PPARGC1B

Summary

PPARGC1B (PPARG coactivator 1 beta, HGNC:30022) is a protein-coding gene on chromosome 5q32, encoding Peroxisome proliferator-activated receptor gamma coactivator 1-beta (Q86YN6). Plays a role of stimulator of transcription factors and nuclear receptors activities. It is a selective cancer dependency (DepMap: 31.6% of cell lines).

The protein encoded by this gene stimulates the activity of several transcription factors and nuclear receptors, including estrogen receptor alpha, nuclear respiratory factor 1, and glucocorticoid receptor. The encoded protein may be involved in fat oxidation, non-oxidative glucose metabolism, and the regulation of energy expenditure. This protein is downregulated in prediabetic and type 2 diabetes mellitus patients. Certain allelic variations in this gene increase the risk of the development of obesity. Three transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 133522 — RefSeq curated summary.

At a glance

• GWAS associations: 18
• Clinical variants (ClinVar): 257 total
• Cancer dependency (DepMap): dependent in 31.6% of screened cell lines
• MANE Select transcript: NM_133263

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:30022
Approved symbol	PPARGC1B
Name	PPARG coactivator 1 beta
Location	5q32
Locus type	gene with protein product
Status	Approved
Aliases	PERC, PGC1B, PPARAGCIβ
Ensembl gene	ENSG00000155846
Ensembl biotype	protein_coding
OMIM	608886
Entrez	133522

Gene structure

Transcript identifiers

Ensembl transcripts: 18 — 16 protein_coding, 1 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000309241, ENST00000360453, ENST00000394320, ENST00000403750, ENST00000434684, ENST00000461780, ENST00000492495, ENST00000884559, ENST00000884560, ENST00000884561, ENST00000884562, ENST00000884563, ENST00000884564, ENST00000884565, ENST00000884566, ENST00000941532, ENST00000941533, ENST00000941534

RefSeq mRNA: 3 — MANE Select: NM_133263 NM_001172698, NM_001172699, NM_133263

CCDS: CCDS4298, CCDS54933, CCDS54934

Canonical transcript exons

ENST00000309241 — 12 exons

Exon	Start	End
ENSE00001023045	149842256	149842377
ENSE00001023046	149845760	149845914
ENSE00001023049	149840041	149840116
ENSE00001023050	149836263	149837073
ENSE00001124349	149835301	149835365
ENSE00001124356	149834674	149834710
ENSE00001619948	149820433	149820606
ENSE00001670819	149826673	149826885
ENSE00001683529	149832656	149833778
ENSE00001783702	149830767	149830883
ENSE00001845064	149730310	149730420
ENSE00001957907	149847458	149855022

Expression profiles

Bgee: expression breadth ubiquitous, 227 present calls, max score 89.20.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 8.3834 / max 127.2513, expressed in 1385 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
59389	7.7900	1363
59387	0.3469	180
59388	0.2465	114

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
endothelial cell	CL:0000115	89.20	gold quality
secondary oocyte	CL:0000655	84.23	gold quality
germinal epithelium of ovary	UBERON:0001304	80.96	gold quality
esophagus squamous epithelium	UBERON:0006920	80.38	gold quality
jejunal mucosa	UBERON:0000399	80.03	gold quality
duodenum	UBERON:0002114	79.66	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	78.90	gold quality
Brodmann (1909) area 23	UBERON:0013554	78.84	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	78.57	gold quality
apex of heart	UBERON:0002098	78.31	gold quality
monocyte	CL:0000576	78.24	gold quality
transverse colon	UBERON:0001157	78.10	gold quality
mononuclear cell	CL:0000842	77.98	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	77.64	gold quality
leukocyte	CL:0000738	77.44	gold quality
heart left ventricle	UBERON:0002084	77.05	gold quality
cardiac ventricle	UBERON:0002082	76.98	gold quality
parietal pleura	UBERON:0002400	76.98	gold quality
mucosa of transverse colon	UBERON:0004991	76.93	gold quality
rectum	UBERON:0001052	76.60	gold quality
colon	UBERON:0001155	76.14	gold quality
large intestine	UBERON:0000059	76.09	gold quality
muscle layer of sigmoid colon	UBERON:0035805	76.03	gold quality
jejunum	UBERON:0002115	75.90	gold quality
biceps brachii	UBERON:0001507	75.72	gold quality
epithelium of esophagus	UBERON:0001976	75.58	gold quality
cerebellar vermis	UBERON:0004720	75.58	gold quality
lower esophagus mucosa	UBERON:0035834	75.55	gold quality
oocyte	CL:0000023	75.50	gold quality
middle temporal gyrus	UBERON:0002771	75.18	silver quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.64

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

5 targets.

Target	Regulation
FABP1
MTTP
SYTL4
TRIB3
UCP2

Upstream regulators (CollecTRI, top): AHR, CREB1, CREBZF, ESR1, ESRRG, FOXO1, NFE2L1, NFE2L2, NRF1, PID1, PPARG, TNF, TRPV4

miRNA regulators (miRDB)

219 targeting PPARGC1B, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-4425	100.00	67.59	1049
HSA-MIR-4455	100.00	65.48	1587
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-LET-7G-5P	99.98	72.37	1784
HSA-LET-7I-5P	99.98	72.37	1788
HSA-MIR-98-5P	99.98	72.33	1787

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 31.6% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• The PGC-1-related protein PERC is a selective coactivator of estrogen receptor alpha (PMID:11854298)
• role in coactivating the cardiac-enriched nuclear receptors estrogen-related receptor-alpha and -gamma (PMID:12181319)
• role in activating orphan nuclear constitutive androstane receptor (PMID:12551939)
• Variation of PGC-1beta may contribute to the pathogenesis of obesity, with a widespread Ala203 allele being a risk factor for the development of this common disorder. (PMID:15863669)
• fatty acids differentially regulated expression of the genes encoding the PGC-1B isoform (PMID:16132959)
• PPARGC1A, PPARGC1B, and EP300 may have roles for familial breast cancer susceptibility (PMID:16704985)
• Acute elevation of plasma non-esterified fatty acd levels downregulates PPARGC1A, PPARGC1B and PPARA expression. (PMID:16896940)
• Recent studies have elucidated the function of the PGC-1 coactivators in different tissues and have highlighted the implications of PGC-1 dysregulation in diseases such as diabetes, obesity, cardiomyopathy, or neurodegeneration. (PMID:17018837)
• Upregulation of PGC-1alpha and PGC-1beta in the colorectal tumor cells can be part of an adaptation mechanism to help overcome the severe consequences of mtDNA mutations on oxidative phosphorylation. (PMID:17341490)
• Study suggests that young carriers of a PGC-1beta 203Pro allele have enhanced insulin-stimulated glucose metabolism and may be protected against an age-related decline in PGC-1beta expression in muscle. (PMID:17579828)
• training caused a decrease in PGC-1beta mRNA levels. (PMID:17690194)
• A novel role of PGC-1beta in mitochondrial physiology, namely the control of mitochondrial fusion mainly through Mfn2. (PMID:18974884)
• the association of the 482G/A polymorphism of the PGC-1alpha gene with type 2 diabetes and the quantitative and qualitative binding force changes between the PGC-1alpha domain mutant and MEF2C (PMID:19065516)
• PGC-1alpha and PGC-1beta expression improved mitochondrial respiration in cells from patients with mitochondrial disorders. (PMID:19297390)
• PGC-1beta is a substrate for general control of amino-acid synthesis (GCN5) and is acetylated on at least 10 lysine residues that are distributed along multiple domains of the protein. (PMID:19491097)
• the PPARGC1B gene Ala203Pro polymorphism is associated with physical performance of athletes. (PMID:20058823)
• Taken together, these results confirm the direct interaction of NRF-1 and ERR alpha with PGC-1 beta, and their participation in mitochondrial biogenesis and respiration. (PMID:20561910)
• 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)
• physiological role of PGC-1beta: investigation of mitochondrial homeostasis regulatory pathway involving PGC-1beta and PI3K; investigation of regulation of PGC-1beta gene expression (PMID:21054343)
• DNA polymorphisms of PPARGC1B, coding a bona fide ER co-activator, are associated with ER-positive breast cancer risk. (PMID:21269472)
• PGC-1beta is a potent regulator of angiogenesis, thus providing a novel link between the regulations of oxidative metabolism and vascular density. (PMID:21364124)
• Data show that mitogen-activated protein kinase kinases direct mitochondrial biogenesis by selectively inducing PGC-1beta expression. (PMID:21458501)
• Polymorphisms of -427C>T on the promoter and those of +102525G>A on exon 5 of the PPARGC1B gene may affect the development of AHR through the modulation of PPARGC1B gene products. (PMID:21692888)
• Exercise can activate an upstream promoter in humans and support AMPK as a major regulator of transcripts from the canonical PGC-1alpha promoter and the involvement of beta-adrenergic stimulation in combination with AMPK in the regulation of PGC-1alpha-b. (PMID:21862727)
• Acetyl-L-carnitine activates the peroxisome proliferator-activated receptor-gamma coactivators PGC-1alpha/PGC-1beta-dependent signaling cascade of mitochondrial biogenesis and decreases the oxidized peroxiredoxins content in old rat liver (PMID:22533417)
• PGC-1beta mediates adaptive chemoresistance to cisplatin associated with mitochondrial DNA mutations in non-small-cell lung cancer cells. (PMID:22777349)
• Absence of PGC-1 proteins accelerated the transition to heart failure following pressure overload. (PMID:22939990)
• Inhibition of PGC-1a and PGC-1b blocks the alpha-MSH-mediated induction of MITF and melanogenic genes. (PMID:23201126)
• Peroxisome proliferator-activated receptor gamma coactivator 1beta (PGC-1beta) protein attenuates vascular lesion formation by inhibition of chromatin loading of minichromosome maintenance complex in smooth muscle cells (PMID:23264620)
• PPARGC1B is associated with the susceptibility to ankylosing spondylitis in the Chinese Han population. (PMID:23637848)
• PGC-1b, a coactivator of both LXR-alpha and SREBP-1, was markedly down-regulated by OEPAs compared with EPA. (PMID:23680128)
• PPARgamma and PPARGC1B polymorphisms modulate the association between phthalate exposure and BC risk (PMID:23866026)
• cell apoptosis is orchestrated by the balance between several signaling pathways, and PGC-1beta takes part in these events in breast cancer cells mediated by the mTOR signaling pathway. (PMID:23877360)
• Variation in the PPARGC1B gene may be associated with type 2 diabetes among middle-aged Chinese men and women. (PMID:24359475)
• Data show that PGC-1beta protein mediated the expression of proinflammatory cytokines and apoptosis through extracellular signal-regulated kinase (ERK), p38 and NF-kappaB in rheumatoid arthritis fibroblast-like synoviocytes. (PMID:25367151)
• RUNX3 is related to both the severity of AS and the function of daily life. PPARGC1B is related to the function of daily life. (PMID:25494292)
• PGC-1(beta) and estrogen-related receptor alpha are aberrantly expressed in human colon cell lines and tumors. (PMID:26351140)
• Data suggest that PGC-1alpha and PGC-1beta could play a role in regulating retina cell survival, and may be therapeutic targets to prevent retinal degeneration. (PMID:26427438)
• we show an association of HER2-overexpression and PGC-1beta. PGC-1beta knockdown impairs HER2-overexpressing cells proliferation acting on ERRalpha signaling, metabolism, and redox balance. (PMID:26602383)
• Insulin-like growth factor 1 receptor, associate of Myc 1, and peroxisome proliferator-activated receptor gamma coactivator 1beta are direct targets of miR-139 (PMID:26868851)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	ppargc1b	ENSDARG00000101569
mus_musculus	Ppargc1b	ENSMUSG00000033871
rattus_norvegicus	Ppargc1b	ENSRNOG00000017503
drosophila_melanogaster	srl	FBGN0037248

Paralogs (2): PPARGC1A (ENSG00000109819), PPRC1 (ENSG00000148840)

Protein

Protein identifiers

Peroxisome proliferator-activated receptor gamma coactivator 1-beta — Q86YN6 (reviewed: Q86YN6)

Alternative names: PGC-1-related estrogen receptor alpha coactivator

All UniProt accessions (2): Q86YN6, H0Y713

UniProt curated annotations — full annotation on UniProt →

Function. Plays a role of stimulator of transcription factors and nuclear receptors activities. Activates transcriptional activity of estrogen receptor alpha, nuclear respiratory factor 1 (NRF1) and glucocorticoid receptor in the presence of glucocorticoids. May play a role in constitutive non-adrenergic-mediated mitochondrial biogenesis as suggested by increased basal oxygen consumption and mitochondrial number when overexpressed. May be involved in fat oxidation and non-oxidative glucose metabolism and in the regulation of energy expenditure. Induces the expression of PERM1 in the skeletal muscle in an ESRRA-dependent manner.

Subunit / interactions. Interacts with hepatocyte nuclear factor 4-alpha/HNF4A, Sterol regulatory binding transcription factor 1/SREBF1, PPAR-alpha/PPARA, thyroid hormone receptor beta/THRB and host cell factor/HCFC1. Interacts with estrogen-related receptor gamma/ESRRG and alpha/ESRRA. Interacts with PRDM16. Interacts with estrogen receptor alpha/ESR1.

Subcellular location. Nucleus.

Tissue specificity. Ubiquitous with higher expression in heart, brain and skeletal muscle.

Domain organisation. Contains 2 Leu-Xaa-Xaa-Leu-Leu (LXXLL) motif, which are usually required for the association with nuclear receptors.

Induction. Repressed by saturated fatty acids such as palmitate and stearate in skeletal muscle cells. Induced by insulin and reduced by aging in skeletal muscle biopsies. Down-regulated in type 2 diabetes mellitus subjects as well as in pre-diabetics.

Polymorphism. Variation of PPARGC1B may contribute to the pathogenesis of obesity, with a widespread Ala-203 allele being a risk factor for the development of this common disorders.

Miscellaneous. Lacks LXXLL motif 1 and has a reduced ability to enhance the hormone-dependent activity of estrogen receptor alpha.

Isoforms (6)

UniProt ID	Names	Canonical?
Q86YN6-1	1, PGC1beta-1a	yes
Q86YN6-2	2, PGC1beta-2a
Q86YN6-3	3, PGC1beta-1b
Q86YN6-4	4, PGC1beta-2b
Q86YN6-5	5, PERC-s
Q86YN6-6	6

RefSeq proteins (3): NP_001166169, NP_001166170, NP_573570* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000504	RRM_dom	Domain
IPR012677	Nucleotide-bd_a/b_plait_sf	Homologous_superfamily
IPR034177	PPARGC1B_RRM	Domain
IPR034605	PGC-1	Family
IPR035979	RBD_domain_sf	Homologous_superfamily

Pfam: PF00076

UniProt features (40 total): region of interest 11, compositionally biased region 7, splice variant 4, sequence variant 4, short sequence motif 3, modified residue 3, mutagenesis site 3, helix 2, chain 1, domain 1, sequence conflict 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
3SP6	X-RAY DIFFRACTION	2.21
6D0Y	X-RAY DIFFRACTION	2.68

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q86YN6-F1	50.75	0.06

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): 384, 524, 638

Mutagenesis-validated functional residues (3):

Position	Phenotype
92–96	reduces dna transcriptional activity.
155–160	reduces interaction and activation of esr1. loss of interaction and activation of esr1; when associated with 343-areaa-3
343–347	reduces interaction and activation of esr1. loss of interaction and activation of esr1; when associated with 155-aaqkaa-

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-1989781	PPARA activates gene expression
R-HSA-2151201	Transcriptional activation of mitochondrial biogenesis
R-HSA-8939902	Regulation of RUNX2 expression and activity
R-HSA-9841922	MLL4 and MLL3 complexes regulate expression of PPARG target genes in adipogenesis and hepatic steatosis
R-HSA-9844594	Transcriptional regulation of brown and beige adipocyte differentiation by EBF2

MSigDB gene sets: 280 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, GOBP_REGULATION_OF_OSTEOCLAST_DIFFERENTIATION, GOBP_POSITIVE_REGULATION_OF_HEMOPOIESIS, TGCGCANK_UNKNOWN, GOBP_CELLULAR_RESPONSE_TO_LIPID, GCANCTGNY_MYOD_Q6, ATACCTC_MIR202, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GOBP_MYELOID_LEUKOCYTE_DIFFERENTIATION, GGGTGGRR_PAX4_03, USF_C, GOBP_REGULATION_OF_LEUKOCYTE_DIFFERENTIATION, GOBP_HORMONE_MEDIATED_SIGNALING_PATHWAY, GOBP_REGULATION_OF_HEMOPOIESIS, MCBRYAN_PUBERTAL_BREAST_4_5WK_DN

GO Biological Process (6): regulation of DNA-templated transcription (GO:0006355), estrogen receptor signaling pathway (GO:0030520), positive regulation of osteoclast differentiation (GO:0045672), positive regulation of transcription by RNA polymerase II (GO:0045944), energy homeostasis (GO:0097009), positive regulation of cold-induced thermogenesis (GO:0120162)

GO Molecular Function (8): transcription coactivator activity (GO:0003713), RNA binding (GO:0003723), nuclear estrogen receptor binding (GO:0030331), AF-2 domain binding (GO:0050682), nucleic acid binding (GO:0003676), transcription coregulator activity (GO:0003712), protein binding (GO:0005515), transcription factor binding (GO:0008134)

GO Cellular Component (4): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytosol (GO:0005829), mediator complex (GO:0016592)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Regulation of lipid metabolism by PPARalpha	1
Mitochondrial biogenesis	1
Transcriptional regulation by RUNX2	1
Epigenetic regulation of adipogenesis genes by MLL3 and MLL4 complexes	1
Transcriptional regulation of brown and beige adipocyte differentiation	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
positive regulation of DNA-templated transcription	2
binding	2
cellular anatomical structure	2
DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
nuclear receptor-mediated steroid hormone signaling pathway	1
positive regulation of myeloid leukocyte differentiation	1
osteoclast differentiation	1
regulation of osteoclast differentiation	1
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
multicellular organismal-level homeostasis	1
positive regulation of multicellular organismal process	1
cold-induced thermogenesis	1
regulation of cold-induced thermogenesis	1
transcription coregulator activity	1
nucleic acid binding	1
nuclear receptor binding	1
protein domain specific binding	1
transcription regulator activity	1
protein binding	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
cytoplasm	1
core mediator complex	1
nuclear protein-containing complex	1

Protein interactions and networks

STRING

1584 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PPARGC1B	ESRRA	P11474	970
PPARGC1B	NRF1	Q16656	916
PPARGC1B	ESRRG	P62508	905
PPARGC1B	SLC7A1	P30825	904
PPARGC1B	PPARG	P37231	894
PPARGC1B	PRDM16	Q9HAZ2	872
PPARGC1B	SREBF1	P36956	858
PPARGC1B	PPARA	Q07869	849
PPARGC1B	PPARD	Q03181	774
PPARGC1B	TFAM	Q00059	762
PPARGC1B	SREBF2	Q12772	752
PPARGC1B	GABPA	Q06546	675
PPARGC1B	HCFC1	P51610	664
PPARGC1B	ACADM	P11310	664
PPARGC1B	HIF1A	Q16665	642

IntAct

17 interactions, top by confidence:

A	B	Type	Score
ESRRG	PPARGC1B	psi-mi:“MI:0915”(physical association)	0.660
	PPARA	psi-mi:“MI:0407”(direct interaction)	0.440
PPARGC1B	H1-1	psi-mi:“MI:0915”(physical association)	0.400
PPARGC1B	PARP1	psi-mi:“MI:0915”(physical association)	0.400
PPARGC1B	ESR1	psi-mi:“MI:0915”(physical association)	0.370
ZNF513	PPARGC1B	psi-mi:“MI:0915”(physical association)	0.370
HCFC1	PPARGC1B	psi-mi:“MI:0915”(physical association)	0.370
ZFP64	PPARGC1B	psi-mi:“MI:0915”(physical association)	0.370
ZNF200	PPARGC1B	psi-mi:“MI:0915”(physical association)	0.370
ZNF212	PPARGC1B	psi-mi:“MI:0915”(physical association)	0.370
PPARGC1B	ZBTB9	psi-mi:“MI:0915”(physical association)	0.370
DNAJC10	TRAPPC13	psi-mi:“MI:0914”(association)	0.350
ESRRG	DDX3Y	psi-mi:“MI:0914”(association)	0.350
ESRRG	TTR	psi-mi:“MI:0914”(association)	0.350

BioGRID (35): PPARGC1B (Affinity Capture-MS), PPARGC1B (Affinity Capture-Western), PPARGC1B (Affinity Capture-Western), PPARG (Affinity Capture-Western), PPARGC1B (Affinity Capture-MS), PPARGC1B (Affinity Capture-MS), PPARGC1B (Affinity Capture-RNA), PPARGC1B (Affinity Capture-RNA), PPARGC1B (Affinity Capture-RNA), PPARGC1B (Proximity Label-MS), PPARGC1B (Proximity Label-MS), HNF4A (Reconstituted Complex), THRB (Reconstituted Complex), PPARA (Reconstituted Complex), PPARGC1B (Affinity Capture-MS)

ESM2 similar proteins: A0A0A6YY25, A6NGG8, A6X8Z5, B2RQL2, B2RXH4, D3ZMK9, D3ZUE1, E9Q7F2, O08696, O14513, P59598, P97691, Q05860, Q05AH6, Q08050, Q0GGX2, Q0VET5, Q13029, Q2M1Z3, Q3U0P1, Q571I4, Q5PSV9, Q5SSG4, Q5U2M8, Q5VV67, Q63755, Q66H04, Q68DA7, Q69ZL1, Q6DIA7, Q6JPI3, Q6P1D7, Q6PAC4, Q6PG16, Q71F56, Q76N32, Q811R2, Q86YN6, Q86YV5, Q8BJS7

Diamond homologs: O70343, Q5VV67, Q6NZN1, Q811R2, Q865B6, Q865B7, Q86YN6, Q8VHJ7, Q9QYK2, Q9UBK2

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	184
Likely benign	10
Benign	42

Top pathogenic / likely-pathogenic (0)

SpliceAI

2781 predictions. Top by Δscore:

Variant	Effect	Δscore
5:149730417:GCAG:G	donor_gain	1.0000
5:149730418:CAGG:C	donor_loss	1.0000
5:149730419:AGGT:A	donor_loss	1.0000
5:149730420:GGT:G	donor_loss	1.0000
5:149730421:GTAC:G	donor_loss	1.0000
5:149820422:T:A	acceptor_gain	1.0000
5:149820431:AG:A	acceptor_gain	1.0000
5:149820431:AGGGT:A	acceptor_gain	1.0000
5:149820432:GG:G	acceptor_gain	1.0000
5:149820432:GGGTG:G	acceptor_gain	1.0000
5:149820607:GTATG:G	donor_loss	1.0000
5:149820608:T:G	donor_loss	1.0000
5:149826647:T:A	acceptor_gain	1.0000
5:149826882:ACTGG:A	donor_loss	1.0000
5:149826883:CTGG:C	donor_loss	1.0000
5:149826884:TGGTA:T	donor_loss	1.0000
5:149826886:G:GG	donor_gain	1.0000
5:149826886:GTAAG:G	donor_loss	1.0000
5:149826887:T:A	donor_loss	1.0000
5:149832652:CTAG:C	acceptor_loss	1.0000
5:149832654:A:AC	acceptor_loss	1.0000
5:149832654:A:AG	acceptor_gain	1.0000
5:149832655:G:GG	acceptor_gain	1.0000
5:149832655:GGC:G	acceptor_gain	1.0000
5:149835280:T:A	acceptor_gain	1.0000
5:149835289:T:TA	acceptor_gain	1.0000
5:149835299:A:AG	acceptor_gain	1.0000
5:149835300:G:GA	acceptor_gain	1.0000
5:149835300:GC:G	acceptor_gain	1.0000
5:149842249:T:A	acceptor_gain	1.0000

AlphaMissense

6651 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:149836266:T:C	L604P	0.998
5:149847517:T:C	F1011L	0.996
5:149847519:T:A	F1011L	0.996
5:149847519:T:G	F1011L	0.996
5:149847530:T:C	L1015P	0.996
5:149847538:G:C	A1018P	0.996
5:149847527:T:C	L1014S	0.995
5:149836266:T:A	L604H	0.994
5:149836275:C:A	P607H	0.994
5:149836734:T:C	I760T	0.994
5:149842325:T:C	F922L	0.994
5:149842327:T:A	F922L	0.994
5:149842327:T:G	F922L	0.994
5:149842334:T:C	F925L	0.994
5:149842336:T:A	F925L	0.994
5:149842336:T:G	F925L	0.994
5:149842314:T:C	L918P	0.993
5:149842338:G:T	G926V	0.993
5:149845785:T:G	Y948D	0.993
5:149826707:T:C	L96P	0.992
5:149836533:A:T	D693V	0.992
5:149836734:T:G	I760S	0.992
5:149842266:G:C	R902P	0.992
5:149842326:T:C	F922S	0.992
5:149830777:T:C	L159P	0.991
5:149836272:C:A	P606Q	0.991
5:149836746:T:C	L764P	0.991
5:149836757:T:C	F768L	0.991
5:149836759:T:A	F768L	0.991
5:149836759:T:G	F768L	0.991

dbSNP variants (sampled 300 via entrez): RS1000027676 (5:149805150 C>T), RS1000044402 (5:149831264 A>G), RS1000050389 (5:149748372 G>A,T), RS1000051450 (5:149801704 G>A,C), RS1000051474 (5:149790971 G>C,T), RS1000098349 (5:149751458 C>G), RS1000201044 (5:149849968 G>A), RS1000254823 (5:149784693 G>A), RS1000265174 (5:149836117 G>T), RS1000302788 (5:149788398 A>G), RS1000315779 (5:149778525 A>G), RS1000375391 (5:149788676 C>G,T), RS1000425484 (5:149732747 T>C), RS1000428007 (5:149830170 G>A,C), RS1000433548 (5:149823922 C>G)

Disease associations

OMIM: gene MIM:608886 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

18 associations (top):

Study	Trait	p-value
GCST000371_1	Tanning	4.000000e-06
GCST001762_110	Obesity-related traits	5.000000e-06
GCST004785_2	Vitiligo	8.000000e-08
GCST005897_34	Low tan response	2.000000e-09
GCST006091_1	Freckles	1.000000e-21
GCST006096_1	Age spots	6.000000e-12
GCST007504_11	Nevus count	5.000000e-07
GCST007505_15	Nevus count or cutaneous melanoma	2.000000e-09
GCST008870_21	Keratinocyte cancer (MTAG)	2.000000e-09
GCST008871_31	Basal cell carcinoma	3.000000e-09
GCST010241_284	Apolipoprotein A1 levels	6.000000e-09
GCST010242_357	HDL cholesterol levels	1.000000e-10
GCST010304_31	Cutaneous malignant melanoma	7.000000e-17
GCST010727_13	Deep white matter hyperintensities	5.000000e-06
GCST011010_57	Electrocardiographic traits (multivariate)	2.000000e-07
GCST011155_10	Nontraumatic osteonecrosis of the femoral head	1.000000e-06
GCST90002283_2	Facial pigmentation measurement (UV light)	9.000000e-42
GCST90002284_2	Facial pigmentation measurement (polar light)	4.000000e-31

EFO canonical traits (11, from GWAS)

EFO ID	Trait name
EFO:0004279	suntan
EFO:0004697	estradiol measurement
EFO:0003963	freckles
EFO:0007850	solar lentigines measurement
EFO:0004632	nevus count
EFO:0010176	keratinocyte carcinoma
EFO:0004614	apolipoprotein A 1 measurement
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0005665	white matter hyperintensity measurement
EFO:0004327	electrocardiography
EFO:1001930	idiopathic osteonecrosis of the femoral head

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression	5
sodium arsenite	increases expression, affects expression, decreases expression, increases abundance	4
Estradiol	affects binding, increases reaction, increases expression	4
bisphenol A	affects expression, affects reaction, affects cotreatment, increases expression, decreases methylation	3
trichostatin A	affects cotreatment, increases expression	2
entinostat	increases expression, affects cotreatment	2
belinostat	increases expression, affects cotreatment	2
Panobinostat	affects cotreatment, increases expression	2
Arsenic	affects methylation, increases abundance, increases expression	2
Tamoxifen	increases expression, decreases reaction, decreases expression, affects expression, affects reaction (+1 more)	2
FR900359	decreases phosphorylation	1
triphenyl phosphate	affects expression	1
tris(2-butoxyethyl) phosphate	affects expression	1
beta-lapachone	decreases expression, increases expression	1
3,4,5,3’,4’-pentachlorobiphenyl	decreases expression	1
2-chloroethyl ethyl sulfide	increases expression	1
polydatin	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
dihydroxy-vitamin D3	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, increases expression	1
MRK 003	increases expression	1
bisphenol S	affects binding, increases reaction	1
jinfukang	increases expression	1
eldecalcitol	affects binding, increases reaction	1
NSC 689534	affects binding, decreases expression	1
(+)-JQ1 compound	decreases expression	1
bisphenol AF	affects binding, decreases reaction	1
Sunitinib	increases expression	1

Clinical trials (associated diseases)

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