507.1653, expressed in 431 samples.

Highest expression (Bgee): pons, nephron tubule, endothelial cell, renal medulla, Brodmann (1909) area 23.

Genetic regulation across tissues (GTEx eQTL / sQTL)

ESRRG is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 14 tissues and its splicing (sQTL) in 0 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

14 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Adrenal Gland	eqtl	2.4e-10	+0.80	1:216736712:C:G
Testis	eqtl	2.7e-09	-0.35	1:216730099:C:A
Esophagus Muscularis	eqtl	8.2e-06	-0.14	1:216871259:T:C
Nerve Tibial	eqtl	9.1e-05	+0.53	1:216902855:G:A
Colon Transverse	eqtl	1.5e-03	+0.28	1:216980363:A:G
Thyroid	eqtl	2.6e-03	-0.16	1:216666162:C:T
Pancreas	eqtl	3.9e-03	+0.28	1:217099488:A:T
Esophagus Mucosa	eqtl	5.0e-03	-0.42	1:216825271:T:C
Adipose Subcutaneous	eqtl	1.7e-02	-0.73	1:217269354:G:A
Lung	eqtl	2.3e-02	+0.14	1:218115169:C:T
Spleen	eqtl	3.9e-02	+0.34	1:216883551:T:C
Adipose Visceral Omentum	eqtl	4.0e-02	+0.80	1:217881490:C:T
Heart Left Ventricle	eqtl	4.1e-02	+0.20	1:216742747:T:C
Ovary	eqtl	4.1e-02	+0.51	1:217877855:GGAAGGAAGATGATTCA:G

FANTOM5 promoters

showing 10 of 21 alternative TSS:

Promoter ID	TPM avg	Samples expressed
17475	1.2978	193
17476	0.5061	145
17490	0.3029	143
17492	0.2513	104
17477	0.2042	85
17491	0.1670	93
17483	0.1441	61
17488	0.1424	72
17485	0.1298	56
17486	0.1158	64

Top tissues by expression

showing 100 of 292 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
pons	UBERON:0000988	97.91	gold quality
nephron tubule	UBERON:0001231	96.27	gold quality
endothelial cell	CL:0000115	94.34	gold quality
renal medulla	UBERON:0000362	94.27	gold quality
Brodmann (1909) area 23	UBERON:0013554	92.17	gold quality
kidney epithelium	UBERON:0004819	92.13	gold quality
heart right ventricle	UBERON:0002080	91.29	gold quality
parotid gland	UBERON:0001831	90.60	gold quality
diaphragm	UBERON:0001103	90.36	gold quality
choroid plexus epithelium	UBERON:0003911	90.14	gold quality
biceps brachii	UBERON:0001507	90.04	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	89.82	gold quality
primary visual cortex	UBERON:0002436	89.24	gold quality
myocardium	UBERON:0002349	89.17	gold quality
renal glomerulus	UBERON:0000074	88.52	gold quality
placenta	UBERON:0001987	88.44	gold quality
metanephric glomerulus	UBERON:0004736	87.88	gold quality
kidney	UBERON:0002113	87.79	gold quality
left ventricle myocardium	UBERON:0006566	87.58	gold quality
cerebellar vermis	UBERON:0004720	87.38	gold quality
adult mammalian kidney	UBERON:0000082	86.26	gold quality
pigmented layer of retina	UBERON:0001782	86.22	gold quality
cardiac muscle of right atrium	UBERON:0003379	85.78	gold quality
middle temporal gyrus	UBERON:0002771	85.68	gold quality
occipital lobe	UBERON:0002021	85.62	gold quality
deltoid	UBERON:0001476	85.37	gold quality
jejunal mucosa	UBERON:0000399	84.89	gold quality
metanephros	UBERON:0000081	84.48	gold quality
cardia of stomach	UBERON:0001162	83.41	gold quality
vastus lateralis	UBERON:0001379	83.35	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	82.90	gold quality
quadriceps femoris	UBERON:0001377	82.53	gold quality
caput epididymis	UBERON:0004358	82.42	gold quality
cortex of kidney	UBERON:0001225	82.17	gold quality
skeletal muscle tissue	UBERON:0001134	82.15	gold quality
bronchial epithelial cell	CL:0002328	82.01	gold quality
gluteal muscle	UBERON:0002000	82.01	gold quality
superior vestibular nucleus	UBERON:0007227	81.30	gold quality
cardiac ventricle	UBERON:0002082	81.07	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	81.00	gold quality
jejunum	UBERON:0002115	80.96	gold quality
heart left ventricle	UBERON:0002084	80.90	gold quality
muscle tissue	UBERON:0002385	80.84	gold quality
postcentral gyrus	UBERON:0002581	80.38	gold quality
stomach	UBERON:0000945	80.21	gold quality
duodenum	UBERON:0002114	79.91	gold quality
palpebral conjunctiva	UBERON:0001812	79.75	gold quality
epithelium of bronchus	UBERON:0002031	79.73	gold quality
parietal lobe	UBERON:0001872	79.54	gold quality
substantia nigra pars compacta	UBERON:0001965	79.46	gold quality
cardiac atrium	UBERON:0002081	79.33	gold quality
bronchus	UBERON:0002185	79.15	gold quality
secondary oocyte	CL:0000655	79.09	gold quality
right atrium auricular region	UBERON:0006631	78.77	gold quality
body of stomach	UBERON:0001161	78.76	gold quality
Brodmann (1909) area 46	UBERON:0006483	78.65	gold quality
Brodmann (1909) area 10	UBERON:0013541	78.33	gold quality
tibialis anterior	UBERON:0001385	78.29	gold quality
hindlimb stylopod muscle	UBERON:0004252	78.24	gold quality
inferior olivary complex	UBERON:0002127	78.16	gold quality
heart	UBERON:0000948	77.83	gold quality
triceps brachii	UBERON:0001509	77.75	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	77.41	gold quality
fundus of stomach	UBERON:0001160	77.26	gold quality
medulla oblongata	UBERON:0001896	77.13	gold quality
mucosa of paranasal sinus	UBERON:0005030	77.04	gold quality
prefrontal cortex	UBERON:0000451	76.81	gold quality
metanephros cortex	UBERON:0010533	76.77	gold quality
superior frontal gyrus	UBERON:0002661	76.69	gold quality
lateral nuclear group of thalamus	UBERON:0002736	76.57	gold quality
lateral globus pallidus	UBERON:0002476	76.39	gold quality
muscle organ	UBERON:0001630	76.08	gold quality
epithelial cell of pancreas	CL:0000083	75.90	silver quality
islet of Langerhans	UBERON:0000006	75.76	gold quality
germinal epithelium of ovary	UBERON:0001304	75.74	gold quality
inferior vagus X ganglion	UBERON:0005363	75.45	gold quality
apex of heart	UBERON:0002098	74.80	gold quality
pancreatic ductal cell	CL:0002079	74.37	silver quality
buccal mucosa cell	CL:0002336	74.28	gold quality
right adrenal gland cortex	UBERON:0035827	74.26	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	74.11	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	74.06	gold quality
orbitofrontal cortex	UBERON:0004167	74.00	gold quality
frontal cortex	UBERON:0001870	73.87	gold quality
pancreas	UBERON:0001264	73.85	gold quality
neocortex	UBERON:0001950	73.82	gold quality
paraflocculus	UBERON:0005351	73.78	gold quality
gastrocnemius	UBERON:0001388	73.65	gold quality
entorhinal cortex	UBERON:0002728	73.65	gold quality
Brodmann (1909) area 9	UBERON:0013540	73.63	gold quality
ventricular zone	UBERON:0003053	73.50	gold quality
CA1 field of hippocampus	UBERON:0003881	73.39	gold quality
right adrenal gland	UBERON:0001233	73.35	gold quality
muscle of leg	UBERON:0001383	73.35	gold quality
cerebral cortex	UBERON:0000956	73.09	gold quality
substantia nigra pars reticulata	UBERON:0001966	72.61	gold quality
cerebellum	UBERON:0002037	72.52	gold quality
body of tongue	UBERON:0011876	72.48	gold quality
left adrenal gland	UBERON:0001234	72.27	gold quality
midbrain	UBERON:0001891	72.24	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-CURD-119	yes	65.30
E-HCAD-10	yes	13.05
E-ANND-3	yes	7.67
E-CURD-135	no	820.14

HPA expression

RNA tissue specificity: Tissue enhanced

showing 60 of 77 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Parathyroid gland	tissue	43.5	not detected
Postcentral gyrus	tissue	34.3
Retina	tissue	33.5
Stomach 1	tissue	33.1	medium
Choroid plexus	tissue	28.7
Cerebral cortex	tissue	28.0	low
Somatosensory cortex	tissue	28.0
Kidney	tissue	27.1	medium
Occipital cortex	tissue	26.5
Pons	tissue	25.9
Olfactory bulb	tissue	21.0
Cerebellum	tissue	18.5	low
Medulla oblongata	tissue	18.0
Superior colliculi	tissue	16.0
Retrosplenial and cingulate cortex	tissue	15.4
Motor cortex	tissue	15.1
Salivary gland	tissue	15.0	not detected
Nucleus accumbens	tissue	14.2
Locus coeruleus	tissue	14.0
Thalamus	tissue	13.7
Spinal cord	tissue	13.5
Retrosplenial cortex	tissue	13.5
Temporal cortex	tissue	13.3
Hippocampus	tissue	13.2	not detected
Hippocampal formation	tissue	13.2
Entorhinal cortex	tissue	13.2
Caudate putamen	tissue	13.1
Midbrain	tissue	12.8
Prefrontal cortex	tissue	12.7
Substantia nigra	tissue	12.3
Periaqueductal gray	tissue	12.1
Frontal cortex	tissue	10.2
Putamen	tissue	10.1
Placenta	tissue	10.0	not detected
Heart muscle	tissue	9.9	low
Insular cortex	tissue	9.9
Ventral forebrain	tissue	9.8
Tongue	tissue	9.5
Septum	tissue	8.1
Basal ganglia	tissue	8.0	not detected
Hypothalamus	tissue	7.5
Amygdala	tissue	6.6
Adrenal gland	tissue	6.1	not detected
Thyroid gland	tissue	5.5	not detected
Skeletal muscle	tissue	5.4	low
Pancreas	tissue	5.4	not detected
Duodenum	tissue	5.0	not detected
Small intestine	tissue	4.7	not detected
Breast	tissue	3.4	low
Prostate	tissue	2.9	low
Corpus callosum	tissue	2.8
Fallopian tube	tissue	2.3	not detected
Esophagus	tissue	1.5	low
Cervix	tissue	1.4	not detected
Pituitary gland	tissue	1.4
Testis	tissue	1.0	low
Spleen	tissue	1.0	not detected
Epididymis	tissue	0.9	not detected
Seminal vesicle	tissue	0.7	not detected
Liver	tissue	0.7	not detected

Brain sub-regions (HPA Brain Atlas): detected in 190; highest nTPM — Nuclei of the trapezoid body (117.0), Ventral periolivary nuclei (113.8), Nucleus raphe magnus (108.4), Lateral lemniscal nuclei (105.0), Superior olive (98.2).

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

30 targets:

Target	Regulation
ACADM
ATF6	Unknown
BGLAP	Repression
CDKN1A	Activation
CDKN1B
CREB3L3
CREBZF
CRP
CYP19A1
DNASE1
DNMT1	Unknown
ESRRA	Unknown
ESRRG
GATA4
IBSP	Repression
MIR127	Activation
MIR206
MIR433	Activation
NOTCH1
NR0B1	Activation
NR0B2	Activation
NRIP1
PCK1
PDK4	Activation
PLK2	Unknown
PPARGC1A	Activation
PPARGC1B
SPP1
WDR5	Repression
YY1	Unknown

Upstream regulators (CollecTRI, top): ATF6, CREBZF, ESRRG, FOXC1, HIF1A, NCOA2, NR0B1, NR0B2, NR5A1, SIRT1

miRNA regulators (miRDB)

Targeting ESRRG by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 198 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-6758-5P	100.00	66.21	1470
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-6851-5P	100.00	65.63	1294
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-3689D	100.00	66.14	1181
HSA-MIR-3134	100.00	66.43	777
HSA-MIR-6740-5P	100.00	65.64	932
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-4533	100.00	69.48	2758
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-4514	99.99	67.10	1870

Functional genomics

gnomAD constraint: pLI 0.994, LOEUF 0.464, missense Z 2.77 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD)

ENST00000408911 splits into 5 regions with different missense tolerance; 2 are missense-constrained (≈25% of the expected missense variation). Missense variants in a constrained region (low observed/expected) are more likely to be pathogenic. gnomAD

Region (GRCh38)	Missense obs / exp	o/e	Constrained
1:216,506,942–216,507,008	8 / 25.4	0.32	yes (p 5.6e-04)
1:216,507,009–216,564,371	167 / 251.8	0.66	no
1:216,564,372–216,568,054	37 / 32.9	1.13	no
1:216,568,055–216,677,184	35 / 120.1	0.29	yes (p 8.0e-15)
1:216,677,185–216,723,299	148 / 150.4	0.98	no

Literature-anchored findings (GeneRIF, showing 40)

• Transcriptional activation by ERR3 can be ligand-independent. (PMID:11864604)
• Not only PNRC2 but also the corepressor TLE1 functioned as ERRgamma coactivator in a reporter gene analysis (PMID:14651967)
• ERRs, which are coexpressed with ERs in prostatic cells, could regulate cell growth and modulate ER-mediated pathways via interference on ERalpha transcription in prostatic cells. (PMID:15598686)
• Data demonstrate that the multi-hormone response element of the estrogen-related receptor-alpha (ERRalpha) gene is a target for ERRgamma transactivation, which is enhanced by peroxisome proliferator-activated receptor-gamma coactivator-1alpha. (PMID:15821111)
• Up-regulation of estrogen-related receptor gamma is associated with endometrial adenocarcinoma (PMID:16681769)
• Thermal stability studies show that agonist binding leads to global stabilization of the ligand binding domain. (PMID:16990259)
• First evidence is provided that the nuclear receptor estrogen-related receptor gamma forms complexes with the endocrine disruptor, providing detailed molecular insight into the interaction features. (PMID:17761695)
• Results clearly indicate that estrogen-related receptor gamma forms an appropriate structure presumably to adopt an unidentified endogenous ligand. (PMID:18005256)
• ERRGamma (estrogen-related receptor gamma ) mRNA levels decreased from normal vagina of the pre-menopausal women to atrophic vaginal tissue in post-menopausal women (PMID:18328649)
• Receptor estrogen-related receptors alpha, beta and gamma physically interact with HIF and stimulate HIF-induced transcription in tumor cells cultured under hypoxia. (PMID:18509053)
• The 2.0 A crystal structure of the 4-alpha-cumylphenol/ERRgamma complex clearly revealed that ERRgamma’s Leu345-beta-isopropyl plays a role in the tight binding of 4-alpha-cumylphenol and BPA, rotating in a back-and-forth induced-fit manner. (PMID:18582436)
• Kaempferol is an estrogen-related receptor gamma inverse agonist. (PMID:19171140)
• placenta expresses ERRgamma mRNA extremely highly; among the 3 ERRgamma protein isoforms, placenta exclusively expresses the type-1 isoform; results suggest that bisphenol A accumulates in the placenta by binding to ERRgamma (PMID:19304792)
• Single nucleotide polymorphisms in the estrogen-related receptor gamma is Associated with post-menopausal breast cancer women. (PMID:19415745)
• SMILE is a novel corepressor of ERRgamma, and SIRT1 has a role as a novel repressive mechanism for SMILE and ERRgamma inverse agonist (PMID:19690166)
• These results suggest involvement of ESRRgamma in the determination of bone density in women. (PMID:19821770)
• These results indicate that ERRalpha and ERRgamma are differentially expressed in these tumor cell lines and likely contribute to agonist-dependent ERR transcriptional activity. (PMID:19822186)
• PPARalpha promoter variant impairs ERRA and ERRG dependent transactivation and decreases mortality after acute coronary ischemia in patients with diabetes. (PMID:20838448)
• Estrogen-related receptor gamma modulates cell proliferation and estrogen signaling in breast cancer. (PMID:20883782)
• miR-378( *) inhibits the expression of two PGC-1beta partners, ERRgamma and GABPA, leading to a reduction in TCA cycle gene expression and oxygen consumption as well as an increase in lactate production and in cell proliferation (PMID:20889127)
• Our study indicates that the AAAG tetranucleotide repeat polymorphism in ERR-gamma gene 5’ UTR region may be a new biomarker for genetic susceptibility to breast cancer. (PMID:21153485)
• Parkin degrades ESRRA, ESRRB and ESRRG to limit the expression of MAOA and MAOB. (PMID:21177257)
• Study provides evidence for nuclear receptor mediated regulation of Dnmt1 expression through ERRgamma and SHP crosstalk. (PMID:21459093)
• These novel findings identify ERRgamma as an O(2)-dependent transcription factor and HIF-1alpha target gene that serves a critical role in the induction of hCYP19 expression during human trophoblast differentiation. (PMID:21757507)
• Estrogen-related receptor gamma (ERRgamma) is a novel transcriptional regulator of phosphatidic acid phosphatase, LIPIN1, and inhibits hepatic insulin signaling (PMID:21911493)
• Disorder-to-order transition underlies the structural basis for the assembly of a transcriptionally active PGC-1alpha/ERRgamma complex (PMID:22049338)
• Orphan nuclear receptor estrogen-related receptor gamma (ERRgamma) is key regulator of hepatic gluconeogenesis (PMID:22549789)
• results suggest that Estrogen-Related Receptor gamma (ERRgamma) could be implicated in the energy metabolism regulation of human trophoblasts (PMID:22763271)
• Data show that the orphan nuclear receptor estrogen related receptor gamma (ERRgamma) plays a critical role in hypoxia-mediated activation of pyruvate dehydrogenase kinase 4 (PDK4) gene expression. (PMID:23050013)
• The relationship between ERRgamma and ERalpha status could be a predictive marker for the treatment of uterine endometrial cancer. (PMID:23051957)
• plays a role in maintenance of hearing in both humans and mice. (PMID:23540940)
• ERRGamma mediates oxygen-dependent expression of genes involved in human trophoblast differentiation, function, and vascular homeostasis. (PMID:23584901)
• The ESRRG gene is a novel target of miR-205 mediated RNA-interference. (PMID:23589079)
• Nuclear ANG directly binds to the ANG-Binding Sequence within ERRgamma of ERRgamma gene and inhibits ERRgamma transcription to promote breast cancer cell proliferation. (PMID:23977052)
• These findings demonstrate a novel ERRgamma/GATA4 signal cascade in the development of cardiac hypertrophy. (PMID:24083978)
• Iranian women with short AAAG repeat are at higher risk of breast cancer. (PMID:24125170)
• ERRgamma protein levels are affected by the activation state of ERK/mitogen-activated protein kinase, and mutation of consensus ERK target sites impairs ERRgamma-driven transcriptional activity and tamoxifen resistance. (PMID:24684682)
• Report estrogen-mediated cell kinetics and the role of oestrogen-related receptor gamma on biliary epithelial cells in the pathogenesis of primary biliary cirrhosis. (PMID:24687322)
• A role for ESRRG in maternal blood pressure homeostasis during pregnancy. (PMID:24725083)
• The results reveal that the double-layer binding sites, namely, the ordinary ligand binding sites and their back support residues, substantiate the strong binding of BPA to ERRgamma. (PMID:24978476)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	esrrga	ENSDARG00000004861
mus_musculus	Esrrg	ENSMUSG00000026610
rattus_norvegicus	Esrrg	ENSRNOG00000002593
drosophila_melanogaster	ERR	FBGN0035849

Paralogs (8): PGR (ENSG00000082175), ESR1 (ENSG00000091831), NR3C1 (ENSG00000113580), ESRRB (ENSG00000119715), ESR2 (ENSG00000140009), NR3C2 (ENSG00000151623), AR (ENSG00000169083), ESRRA (ENSG00000173153)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:1347056) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 23 distinct phenotype terms.

Mouse phenotype (MP)	Records
postnatal lethality, complete penetrance	3
abnormal kidney medulla morphology	1
abnormal impulse conducting system conduction	1
prolonged QT interval	1
abnormal kidney papilla morphology	1
abnormal kidney pelvis morphology	1
abnormal myocardial fiber physiology	1
abnormal renal glomerulus morphology	1
hyperekplexia	1
impaired hearing	1
decreased survivor rate	1
absent gastric milk in neonates	1
decreased birth weight	1
prolonged QRS complex duration	1
prolonged ST segment	1
bundle branch block	1
abnormal respiratory electron transport chain	1
postnatal lethality, incomplete penetrance	1
absent kidney papilla	1
increased mitochondrial number	1
increased or absent threshold for auditory brainstem response	1
increased circulating lactate level	1
decreased auditory brainstem response wave amplitude	1

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Gallus gallus	P04625	100.0%	Diamond
Cairina moschata	P68305	100.0%	Diamond
Bos taurus	Q08E53	99.8%	Diamond
Pongo abelii	Q5RAM2	99.8%	Diamond
Saimiri boliviensis boliviensis	O13186	99.7%	Diamond
Saimiri sciureus	O46567	99.7%	Diamond
Pan troglodytes	A7X8B3	99.5%	Diamond
Pan paniscus	A7X8B5	99.5%	Diamond
Aotus nancymaae	P79686	99.5%	Diamond
Saguinus oedipus	P79269	99.4%	Diamond
Callithrix jacchus	Q6XLJ0	99.4%	Diamond
Ovis aries	B3SV56	99.3%	Diamond
Aptenodytes patagonicus	O42295	99.3%	Diamond
Canis lupus familiaris	Q6QMY5	99.3%	Diamond
Gorilla gorilla gorilla	A7X8B7	99.1%	Diamond
Pygoscelis adeliae	O42450	98.8%	Diamond
Sus scrofa	Q0GFF6	98.5%	Diamond
Macaca sylvanus	A7X8C4	98.3%	Diamond
Papio anubis	A7X8C7	98.3%	Diamond
Felis catus	Q53AD2	98.3%	Diamond
Coturnix japonica	O93511	98.1%	Diamond
Aquarana catesbeiana	Q02965	98.1%	Diamond
Colobus guereza	A7X8D2	98.0%	Diamond
Trachypithecus obscurus	A7X8D4	98.0%	Diamond
Xenopus laevis	P18119	97.6%	Diamond
Chlorocebus aethiops	A7X8C9	97.5%	Diamond
Pongo pygmaeus	A7X8B9	97.4%	Diamond
Hylobates lar	A7X8C2	97.1%	Diamond
Sapajus apella	A7XW16	97.1%	Diamond
Pithecia irrorata	A7XW20	97.1%	Diamond
Ateles paniscus	A7XW25	97.1%	Diamond
Xenopus tropicalis	Q66JK1	97.0%	Diamond
Oryctolagus cuniculus	P06186	96.8%	Diamond
Pagrus major	O42132	96.7%	Diamond
Lymnaea stagnalis	Q5I7G2	96.1%	Diamond
Oncorhynchus mykiss	P16058	95.5%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
USH2A-AS2	ncRNA	102723833
USH2A	protein-coding	7399
GPATCH2	protein-coding	55105
USH2A-AS1	ncRNA	105372918
KCTD3	protein-coding	51133

Protein

Protein identifiers

Estrogen-related receptor gamma — P62508 (reviewed: P62508)

Alternative names: ERR gamma-2, Estrogen receptor-related protein 3, Nuclear receptor subfamily 3 group B member 3

All UniProt accessions (7): C9J0E3, C9J5W9, C9JNX5, C9JU32, F1D8R5, F1D8R6, P62508

UniProt curated annotations — full annotation on UniProt →

Function. Orphan receptor that acts as a transcription activator in the absence of bound ligand. Binds specifically to an estrogen response element and activates reporter genes controlled by estrogen response elements. Induces the expression of PERM1 in the skeletal muscle.

Subunit / interactions. Homodimer. Binds TLE1, PNRC1 and PNRC2. Binds GRIP1. Interacts with NRIP1, NCOA1 and NCOR2.

Subcellular location. Nucleus.

Tissue specificity. Expressed in the heart, kidney, brain, lung, bone marrow, adrenal gland, trachea, spinal cord and thyroid gland.

Post-translational modifications. Acetylated by PCAF/KAT2 (in vitro). Sumoylation on Lys-40 is enhanced by phosphorylation at Ser-45 and represses transcriptional activity. Phosphorylation on Ser-45 enhances sumoylation on Lys-40 thus repressing transcriptional activity.

Miscellaneous. No physiological activating ligand is known for this orphan receptor, but 4-hydroxytamoxifen and diethylstilbestrol act as inverse agonists and deactivate ESRRG.

Similarity. Belongs to the nuclear hormone receptor family. NR3 subfamily.

Isoforms (5)

UniProt ID	Names	Canonical?
P62508-1	1, Long	yes
P62508-2	2, Short
P62508-3	3
P62508-4	4
P62508-5	5

RefSeq proteins (20): NP_001127757, NP_001230434, NP_001230435, NP_001230436, NP_001230438, NP_001230439, NP_001230440, NP_001230441, NP_001230442, NP_001230443, NP_001230444, NP_001230447, NP_001230448, NP_001337051, NP_001337052, NP_001337053, NP_001337054, NP_001429, NP_996317, NP_996318 (=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
IPR024178	Est_rcpt/est-rel_rcp	Family
IPR027289	Oest-rel_rcp	Family
IPR035500	NHR-like_dom_sf	Homologous_superfamily
IPR050200	Nuclear_hormone_rcpt_NR3	Family

Pfam: PF00104, PF00105

UniProt features (58 total): helix 16, sequence conflict 9, mutagenesis site 8, strand 8, splice variant 4, zinc finger region 2, turn 2, compositionally biased region 2, chain 1, domain 1, sequence variant 1, DNA-binding region 1, region of interest 1, modified residue 1, cross-link 1

Structure

Experimental structures (PDB)

showing 30 of 43 structures by resolution:

PDB	Title	Method	Resolution (Å)
6XXC	Ternary complex of 14-3-3 sigma (C38N), Estrogen Related Receptor gamma (DBD) …	X-RAY DIFFRACTION	1.3
6XY5	Ternary complex of 14-3-3 sigma (C38N), Estrogen Related Receptor gamma (DBD) …	X-RAY DIFFRACTION	1.3
6Y18	Ternary complex of 14-3-3 sigma (C38N), Estrogen Related Receptor gamma (DBD) …	X-RAY DIFFRACTION	1.3
6Y3W	Ternary complex of 14-3-3 sigma (C38N), Estrogen Related Receptor gamma (DBD) …	X-RAY DIFFRACTION	1.34
6Y1D	Binary complex of 14-3-3 sigma (C38N) with the Estrogen Related Receptor gamma (DBD) …	X-RAY DIFFRACTION	1.38
8B4Q	Ternary structure of 14-3-3s, ERRg phosphopeptide and dual-reactive compound 5	X-RAY DIFFRACTION	1.4
8BJG	Ternary structure of 14-3-3s, ERRg phosphopeptide and dual-reactive compound 8	X-RAY DIFFRACTION	1.4
8BJN	Ternary structure of 14-3-3s, ERRg phosphopeptide and dual-reactive compound 6	X-RAY DIFFRACTION	1.4
8BM5	Ternary structure of 14-3-3s, ERRg phosphopeptide and dual-reactive compound 7	X-RAY DIFFRACTION	1.4
6I65	Crystal structure of human ERRg LBD in complex with 4-iso-propylphenol	X-RAY DIFFRACTION	1.5
9KNG	Crystal structure of human ERRg LBD in complex with 4034496	X-RAY DIFFRACTION	1.5
9KND	Crystal structure of human ERRg LBD in complex with indole	X-RAY DIFFRACTION	1.52
2E2R	Crystal structure of human estrogen-related receptor gamma ligand binding domain complex …	X-RAY DIFFRACTION	1.6
6I66	Crystal structure of human ERRg LBD in complex with 4-sec-butylphenol	X-RAY DIFFRACTION	1.6
9KNF	Crystal structure of human ERRg LBD in complex with 4028691	X-RAY DIFFRACTION	1.62
6I61	Crystal structure of human ERRg LBD in complex with bisphenol-B	X-RAY DIFFRACTION	1.65
6I62	Crystal structure of human ERRg LBD in complex with HPTE	X-RAY DIFFRACTION	1.65
2GPU	Estrogen Related Receptor-gamma ligand binding domain complexed with 4-hydroxy-tamoxifen	X-RAY DIFFRACTION	1.7
2ZKC	Crystal structure of human estrogen-related receptor gamma ligand binding domain complex …	X-RAY DIFFRACTION	1.7
6I67	Crystal structure of human ERRg LBD in complex with tetrahydro-2-naphtol	X-RAY DIFFRACTION	1.75
2ZBS	Crystal structure of human estrogen-related receptor gamma ligand binding domain apo form	X-RAY DIFFRACTION	1.8
9KNE	Crystal structure of human ERRg LBD in complex with 5-nitroindole	X-RAY DIFFRACTION	1.8
9KNC	Crystal structure of human ERRg LBD in complex with 6-nitroindole	X-RAY DIFFRACTION	1.9
6Y58	Binary complex of 14-3-3 sigma (C38N) with the Estrogen Related Receptor gamma (LBD) …	X-RAY DIFFRACTION	1.9
6I64	Crystal structure of human ERRg LBD in complex with bisphenol-E	X-RAY DIFFRACTION	1.91
2GPO	Estrogen Related Receptor-gamma ligand binding domain complexed with a synthetic peptide …	X-RAY DIFFRACTION	1.95
6K3N	Crystal structure of human estrogen-related receptor gamma ligand binding domain complex …	X-RAY DIFFRACTION	1.97
2ZAS	Crystal structure of human estrogen-related receptor gamma ligand binding domain complex …	X-RAY DIFFRACTION	2
2P7G	X-ray Structure of Estrogen Related Receptor g in complex with Bisphenol A.	X-RAY DIFFRACTION	2.1
8IFO	Crystal structure of estrogen related receptor-gamma DNA binding domain complexed with …	X-RAY DIFFRACTION	2.2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P62508-F1	76.66	0.61

Human Protein Atlas

Protein class: Nuclear receptors, Predicted intracellular proteins, Transcription factors, Zinc-coordinating DNA-binding domains, FDA approved drug targets, Small molecule drugs

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): nucleoplasm

Antibody reliability (HPA): IH uncertain · IF approved

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 (2)

Type	Positions
Phosphoserine	45
Glycyl lysine isopeptide (lys-gly) (interchain with g-cter in sumo)	40

Mutagenesis-validated functional residues (8)

Position	Phenotype
38	no effect on transcriptional activity.
39	4-fold increase in transcriptional activity.
40	abolishes sumoylation. 7-fold increase in transcriptional activity.
41	no effect on transcriptional activity.
42	4-fold increase in transcriptional activity.
44	no effect on transcriptional activity.
45	abolishes sumoylation. increased transcriptional activity.
45	no change in sumoylation nor transcriptional activity.

Function

Pathways and Gene Ontology

Reactome pathways

1 curated (TAS) of 4; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

4 pathways:

ID	Pathway	Evidence
R-HSA-383280	Nuclear Receptor transcription pathway	curated
R-HSA-74160	Gene expression (Transcription)	—
R-HSA-212436	Generic Transcription Pathway	—
R-HSA-73857	RNA Polymerase II Transcription	—

MSigDB gene sets: 335 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_COLON_TUMORAL_MACROPHAGE_DN, AAGCAAT_MIR137, TAATAAT_MIR126, GGTGTGT_MIR329, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, GOBP_CELLULAR_RESPONSE_TO_LIPID, NKX25_02, TATTATA_MIR374, GCM_PPM1D, TGACCTY_ERR1_Q2, MEF2_02, FOXO1_01, AAAYRNCTG_UNKNOWN, AATGGAG_MIR136, CAGCTG_AP4_Q5

GO Biological Process (8): DNA-templated transcription (GO:0006351), regulation of DNA-templated transcription (GO:0006355), regulation of transcription by RNA polymerase II (GO:0006357), positive regulation of transcription by RNA polymerase II (GO:0045944), retinoic acid receptor signaling pathway (GO:0048384), positive regulation of cold-induced thermogenesis (GO:0120162), nuclear receptor-mediated steroid hormone signaling pathway (GO:0030518), positive regulation of DNA-templated transcription (GO:0045893)

GO Molecular Function (16): DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), DNA-binding transcription activator activity, RNA polymerase II-specific (GO:0001228), nuclear steroid receptor activity (GO:0003707), nuclear receptor activity (GO:0004879), steroid binding (GO:0005496), zinc ion binding (GO:0008270), estrogen response element binding (GO:0034056), identical protein binding (GO:0042802), AF-2 domain binding (GO:0050682), sequence-specific double-stranded DNA binding (GO:1990837), RNA polymerase II transcription regulatory region sequence-specific DNA binding (GO:0000977), DNA binding (GO:0003677), DNA-binding transcription factor activity (GO:0003700), protein binding (GO:0005515), sequence-specific DNA binding (GO:0043565), metal ion binding (GO:0046872)

GO Cellular Component (3): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654)

Reactome top-level categories

3 top-level categories:

Category	Pathways
Generic Transcription Pathway	1
RNA Polymerase II Transcription	1
Gene expression (Transcription)	1

GO top-level categories

44 GO namespaces:

Category	Terms
regulation of DNA-templated transcription	3
DNA-templated transcription	2
transcription by RNA polymerase II	2
regulation of transcription by RNA polymerase II	2
nuclear receptor-mediated signaling pathway	2
RNA polymerase II transcription regulatory region sequence-specific DNA binding	2
DNA-binding transcription factor activity, RNA polymerase II-specific	2
transcription cis-regulatory region binding	2
cellular anatomical structure	2
gene expression	1
RNA biosynthetic process	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
positive regulation of DNA-templated transcription	1
hormone-mediated signaling pathway	1
positive regulation of multicellular organismal process	1
cold-induced thermogenesis	1
regulation of cold-induced thermogenesis	1
steroid hormone receptor signaling pathway	1
positive regulation of RNA biosynthetic process	1
chromatin	1
DNA-binding transcription factor activity	1
DNA-binding transcription activator activity	1
positive regulation of transcription by RNA polymerase II	1
nuclear receptor activity	1
nuclear receptor-mediated steroid hormone signaling pathway	1
intracellular receptor signaling pathway	1
signaling receptor activity	1
ligand-modulated transcription factor activity	1
lipid binding	1
transition metal ion binding	1
RNA polymerase II cis-regulatory region sequence-specific DNA binding	1
protein binding	1
protein domain specific binding	1
double-stranded DNA binding	1
sequence-specific DNA binding	1
nucleic acid binding	1
transcription regulator activity	1
binding	1
DNA binding	1
cation binding	1
chromosome	1
intracellular membrane-bounded organelle	1
nuclear lumen	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 3 of 27 annotations. The rest are phylogenetic / computational / electronic (IEA).

3 experimentally-supported GO terms:

GO term	NS	Evidence
regulation of DNA-templated transcription	BP	direct assay
identical protein binding	MF	physical interaction
sequence-specific double-stranded DNA binding	MF	direct assay

Protein interactions and networks

STRING

showing 15 of 1,100 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ESRRG	SLC7A1	P30825	919
ESRRG	PNRC2	Q9NPJ4	857
ESRRG	TLE1	Q04724	780
ESRRG	PPARGC1B	Q86YN6	776
ESRRG	PPARGC1A	Q9UBK2	650
ESRRG	ACADM	P11310	636
ESRRG	GPER1	Q99527	610
ESRRG	USH2A	O75445	546
ESRRG	NCOA1	Q15788	517
ESRRG	HAND2	P61296	510
ESRRG	COMMD7	Q86VX2	496
ESRRG	A0A2R8Y455	A0A2R8Y455	496
ESRRG	SREBF1	P36956	488
ESRRG	IARS1	P41252	486
ESRRG	GRIN3B	O60391	481

IntAct

Human interaction partners of ESRRG in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

28 partners by confidence:

Partner	Interaction type	MIscore	Records
PPARGC1A	physical association	0.720	4
PPARGC1B	physical association	0.660	1
NR0B1	physical association	0.560	4
DEUP1	physical association	0.560	3
KIFC3	physical association	0.560	3
MEOX2	physical association	0.560	3
NUP160	physical association	0.560	3
SHTN1	physical association	0.560	3
SUMO1P1	physical association	0.560	3
NRIP1	physical association	0.550	1
LRRK2	direct interaction	0.440	1
MFHAS1	direct interaction	0.440	1
SRPK1	phosphorylation reaction	0.440	1
SUMO1	sumoylation reaction	0.440	1
SUMO2	sumoylation reaction	0.440	1
CREBZF	physical association	0.400	1
NR0B2	physical association	0.400	1
SUMO3	physical association	0.400	1
ECE1	physical association	0.370	4
CCL8	physical association	0.370	1
EBNA-LP	physical association	0.370	1
IFNA5	physical association	0.370	1
IL12B	physical association	0.370	1
IL17A	physical association	0.370	1
IL31	physical association	0.370	1
DDX3Y	association	0.350	1
TTR	association	0.350	1
TULP3	physical association	0.000	1

BioGRID (110 interactions; top human partners by supporting records): ESRRA (Two-hybrid; 8 records), NR0B2 (Two-hybrid; 5 records), NRIP1 (Two-hybrid; 4 records), DNMT3L (Co-localization; 3 records), NR0B1 (Two-hybrid; 3 records), PNRC2 (Two-hybrid; 3 records), PPARGC1A (Two-hybrid; 3 records), PSMC5 (Two-hybrid; 3 records), CCDC67 (Two-hybrid; 2 records), ESRRB (Two-hybrid; 2 records), HIF1A (Reconstituted Complex; 2 records), KIAA1598 (Two-hybrid; 2 records), NCOA1 (Two-hybrid; 2 records), PROX1 (Affinity Capture-MS; 2 records), TLE1 (Reconstituted Complex; 2 records)

SIGNOR signaling

1 signaling interactions:

A	Effect	B	Mechanism
NR0B2	“down-regulates quantity by repression”	ESRRG	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 28 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
SUMOylation of transcription cofactors	5	60.7×	2e-06

Disease & clinical

Genetic variants

Variant evidence for ESRRG: 67 ClinVar records (9 pathogenic / likely pathogenic); 37 GWAS associations. Per-variant detail is on Sugi Variant.

ClinVar

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

Classification	Count (floor)
Pathogenic	4
Likely pathogenic	5
Uncertain significance	39
Likely benign	0
Benign	2

Top pathogenic / likely-pathogenic (9)

Showing all 9 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
4530565	NM_001438.4(ESRRG):c.539G>A (p.Cys180Tyr)	Likely pathogenic	criteria provided, single submitter	2
4530564	NM_001438.4(ESRRG):c.446A>G (p.Lys149Arg)	Likely pathogenic	criteria provided, single submitter	1
4530567	NM_001438.4(ESRRG):c.1346T>G (p.Leu449Arg)	Likely pathogenic	criteria provided, single submitter	1
4530568	NM_001438.4(ESRRG):c.1352dup (p.Leu451fs)	Likely pathogenic	criteria provided, single submitter	1
4689844	NM_001438.4(ESRRG):c.508T>C (p.Cys170Arg)	Likely pathogenic	criteria provided, single submitter	1
60080	GRCh38/hg38 1q41(chr1:216396695-217549806)x1	Pathogenic	criteria provided, single submitter	1
60081	GRCh38/hg38 1q41(chr1:216518607-219827290)x1	Pathogenic	criteria provided, single submitter	1
1070622	NC_000001.10:g.(?216348580)(216896641_?)del	Pathogenic	criteria provided, single submitter	1
1199384	Single allele	Pathogenic	no assertion criteria provided	1

Per-variant reference — Sugi Variant

Explore ESRRG’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 23 predictions of 1,801):

Position(s)	Effect	Δscore	Sites
1:216507184–216507185	acceptor_loss	1.0000	5
1:216507186	acceptor_gain	1.0000
1:216519422–216519423	acceptor_loss	1.0000	4
1:216564356	acceptor_gain	1.0000
1:216650971–216650972	donor_loss	1.0000	5
1:216657104	donor_gain	1.0000
1:216677506	acceptor_gain	1.0000
1:216507184	acceptor_loss	0.9900
1:216507190–216507191	acceptor_gain	0.9900	2
1:216519423	acceptor_loss	0.9900	2

AlphaMissense

1,714 missense substitutions predicted likely pathogenic (of 3,027 scored), across 343 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
M193	9	0.999	1.000
M298	9	0.994	1.000
M306	9	0.934	0.999
M453	9	0.923	1.000
M446	9	0.908	0.997
M252	9	0.873	0.985
D133	8	1.000	1.000
H139	8	1.000	1.000
D201	8	1.000	1.000
F151	8	0.999	1.000
F152	8	0.999	1.000
D273	8	0.998	1.000
D296	8	0.998	1.000
D270	8	0.993	0.999
F450	8	0.993	1.000
F289	8	0.992	1.000
H447	8	0.986	0.998
D378	8	0.983	0.998
D329	8	0.981	0.999
F435	8	0.972	0.999

HPA cancer prognostics

RNA cancer specificity: Cancer enriched (Kidney Chromophobe)

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

2 prognostic cancer types:

Cancer	Prognostic	p-value
Kidney Renal Clear Cell Carcinoma (TCGA)	favorable	7.11e-08
Thyroid Carcinoma (TCGA)	unfavorable	0.000535

Disease associations

OMIM: gene MIM:602969 | disease phenotypes: MIM:614816

GenCC curated gene-disease

Mondo (2): Loeys-Dietz syndrome 4 (MONDO:0013897), movement disorder (MONDO:0005395)

GWAS associations

showing 30 of 37 associations:

Study	Trait	p-value
GCST003992_27	Photic sneeze reflex	1e-72
GCST010796_4895	Electrocardiogram morphology (amplitude at temporal datapoints)	2e-13
GCST90002384_495	Hemoglobin	2e-13
GCST010796_4892	Electrocardiogram morphology (amplitude at temporal datapoints)	3e-12
GCST010796_4893	Electrocardiogram morphology (amplitude at temporal datapoints)	1e-11
GCST90002383_174	Hematocrit	1e-11
GCST010796_4891	Electrocardiogram morphology (amplitude at temporal datapoints)	4e-10
GCST010796_4894	Electrocardiogram morphology (amplitude at temporal datapoints)	9e-10
GCST007325_137	General risk tolerance (MTAG)	2e-9
GCST004988_489	Breast cancer	4e-9
GCST007324_83	Adventurousness	6e-9
GCST005316_70	Intelligence (MTAG)	1e-8
GCST006269_581	General cognitive ability	2e-8
GCST007327_120	Smoking status (ever vs never smokers)	2e-8
GCST010796_4890	Electrocardiogram morphology (amplitude at temporal datapoints)	2e-8
GCST008857_1	Depressive symptom (anhedonia) (ordinal trait)	3e-8
GCST010002_5	Refractive error	3e-8
GCST005652_1	Cleft lip with or without cleft palate (maternal periconceptional vitamin use interaction)	6e-8
GCST000960_2	Cardiac hypertrophy	1e-7
GCST008529_38	Tea consumption	1e-7
GCST003264_1420	Post bronchodilator FEV1/FVC ratio	4e-7
GCST009028_58	Adverse response to drug	5e-7
GCST90006994_10	Gut microbiota relative abundance (Ruminococcus belonging to family Erysipelotrichaceae)	7e-7
GCST003262_811	Post bronchodilator FEV1	8e-7
GCST002308_1	Mean arterial pressure (alcohol consumption interaction)	9e-7
GCST005576_16	Intracranial aneurysm	1e-6
GCST002001_10	Adverse response to chemotherapy (neutropenia/leucopenia) (all antimicrotubule drugs)	2e-6
GCST006631_22	Nicotine dependence and major depression (severity of comorbidity)	3e-6
GCST001066_7	Dialysis-related mortality	4e-6
GCST008152_62	Weight	4e-6

EFO canonical traits (from GWAS)

23 canonical traits:

EFO ID	Trait name
EFO:0002503	cardiac hypertrophy
EFO:0005260	response to antimicrotubule agent
EFO:0004329	alcohol drinking
EFO:0006340	mean arterial pressure
EFO:0004314	forced expiratory volume
EFO:0004713	FEV/FVC ratio
EFO:0007887	autosomal dominant compelling helio-ophthalmic outburst syndrome
EFO:0004337	intelligence
EFO:0003959	cleft lip
EFO:0009116	vitamin supplement exposure measurement
EFO:0007006	depressive symptom measurement
EFO:0009262	nicotine dependence symptom count
EFO:0008579	risk-taking behaviour
EFO:0004318	smoking behavior
EFO:0004338	body weight
EFO:0010091	tea consumption measurement
EFO:0009587	anhedonia measurement
EFO:0009658	adverse effect
EFO:0004327	electrocardiography
EFO:0004611	low density lipoprotein cholesterol measurement
EFO:0004348	hematocrit
EFO:0004509	hemoglobin measurement
EFO:0007874	gut microbiome measurement

MeSH disease descriptors

1 disease descriptors:

Descriptor	Name	Tree numbers
D009069	Movement Disorders	C10.228.662

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL4245 (SINGLE PROTEIN), CHEMBL4523738 (PROTEIN-PROTEIN INTERACTION)

Drugs by curated mechanism of action (ChEMBL)

Drugs whose curated ChEMBL mechanism of action targets the ESRRG protein itself — single-protein targets only (drugs acting on a protein family or complex that merely includes it are excluded). Includes antibodies and oligonucleotides that bioactivity screening does not capture.

1 curated-mechanism drugs:

Drug	Modality	Max phase
AFIMOXIFENE	Small molecule	3

Molecules with ChEMBL bioactivity

Phase ≥1, by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 547,125 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

2 molecules by phase:

Molecule	Name	Phase	Patents
CHEMBL411	DIETHYLSTILBESTROL	4	373,838
CHEMBL83	TAMOXIFEN	4	173,287

PharmGKB: 1 entry (CPIC guideline: no)

GtoPdb / IUPHAR curated pharmacology

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

Target class: nhr — 3B. Estrogen-related receptors

Most potent curated ligand interactions (5 total), top 5:

Ligand	Action	Affinity	Parameter
4-hydroxytamoxifen	Inverse agonist	7.46	pKd
GSK5182	Inverse agonist	7.1	pIC50
DY131	Agonist	6.2	pIC50
GSK4716	Agonist	5.7	pIC50
diethylstilbestrol	Antagonist	5.3	pIC50

Binding affinities (BindingDB)

234 measured of 304 human assays (306 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
4-OHT	EC50	0.8 nM
4-[(1Z)-4-azido-1-{4-[2-(dimethylamino)ethoxy]phenyl}-2-phenylbut-1-en-1-yl]phenol	IC50	1 nM
4-[(1Z)-4-chloro-1-{4-[2-(dimethylamino)ethoxy]phenyl}-2-phenylbut-1-en-1-yl]phenol	IC50	4 nM
(2-{4-[(1Z)-1,2-diphenylbut-1-en-1-yl]phenoxy}ethyl)dimethylamine	KI	5 nM
4-[(1Z)-1-{4-[2-(dimethylamino)ethoxy]phenyl}-5-(methylsulfanyl)-2-phenylpent-1-en-1-yl]phenol	IC50	10 nM
CHEMBL4071073	IC50	10 nM
4-[(1Z)-5-azido-1-{4-[2-(dimethylamino)ethoxy]phenyl}-2-phenylpent-1-en-1-yl]phenol	IC50	13 nM
CHEMBL3961676	IC50	20 nM
(5Z)-6-{4-[2-(dimethylamino)ethoxy]phenyl}-6-(4-hydroxyphenyl)-5-phenylhex-5-enenitrile	IC50	25 nM
11	IC50	26 nM	US-11285226: Aryl ethene derivative and pharmaceutical composition containing same as active ingredient
10	IC50	34 nM	US-11285226: Aryl ethene derivative and pharmaceutical composition containing same as active ingredient
4-[(1Z)-1-{4-[2-(dimethylamino)ethoxy]phenyl}-6-hydroxy-2-phenylhex-1-en-1-yl]phenol	IC50	79 nM
CHEMBL5630895	EC50	82 nM
CHEMBL4204173	EC50	84 nM
CHEMBL5625070	EC50	89 nM
4-[(1Z)-5-chloro-1-{4-[2-(dimethylamino)ethoxy]phenyl}-2-phenylpent-1-en-1-yl]phenol	IC50	100 nM
CHEMBL4463345	IC50	115 nM
CHEMBL5630878	EC50	117 nM
CHEMBL5630603	EC50	118 nM
CHEMBL5625062	EC50	118 nM
GSK9089	EC50	130 nM
CHEMBL4447488	IC50	140 nM
CHEMBL5624455	EC50	156 nM
CHEMBL4795846	IC50	165 nM
(4Z)-5-{4-[2-(dimethylamino)ethoxy]phenyl}-5-(4-hydroxyphenyl)-4-phenylpent-4-enenitrile	IC50	200 nM
CHEMBL4204610	EC50	210 nM
CHEMBL4526628	IC50	214 nM
CHEMBL5624461	EC50	220 nM
CHEMBL4208749	EC50	230 nM
CHEMBL5612093	EC50	233 nM
CHEMBL5624993	EC50	244 nM
4-[(1Z)-1-{4-[2-(dimethylamino)ethoxy]phenyl}-4-hydroxy-2-phenylbut-1-en-1-yl]phenol	IC50	250 nM
4-[(Z)-1-[4-[2-(2-azaspiro[4.4]nonan-2-yl)ethoxy]phenyl]-5-hydroxy-2-phenylpent-1-enyl]phenol	IC50	256 nM	US-10934303: Aryl ethene derivative and pharmaceutical composition containing same as active ingredient
CHEMBL5625153	EC50	258 nM
4-[(Z)-5-hydroxy-2-phenyl-1-[4-(2-piperidin-1-ylethoxy)phenyl]pent-1-enyl]phenol	IC50	262 nM	US-11285226: Aryl ethene derivative and pharmaceutical composition containing same as active ingredient
4-[(Z)-5-hydroxy-1-[4-[2-[(2S)-2-(hydroxymethyl)-3-azabicyclo[3.1.0]hexan-3-yl]ethoxy]phenyl]-2-phenylpent-1-enyl]phenol	IC50	276 nM	US-10934303: Aryl ethene derivative and pharmaceutical composition containing same as active ingredient
CHEMBL4764628	IC50	276 nM
109	IC50	276 nM	US-11285226: Aryl ethene derivative and pharmaceutical composition containing same as active ingredient
CHEMBL5630792	EC50	287 nM
CHEMBL4092854	IC50	290 nM
CHEMBL5631058	EC50	293 nM
4-[(Z)-1-[4-[2-(aziridin-1-yl)ethoxy]phenyl]-5-hydroxy-2-phenylpent-1-enyl]phenol	IC50	296 nM	US-10934303: Aryl ethene derivative and pharmaceutical composition containing same as active ingredient
CHEMBL4064246	IC50	300 nM
CHEMBL4211016	EC50	300 nM
4-[(Z)-5-hydroxy-1-[4-[2-(1-methylpyrrolidin-2-yl)ethoxy]phenyl]-2-phenylpent-1-enyl]phenol	IC50	331 nM	US-10934303: Aryl ethene derivative and pharmaceutical composition containing same as active ingredient
CHEMBL4438167	IC50	340 nM
CHEMBL5630159	EC50	343 nM
CHEMBL5630000	EC50	345 nM
CHEMBL4064664	IC50	350 nM
CHEMBL4469370	IC50	354 nM

ChEMBL bioactivities

327 potent at pChembl≥5 of 329 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.31	IC50	4.91	nM	BISPHENOL A
8.30	IC50	5	nM	CHEMBL203472
8.26	Kd	5.5	nM	BISPHENOL A
8.22	IC50	6	nM	CHEMBL4436391
7.96	IC50	11	nM	CHEMBL2137046
7.89	IC50	13	nM	CHEMBL2137046
7.89	IC50	13	nM	4-HYDROXYTORMIFENE
7.89	IC50	13	nM	CHEMBL4741828
7.82	EC50	15	nM	CHEMBL2137046
7.77	IC50	17	nM	CHEMBL4437929
7.77	IC50	17	nM	CHEMBL4598385
7.75	IC50	18	nM	CHEMBL4437929
7.75	IC50	18	nM	CHEMBL4580171
7.75	IC50	18	nM	CHEMBL4579002
7.70	IC50	20	nM	CHEMBL3961676
7.70	IC50	20	nM	CHEMBL2137046
7.70	IC50	20	nM	CHEMBL4451327
7.70	IC50	20	nM	CHEMBL4757503
7.70	IC50	20	nM	CHEMBL4597874
7.68	IC50	21	nM	CHEMBL4541589
7.68	IC50	21	nM	CHEMBL4746616
7.60	IC50	25	nM	CHEMBL4580171
7.60	IC50	25	nM	CHEMBL4596569
7.58	IC50	26	nM	CHEMBL4472718
7.58	IC50	26	nM	CHEMBL4744529
7.58	IC50	26	nM	CHEMBL4803014
7.58	IC50	26	nM	CHEMBL4598385
7.58	IC50	26	nM	CHEMBL5829633
7.58	IC50	26	nM	CHEMBL4802584
7.58	IC50	26	nM	CHEMBL4597635
7.58	IC50	26	nM	CHEMBL4596092
7.57	IC50	27	nM	CHEMBL4443694
7.57	IC50	27	nM	CHEMBL4595377
7.55	IC50	28	nM	CHEMBL4585424
7.55	IC50	28	nM	CHEMBL4595194
7.54	IC50	29	nM	CHEMBL6044782
7.52	IC50	30	nM	CHEMBL4791981
7.52	IC50	30	nM	CHEMBL4793030
7.52	IC50	30	nM	CHEMBL4803014
7.50	IC50	32	nM	CHEMBL4597398
7.48	IC50	33	nM	CHEMBL4579002
7.47	IC50	34	nM	CHEMBL4792390
7.47	IC50	34	nM	CHEMBL4803014
7.47	IC50	34	nM	CHEMBL4803828
7.46	IC50	35	nM	CHEMBL4451327
7.46	IC50	35	nM	CHEMBL4597874
7.40	IC50	40	nM	CHEMBL4436391
7.40	IC50	40	nM	CHEMBL4597043
7.38	IC50	42	nM	CHEMBL5740468
7.38	IC50	42	nM	CHEMBL4803772

PubChem BioAssay actives

279 with measured affinity, of 700 total; 50 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-[2-(4-hydroxyphenyl)propan-2-yl]phenol	1464223: Binding affinity to human ERRgamma	ic50	0.0049	uM
4-[(Z)-4-azido-1-[4-[2-(dimethylamino)ethoxy]phenyl]-2-phenylbut-1-enyl]phenol	1798194: Radioligand Displacement Assay from Article 10.1016/j.bmcl.2005.11.030: “Structure-guided synthesis of tamoxifen analogs with improved selectivity for the orphan ERRgamma.”	ic50	0.0050	uM
4-[(E)-5-hydroxy-2-phenyl-1-[4-(4-propan-2-ylpiperazin-1-yl)phenyl]pent-1-enyl]phenol;dihydrochloride	1614397: Inverse agonist activity at CMX-gal4-fused ERRgamma (unknown origin) transfected in human AD293 cells co-expressing CMV-beta galactosidase assessed as effect on beta-galactosidase activity after 24 hrs by luciferase reporter gene assay	ic50	0.0060	uM
4-[(Z)-1-[4-[2-(dimethylamino)ethoxy]phenyl]-2-phenylbut-1-enyl]phenol	1799022: Radioligand Displacement Assay from Article 10.1016/j.bbrc.2008.06.050: “ERRgamma tethers strongly bisphenol A and 4-alpha-cumylphenol in an induced-fit manner.”	ic50	0.0103	uM
4-[1-[4-[2-(dimethylamino)ethoxy]phenyl]-2-phenylbut-1-enyl]phenol	1499723: Antagonist activity at ERRgamma (unknown origin) assessed as inhibition of co-activator peptide recruitment by TR-FRET assay	ic50	0.0110	uM
4-[(E)-5-hydroxy-2-phenyl-1-[4-(1-propan-2-yl-3,6-dihydro-2H-pyridin-4-yl)phenyl]pent-1-enyl]phenol;hydrochloride	1704157: Inverse agonist activity at ERRgamma (unknown origin) by luciferase reporter gene assay	ic50	0.0130	uM
4-[(Z)-4-chloro-1-[4-[2-(dimethylamino)ethoxy]phenyl]-2-phenylbut-1-enyl]phenol	1798194: Radioligand Displacement Assay from Article 10.1016/j.bmcl.2005.11.030: “Structure-guided synthesis of tamoxifen analogs with improved selectivity for the orphan ERRgamma.”	ic50	0.0130	uM
4-(2-phenylpropan-2-yl)phenol	1799022: Radioligand Displacement Assay from Article 10.1016/j.bbrc.2008.06.050: “ERRgamma tethers strongly bisphenol A and 4-alpha-cumylphenol in an induced-fit manner.”	ic50	0.0139	uM
(Z)-5-(4-methylphenyl)-4-phenyl-5-[4-(4-propan-2-ylpiperazin-1-yl)phenyl]pent-4-en-1-ol;dihydrochloride	1614392: Binding affinity to GST-tagged ERRgamma LBD (unknown origin) using fluorescein-conjugated coactivator PGC-1alpha incubated for 1 hr by TR-FRET assay	ic50	0.0170	uM
(Z)-5-[4-(4-ethylpiperazin-1-yl)phenyl]-5-(4-methylphenyl)-4-phenylpent-4-en-1-ol;dihydrochloride	1614397: Inverse agonist activity at CMX-gal4-fused ERRgamma (unknown origin) transfected in human AD293 cells co-expressing CMV-beta galactosidase assessed as effect on beta-galactosidase activity after 24 hrs by luciferase reporter gene assay	ic50	0.0180	uM
(E)-5-(3-bromophenyl)-4-phenyl-5-[4-(4-propan-2-ylpiperazin-1-yl)phenyl]pent-4-en-1-ol;dihydrochloride	1614397: Inverse agonist activity at CMX-gal4-fused ERRgamma (unknown origin) transfected in human AD293 cells co-expressing CMV-beta galactosidase assessed as effect on beta-galactosidase activity after 24 hrs by luciferase reporter gene assay	ic50	0.0180	uM
4-[(Z)-1-[4-[2-(dimethylamino)ethoxy]phenyl]-5-fluoro-2-phenylpent-1-enyl]phenol;hydrochloride	1317925: Inhibition of fluorescien-conjugated coactivator PGC1a binding to GST-tagged human ERRgamma LBD after 1 hr by TR-FRET assay	ic50	0.0200	uM
3-[(E)-5-hydroxy-2-phenyl-1-[4-(4-propan-2-ylpiperazin-1-yl)phenyl]pent-1-enyl]phenol;dihydrochloride	1614397: Inverse agonist activity at CMX-gal4-fused ERRgamma (unknown origin) transfected in human AD293 cells co-expressing CMV-beta galactosidase assessed as effect on beta-galactosidase activity after 24 hrs by luciferase reporter gene assay	ic50	0.0200	uM
3-[(E)-5-hydroxy-2-phenyl-1-[4-(4-propan-2-ylpiperazin-1-yl)phenyl]pent-1-enyl]phenol	1704157: Inverse agonist activity at ERRgamma (unknown origin) by luciferase reporter gene assay	ic50	0.0200	uM
4-[(Z)-5-hydroxy-1-[4-[2-(1-methylpyrrolidin-2-yl)ethoxy]phenyl]-2-phenylpent-1-enyl]phenol;hydrochloride	1686562: Binding affinity to GST-tagged ERRgamma LBD (unknown origin) using fluorescein PGC1alpha as coactivator incubated for 1 hr by LanthaScreen TR-FRET co-regulator assay	ic50	0.0200	uM
(E)-5-(4-bromophenyl)-4-phenyl-5-[4-(4-propan-2-ylpiperazin-1-yl)phenyl]pent-4-en-1-ol;dihydrochloride	1614392: Binding affinity to GST-tagged ERRgamma LBD (unknown origin) using fluorescein-conjugated coactivator PGC-1alpha incubated for 1 hr by TR-FRET assay	ic50	0.0210	uM
4-[(E)-2-(2,4-difluorophenyl)-5-hydroxy-1-[4-(1-propan-2-ylpiperidin-4-yl)phenyl]pent-1-enyl]phenol;hydrochloride	1704157: Inverse agonist activity at ERRgamma (unknown origin) by luciferase reporter gene assay	ic50	0.0210	uM
(Z)-5-(4-methylphenyl)-5-[4-(4-methylpiperazin-1-yl)phenyl]-4-phenylpent-4-en-1-ol;dihydrochloride	1614392: Binding affinity to GST-tagged ERRgamma LBD (unknown origin) using fluorescein-conjugated coactivator PGC-1alpha incubated for 1 hr by TR-FRET assay	ic50	0.0260	uM
4-[(Z)-5-hydroxy-1-[4-[2-[(2R)-1-methylpyrrolidin-2-yl]ethoxy]phenyl]-2-phenylpent-1-enyl]phenol;dihydrochloride	1686562: Binding affinity to GST-tagged ERRgamma LBD (unknown origin) using fluorescein PGC1alpha as coactivator incubated for 1 hr by LanthaScreen TR-FRET co-regulator assay	ic50	0.0260	uM
(Z)-5-(4-methylphenyl)-4-phenyl-5-(4-piperazin-1-ylphenyl)pent-4-en-1-ol;dihydrochloride	1614392: Binding affinity to GST-tagged ERRgamma LBD (unknown origin) using fluorescein-conjugated coactivator PGC-1alpha incubated for 1 hr by TR-FRET assay	ic50	0.0270	uM
(E)-5-(4-bromophenyl)-4-phenyl-5-(4-piperazin-1-ylphenyl)pent-4-en-1-ol;dihydrochloride	1614392: Binding affinity to GST-tagged ERRgamma LBD (unknown origin) using fluorescein-conjugated coactivator PGC-1alpha incubated for 1 hr by TR-FRET assay	ic50	0.0280	uM
3-[(E)-5-hydroxy-2-phenyl-1-[4-(1-propan-2-yl-3,6-dihydro-2H-pyridin-4-yl)phenyl]pent-1-enyl]phenol;hydrochloride	1704157: Inverse agonist activity at ERRgamma (unknown origin) by luciferase reporter gene assay	ic50	0.0300	uM
4-[(Z)-5-hydroxy-1-[4-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]phenyl]-2-phenylpent-1-enyl]phenol;hydrochloride	1686562: Binding affinity to GST-tagged ERRgamma LBD (unknown origin) using fluorescein PGC1alpha as coactivator incubated for 1 hr by LanthaScreen TR-FRET co-regulator assay	ic50	0.0300	uM
4-[(Z)-5-hydroxy-1-[4-[2-[(2S)-1-methylpyrrolidin-2-yl]ethoxy]phenyl]-2-phenylpent-1-enyl]phenol;hydrochloride	1686562: Binding affinity to GST-tagged ERRgamma LBD (unknown origin) using fluorescein PGC1alpha as coactivator incubated for 1 hr by LanthaScreen TR-FRET co-regulator assay	ic50	0.0340	uM
4-[(E)-1-[4-(1-cyclopropylpiperidin-4-yl)phenyl]-5-hydroxy-2-phenylpent-1-enyl]phenol;hydrochloride	1704157: Inverse agonist activity at ERRgamma (unknown origin) by luciferase reporter gene assay	ic50	0.0440	uM
4-[(E)-5-hydroxy-2-phenyl-1-(4-piperidin-4-ylphenyl)pent-1-enyl]phenol;hydrochloride	1704113: Binding affinity to ERRgamma (unknown origin) by TR-FRET assay	ic50	0.0480	uM
4-[(E)-1-[4-(4-ethylpiperazin-1-yl)phenyl]-5-hydroxy-2-phenylpent-1-enyl]phenol;dihydrochloride	1614392: Binding affinity to GST-tagged ERRgamma LBD (unknown origin) using fluorescein-conjugated coactivator PGC-1alpha incubated for 1 hr by TR-FRET assay	ic50	0.0500	uM
4-[(Z)-1-[4-[2-(2-azaspiro[4.4]nonan-2-yl)ethoxy]phenyl]-5-hydroxy-2-phenylpent-1-enyl]phenol;hydrochloride	1686562: Binding affinity to GST-tagged ERRgamma LBD (unknown origin) using fluorescein PGC1alpha as coactivator incubated for 1 hr by LanthaScreen TR-FRET co-regulator assay	ic50	0.0500	uM
4-[(E)-1-[4-(4-cyclobutylpiperazin-1-yl)phenyl]-5-hydroxy-2-phenylpent-1-enyl]phenol;dihydrochloride	1614392: Binding affinity to GST-tagged ERRgamma LBD (unknown origin) using fluorescein-conjugated coactivator PGC-1alpha incubated for 1 hr by TR-FRET assay	ic50	0.0530	uM
4-[(Z)-1-[4-[3-(dimethylamino)propoxy]phenyl]-5-hydroxy-2-phenylpent-1-enyl]phenol;hydrochloride	1317931: Inverse agonist activity at ERRgamma (unknown origin) expressed in human AD293 cells after 24 hrs by beta-galactosidase/luciferase reporter gene assay	ic50	0.0580	uM
4-[(E)-5-hydroxy-1-[4-(4-methylpiperazin-1-yl)phenyl]-2-phenylpent-1-enyl]phenol;dihydrochloride	1614392: Binding affinity to GST-tagged ERRgamma LBD (unknown origin) using fluorescein-conjugated coactivator PGC-1alpha incubated for 1 hr by TR-FRET assay	ic50	0.0600	uM
(E)-5-(4-bromophenyl)-5-[4-(4-methylpiperazin-1-yl)phenyl]-4-phenylpent-4-en-1-ol;dihydrochloride	1614392: Binding affinity to GST-tagged ERRgamma LBD (unknown origin) using fluorescein-conjugated coactivator PGC-1alpha incubated for 1 hr by TR-FRET assay	ic50	0.0600	uM
4-[(E)-1-[4-(azetidin-3-yl)phenyl]-5-fluoro-2-phenylpent-1-enyl]phenol;hydrochloride	1704113: Binding affinity to ERRgamma (unknown origin) by TR-FRET assay	ic50	0.0610	uM
Tamoxifen	1464223: Binding affinity to human ERRgamma	ic50	0.0622	uM
(E)-5-(4-bromophenyl)-5-[4-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]phenyl]-4-phenylpent-4-en-1-ol;hydrochloride	1686562: Binding affinity to GST-tagged ERRgamma LBD (unknown origin) using fluorescein PGC1alpha as coactivator incubated for 1 hr by LanthaScreen TR-FRET co-regulator assay	ic50	0.0640	uM
4-[(Z)-5-hydroxy-2-phenyl-1-[4-(2-pyrrolidin-1-ylethoxy)phenyl]pent-1-enyl]phenol;hydrochloride	1686562: Binding affinity to GST-tagged ERRgamma LBD (unknown origin) using fluorescein PGC1alpha as coactivator incubated for 1 hr by LanthaScreen TR-FRET co-regulator assay	ic50	0.0670	uM
4-[(Z)-1-[4-[2-(aziridin-1-yl)ethoxy]phenyl]-5-hydroxy-2-phenylpent-1-enyl]phenol;hydrochloride	1686562: Binding affinity to GST-tagged ERRgamma LBD (unknown origin) using fluorescein PGC1alpha as coactivator incubated for 1 hr by LanthaScreen TR-FRET co-regulator assay	ic50	0.0700	uM
4-[(E)-2-(4-fluorophenyl)-5-hydroxy-1-[4-(1-propan-2-ylpiperidin-4-yl)phenyl]pent-1-enyl]phenol;hydrochloride	1704157: Inverse agonist activity at ERRgamma (unknown origin) by luciferase reporter gene assay	ic50	0.0760	uM
4-[(Z)-1-[4-[2-(dimethylamino)ethoxy]phenyl]-5-hydroxy-2-phenylpent-1-enyl]phenol;hydrochloride	1317931: Inverse agonist activity at ERRgamma (unknown origin) expressed in human AD293 cells after 24 hrs by beta-galactosidase/luciferase reporter gene assay	ic50	0.0770	uM
4-[(Z)-1-[4-[2-(dimethylamino)ethoxy]phenyl]-5-hydroxy-2-phenylpent-1-enyl]phenol	1704157: Inverse agonist activity at ERRgamma (unknown origin) by luciferase reporter gene assay	ic50	0.0770	uM
4-[(Z)-1-[4-[2-(diethylamino)ethoxy]phenyl]-5-hydroxy-2-phenylpent-1-enyl]phenol;hydrochloride	1317931: Inverse agonist activity at ERRgamma (unknown origin) expressed in human AD293 cells after 24 hrs by beta-galactosidase/luciferase reporter gene assay	ic50	0.0790	uM
4-[(Z)-1-[4-[2-(3-azabicyclo[3.1.0]hexan-3-yl)ethoxy]phenyl]-5-hydroxy-2-phenylpent-1-enyl]phenol;hydrochloride	1686562: Binding affinity to GST-tagged ERRgamma LBD (unknown origin) using fluorescein PGC1alpha as coactivator incubated for 1 hr by LanthaScreen TR-FRET co-regulator assay	ic50	0.0790	uM
4-[(Z)-5-hydroxy-1-[4-[2-[(1R,2S,5S)-2-(hydroxymethyl)-3-azabicyclo[3.1.0]hexan-3-yl]ethoxy]phenyl]-2-phenylpent-1-enyl]phenol;hydrochloride	1686562: Binding affinity to GST-tagged ERRgamma LBD (unknown origin) using fluorescein PGC1alpha as coactivator incubated for 1 hr by LanthaScreen TR-FRET co-regulator assay	ic50	0.0830	uM
N-[(E)-(4-tert-butylphenyl)methylideneamino]-4-hydroxybenzamide	1374995: Agonist activity at human N-terminal alphaHis-SUMO-tagged ERRgamma-LBD (229 to 458 residues) expressed in Escherichia coli BL21 gold (DE3) cells assessed as decrease in RIP140 peptide recruitment after 2 hrs by TR-FRET assay	ec50	0.0840	uM
4-[(Z)-5-hydroxy-1-[4-[2-[(2R)-2-(hydroxymethyl)pyrrolidin-1-yl]ethoxy]phenyl]-2-phenylpent-1-enyl]phenol;hydrochloride	1686562: Binding affinity to GST-tagged ERRgamma LBD (unknown origin) using fluorescein PGC1alpha as coactivator incubated for 1 hr by LanthaScreen TR-FRET co-regulator assay	ic50	0.0910	uM
4-[(Z)-5-hydroxy-2-phenyl-1-[4-(2-piperidin-1-ylethoxy)phenyl]pent-1-enyl]phenol;hydrochloride	1686562: Binding affinity to GST-tagged ERRgamma LBD (unknown origin) using fluorescein PGC1alpha as coactivator incubated for 1 hr by LanthaScreen TR-FRET co-regulator assay	ic50	0.0930	uM
4-[(E)-5-hydroxy-2-phenyl-1-[4-(1-propan-2-ylpiperidin-4-yl)phenyl]pent-1-enyl]phenol;hydrochloride	1704113: Binding affinity to ERRgamma (unknown origin) by TR-FRET assay	ic50	0.0950	uM
4-[(E)-1-[4-(1-cyclopropylpyrrolidin-3-yl)phenyl]-5-hydroxy-2-phenylpent-1-enyl]phenol;hydrochloride	1704113: Binding affinity to ERRgamma (unknown origin) by TR-FRET assay	ic50	0.0960	uM
4-[(E)-1-[4-(4-cyclohexylpiperazin-1-yl)phenyl]-5-hydroxy-2-phenylpent-1-enyl]phenol;dihydrochloride	1614392: Binding affinity to GST-tagged ERRgamma LBD (unknown origin) using fluorescein-conjugated coactivator PGC-1alpha incubated for 1 hr by TR-FRET assay	ic50	0.0990	uM
4-[(E)-5-hydroxy-2-phenyl-1-(4-piperazin-1-ylphenyl)pent-1-enyl]phenol;dihydrochloride	1614392: Binding affinity to GST-tagged ERRgamma LBD (unknown origin) using fluorescein-conjugated coactivator PGC-1alpha incubated for 1 hr by TR-FRET assay	ic50	0.1040	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects expression, affects methylation, increases activity, decreases activity, decreases expression (+6 more)	25
afimoxifene	affects binding, decreases activity, decreases reaction, affects activity	11
Valproic Acid	affects cotreatment, increases expression, affects expression, decreases methylation	8
Diethylstilbestrol	affects activity, affects binding, decreases activity, increases activity, decreases reaction (+1 more)	6
Benzo(a)pyrene	affects methylation, decreases expression	4
Tamoxifen	affects binding, decreases expression, decreases reaction, affects activity	3
Aflatoxin B1	affects expression, decreases methylation, increases methylation	3
daidzein	decreases reaction, increases expression, affects binding, increases reaction	2
trichostatin A	increases activity, increases expression	2
4-isopropylphenol	affects binding, increases activity, decreases activity, decreases reaction	2
2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one	decreases reaction, increases expression	2
arachidonyl-2-chloroethylamide	increases expression, affects reaction	2
2,2-bis(4-hydroxyphenyl)-1,1,1-trichloroethane	affects binding, increases activity, decreases activity, decreases reaction	2
4-cumylphenol	affects binding, increases activity	2
bisphenol S	increases expression, affects binding, decreases reaction	2
Vorinostat	affects cotreatment, increases expression	2
Estradiol	affects binding, increases expression	2
Nickel	decreases expression	2
Genistein	affects binding, increases reaction, decreases reaction, increases expression	2
aristolochic acid I	decreases expression	1
bisphenol F	increases activity	1
biochanin A	affects binding, increases reaction	1
testosterone enanthate	affects expression	1
methylmercuric chloride	decreases expression	1
methyleugenol	decreases expression	1
propylparaben	affects binding, decreases reaction	1
pirinixic acid	increases activity, affects binding, decreases expression	1
butylphen	increases activity	1
chlorocresol	affects binding, decreases reaction	1
4,4’-bisphenol F	affects binding, decreases reaction	1

ChEMBL screening assays

135 unique, capped per target: 121 binding, 13 functional, 1 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1679777	Functional	Antagonist activity at ERRgamma LBD assessed as inhibition of recruitment of GST-labeled coactivator Scr2 by TR-FRET assay	Identification of diaryl ether-based ligands for estrogen-related receptor α as potential antidiabetic agents. — *J Med Chem*
CHEMBL1961859	Binding	Effect on ERR3(NR3B3) dependent reporter activity in HEK293 cells at 20 uM	Regulation of circadian behaviour and metabolism by synthetic REV-ERB agonists. — *Nature*
CHEMBL4047020	ADMET	Binding affinity to human ERRgamma	Design and synthesis of benzoacridines as estrogenic and anti-estrogenic agents. — *Bioorg Med Chem*

Cellosaurus cell lines

4 cell lines: 3 embryonic stem cell, 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_A1L6	SEES3-1V human ESRRG, clone1	Embryonic stem cell	Male
CVCL_A1L7	SEES3-1V human ESRRG, clone2	Embryonic stem cell	Male
CVCL_A1L8	SEES3-1V human ESRRG, clone3	Embryonic stem cell	Male
CVCL_SM45	HAP1 ESRRG (-)	Cancer cell line	Male

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.

showing 60 of 184 trials:

NCT	Phase	Status	Title
NCT01662414	Phase 4	COMPLETED	Effect of Undenatured Cysteine-Rich Whey Protein Isolate (HMS 90®) in Patients With Parkinson’s Disease
NCT04871464	Phase 4	UNKNOWN	Role and Mechanism of Probiotics in Improving Motor Symptoms in Mild to Moderate Parkinson’s Disease
NCT06710574	Phase 4	RECRUITING	Multimodal Image Technologies Investigate the Role and Mechanism of Probiotics in Improving RBD with Parkinson’s Disease
NCT01838278	Phase 3	UNKNOWN	Effectiveness of Vojta Therapy in Motor Development of Preterm Children
NCT00001929	Phase 2	COMPLETED	Treatment of Parkinson’s Disease With Eliprodil
NCT00331669	Phase 2	UNKNOWN	Efficacy and Safety of Deep Brain Stimulation (DBS) of the Pallidal (GPi) in Patients With Tardive Dystonia
NCT00406029	Phase 2	COMPLETED	Dyskinesia in Parkinson’s Disease (Study P04501)
NCT00537017	Phase 2	COMPLETED	Follow Up Safety Study of SCH 420814 in Subjects With Parkinson’s Disease (P05175)
NCT00693472	Phase 2	TERMINATED	Study of Preladenant for the Treatment of Neuroleptic Induced Akathisia (Study P05145)
NCT01385592	Phase 2	COMPLETED	Evaluation of the Efficacy and Safety of AFQ056 in Parkinson’s Patients With L-dopa Induced Dyskinesias
NCT01491529	Phase 2	COMPLETED	Evaluation of the Efficacy and Safety of Modified Release AFQ056 in Parkinson’s Patients With L-dopa Induced Dyskinesias
NCT01491932	Phase 2	COMPLETED	Open-label, Long-term Safety Extension Study of AFQ056 in Parkinson’s Patients With L-dopa Induced Dyskinesias
NCT02500628	Phase 2	COMPLETED	Heart Rate Variability in Response to Metformin Challenge
NCT04536987	Phase 2	COMPLETED	Robot Therapy for Rehabilitation of Hand Movement After Stroke
NCT04912115	Phase 2	SUSPENDED	Randomized, Double-Blind, Active Placebo-Controlled Study of Ketamine to Treat Levodopa-Induced Dyskinesia
NCT05636852	Phase 2	TERMINATED	Altropane Dose for Imaging Patients With Suspected Parkinson’s Disease
NCT00001663	Phase 1	COMPLETED	Treatment of Cortical Myoclonus With Repetitive Transcranial Magnetic Stimulation
NCT02589340	Phase 1	TERMINATED	Buspirone, in Combination With Amantadine, for the Treatment of Levodopa-induced Dyskinesia
NCT03065192	Phase 1	COMPLETED	Safety and Efficacy Study of VY-AADC01 for Advanced Parkinson’s Disease
NCT07232147	Phase 1	NOT_YET_RECRUITING	Clinical Research on Stem Cell Therapy for Parkinson’s Disease
NCT00036296	Phase 1/2	COMPLETED	Effects of Talampanel on Patients With Advanced Parkinson’s Disease
NCT00037167	Phase 1/2	COMPLETED	Effects of Exercise Poles on Older Adults During Exercise Walking
NCT03295786	Phase 1/2	COMPLETED	Clinical Study to Test the Safety of CDNF by Brain Infusion in Patients With Parkinson’s Disease
NCT03775538	Phase 1/2	COMPLETED	Safety of CDNF by Brain Infusion in Patients With Parkinson’s Disease. Extension to HP-CD-CL-2002 Clinical Study
NCT04228653	Phase 1/2	UNKNOWN	Long-Term Follow-up Safety After DDS Implantation With/Without CDNF Infusions
NCT06948019	Phase 1/2	NOT_YET_RECRUITING	Safety and Efficacy of AAV9/AP4B1 (BFB-101) For Patients With AP4B1-related Hereditary Spastic Paraplegia Type 47 (SPG47)
NCT00500994	Early Phase 1	COMPLETED	Neurobiology of Functional Movement Disorder and Non-Epileptic Seizures
NCT00001208	Not specified	RECRUITING	Botulinum Toxin for the Treatment of Involuntary Movement Disorders
NCT00001252	Not specified	RECRUITING	Human Movement Database
NCT00001324	Not specified	COMPLETED	PET Scan to Study Brain Control of Human Movement
NCT00001361	Not specified	COMPLETED	Magnetic Resonance Imaging Studies of Motor and Thought Processes
NCT00001549	Not specified	COMPLETED	Diagnosis and Natural History Study of Patients With Neurological Conditions
NCT00001665	Not specified	COMPLETED	Transcranial Magnetic Stimulation for the Treatment of Parkinson’s Disease
NCT00001667	Not specified	COMPLETED	Genotype/Phenotype Correlation of Movement Disorders and Other Neurological Diseases
NCT00001780	Not specified	COMPLETED	Magnetic Stimulation of the Human Nervous System
NCT00017966	Not specified	COMPLETED	Brain Excitability During Self-Paced Voluntary Movements
NCT00017979	Not specified	COMPLETED	Study of Brain Control of Movement
NCT00018889	Not specified	RECRUITING	Phenotype/Genotype Correlations in Movement Disorders
NCT00042120	Not specified	COMPLETED	Farming and Movement Evaluation Study (FAME)
NCT00056888	Not specified	COMPLETED	Neurophysiological Studies in Patients With Paroxysmal Hyperkinetic Movement Disorders
NCT00105131	Not specified	COMPLETED	Genetic Characterization of Parkinson’s Disease
NCT00118586	Not specified	COMPLETED	Neuropathology of Spasmodic Dysphonia
NCT00137384	Not specified	COMPLETED	Movement-Related Brain Networks Involved in Hand Dystonia
NCT00307346	Not specified	COMPLETED	Physiology of Weakness in Movement Disorders
NCT00314444	Not specified	COMPLETED	Treatment for Psychogenic Disorders
NCT00355927	Not specified	UNKNOWN	Sedation During Microelectrode Recordings Before Deep Brain Stimulation for Movement Disorders.
NCT00467597	Not specified	COMPLETED	Developing Objective Measures of Levodopa Induced Dyskinesia: (Study 1)
NCT00552474	Not specified	COMPLETED	Deep Brain Stimulation to Treat Symptoms of Parkinson’s Disease
NCT00588926	Not specified	UNKNOWN	Changes of the Neuronal Activity in the Subthalamic Nucleus Under Remifentanil Sedation During Stereotactic Electrode Implantation
NCT00610233	Not specified	COMPLETED	Effect of Deep Brain Stimulation on Lower Urinary Tract Function
NCT00885040	Not specified	TERMINATED	Investigation of Neurofeedback With Real-Time fMRI in Healthy Volunteers and Patients With Hyperkinetic Movement Disorders
NCT00904332	Not specified	COMPLETED	Changes in the Posterior Parietal Cortex - Primary Motor Cortex Pathway Induced by Motor Training
NCT00954772	Not specified	COMPLETED	Mood and Subthalamic Nucleus (STN) Deep Brain Stimulation
NCT01019343	Not specified	COMPLETED	Physiological Investigations of Movement Disorders
NCT01037361	Not specified	COMPLETED	Cerebral Activity Related to Primary Motor Stereotypies in Children: An EEG Study.
NCT01089296	Not specified	COMPLETED	The Norwegian Physical Therapy Study in Preterm Infants
NCT01105845	Not specified	TERMINATED	Genetics of Motor Learning
NCT01139463	Not specified	COMPLETED	Study of Blood Lactate Levels in Patients Treated With Antipsychotics
NCT01188161	Not specified	COMPLETED	Postural Effects of Being Rotated in a Whole Body Gyroscope
NCT01210781	Not specified	UNKNOWN	Target Planning for Placement of DBS-electrodes and Follow-up of the Clinical Efficacy of Stimulation

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for ESRRG across ~30M SureChEMBL compounds — explore on Sugi Predict.