PPARG

peroxisome proliferator activated receptor gamma, the group of Peroxisome proliferator activated receptors

Basic information

Region (hg38): 3:12287368-12434356

Links

ENSG00000132170 ∙ NCBI:5468 ∙ OMIM:601487 ∙ HGNC:9236 ∙ Uniprot:P37231 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• PPARG-related familial partial lipodystrophy (Strong), mode of inheritance: AD
• PPARG-related familial partial lipodystrophy (Definitive), mode of inheritance: AD
• Berardinelli-Seip congenital lipodystrophy (Supportive), mode of inheritance: AR
• PPARG-related familial partial lipodystrophy (Supportive), mode of inheritance: AD
• PPARG-related familial partial lipodystrophy (Strong), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Lipodystrophy, familial, partial, type 3; Insulin resistance, severe, digenic	AD/Digenic (Severe digenic insulin resistance can be due to digenic variants in PPP1R3A and PPARG)	General	Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing	Endocrine	9425261; 9753710; 10622252; 10973253; 11788685; 12453919; 12118251; 15356014; 21079616; 21479595; 21865368; 22748602; 22803842

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the PPARG gene.

• PPARG-related familial partial lipodystrophy (5 variants)
• Type 2 diabetes mellitus (2 variants)
• not provided (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the PPARG gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			4	27	2	33
missense	2	11	65	2		80
nonsense	1	2				3
start loss						0
frameshift	2	4				6
inframe indel			1			1
splice donor/acceptor (+/-2bp)	2					2
splice region			1	5		6
non coding			2	13	11	26
Total	7	17	72	42	13

Variants in PPARG

This is a list of pathogenic ClinVar variants found in the PPARG region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
3-12349804-A-G		Type 2 diabetes mellitus	association (Jan 12, 2016)
3-12349824-A-T		Type 2 diabetes mellitus	association (Jan 12, 2016)
3-12350786-A-C		Type 2 diabetes mellitus	association (Jan 12, 2016)
3-12351571-C-T		Obesity • Diabetes Mellitus, Noninsulin-Dependent, with Acanthosis Nigricans and Hypertension • PPARG-related familial partial lipodystrophy	Benign/Likely benign (Jan 13, 2018)
3-12351585-A-T		PPARG-related disorder	Likely benign (Jan 09, 2024)
3-12351593-A-G		PPARG-related disorder	Uncertain significance (May 08, 2024)
3-12351600-A-G			Uncertain significance (Oct 13, 2023)
3-12351620-A-G		PPARG-related disorder	Uncertain significance (Jan 02, 2024)
3-12351620-AT-A		PPARG-related disorder	Likely pathogenic (Nov 12, 2022)
3-12351621-T-C		PPARG-related disorder	Uncertain significance (May 22, 2024)
3-12351625-C-T			Benign (Jul 22, 2023)
3-12351626-C-A		PPARG-related disorder	Uncertain significance (Aug 31, 2024)
3-12351626-C-G		not specified • Obesity • Diabetes Mellitus, Noninsulin-Dependent, with Acanthosis Nigricans and Hypertension • PPARG-related familial partial lipodystrophy	Benign/Likely benign (Jan 31, 2024)
3-12351631-A-G		PPARG-related disorder	Likely benign (Jun 26, 2024)
3-12351640-C-T		PPARG-related disorder	Likely benign (Aug 02, 2022)
3-12351646-T-C			Likely benign (Jul 27, 2021)
3-12351653-C-G		PPARG-related disorder	Uncertain significance (Jun 28, 2024)
3-12351678-A-C			Uncertain significance (Oct 07, 2023)
3-12351690-G-T			Likely benign (Jun 28, 2021)
3-12379590-C-T			Benign (Nov 12, 2018)
3-12379687-T-G		PPARG-related disorder	Likely benign (Oct 10, 2023)
3-12379690-A-G		PPARG-related disorder	Likely benign (Apr 04, 2019)
3-12379704-A-G		PPARG-related disorder	Uncertain significance (Jan 22, 2024)
3-12379718-G-A		PPARG-related disorder	Uncertain significance (Aug 05, 2024)
3-12379739-C-G		Diabetes mellitus, noninsulin-dependent, modifier of • Body mass index, modifier of • Obesity, modifier of • Intimal medial thickness of internal carotid artery, modifier of	risk factor (Jun 01, 2007)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
PPARG	protein_coding	protein_coding	ENST00000287820	7	146989

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.0292	0.969	125735	0	10	125745	0.0000398

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	2.12	183	283	0.646	0.0000154	3374
Missense in Polyphen		59	126.87	0.46505		1455
Synonymous	-0.0556	109	108	1.01	0.00000627	944
Loss of Function	2.71	6	18.6	0.322	8.70e-7	247

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000868	0.0000868
Ashkenazi Jewish	0.0000997	0.0000992
East Asian	0.00	0.00
Finnish	0.0000462	0.0000462
European (Non-Finnish)	0.0000353	0.0000352
Middle Eastern	0.00	0.00
South Asian	0.0000327	0.0000327
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Nuclear receptor that binds peroxisome proliferators such as hypolipidemic drugs and fatty acids. Once activated by a ligand, the nuclear receptor binds to DNA specific PPAR response elements (PPRE) and modulates the transcription of its target genes, such as acyl-CoA oxidase. It therefore controls the peroxisomal beta-oxidation pathway of fatty acids. Key regulator of adipocyte differentiation and glucose homeostasis. ARF6 acts as a key regulator of the tissue-specific adipocyte P2 (aP2) enhancer. Acts as a critical regulator of gut homeostasis by suppressing NF-kappa-B-mediated proinflammatory responses. Plays a role in the regulation of cardiovascular circadian rhythms by regulating the transcription of ARNTL/BMAL1 in the blood vessels (By similarity). {ECO:0000250|UniProtKB:P37238, ECO:0000269|PubMed:16150867, ECO:0000269|PubMed:20829347, ECO:0000269|PubMed:23525231, ECO:0000269|PubMed:9065481}.
• Disease: DISEASE: Note=Defects in PPARG can lead to type 2 insulin- resistant diabetes and hyptertension. PPARG mutations may be associated with colon cancer. {ECO:0000269|PubMed:10394368}.; DISEASE: Obesity (OBESITY) [MIM:601665]: A condition characterized by an increase of body weight beyond the limitation of skeletal and physical requirements, as the result of excessive accumulation of body fat. {ECO:0000269|PubMed:9753710}. Note=Disease susceptibility may be associated with variations affecting the gene represented in this entry.; DISEASE: Lipodystrophy, familial partial, 3 (FPLD3) [MIM:604367]: A form of lipodystrophy characterized by marked loss of subcutaneous fat from the extremities. Facial adipose tissue may be increased, decreased or normal. Affected individuals show an increased preponderance of insulin resistance, diabetes mellitus and dyslipidemia. {ECO:0000269|PubMed:11788685, ECO:0000269|PubMed:12453919}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Glioma 1 (GLM1) [MIM:137800]: Gliomas are benign or malignant central nervous system neoplasms derived from glial cells. They comprise astrocytomas and glioblastoma multiforme that are derived from astrocytes, oligodendrogliomas derived from oligodendrocytes and ependymomas derived from ependymocytes. {ECO:0000269|PubMed:10851250}. Note=Disease susceptibility may be associated with variations affecting the gene represented in this entry. Polymorphic PPARG alleles have been found to be significantly over-represented among a cohort of American patients with sporadic glioblastoma multiforme suggesting a possible contribution to disease susceptibility.
• Pathway: Huntington,s disease - Homo sapiens (human);AMPK signaling pathway - Homo sapiens (human);Thermogenesis - Homo sapiens (human);Longevity regulating pathway - Homo sapiens (human);PPAR signaling pathway - Homo sapiens (human);Pathways in cancer - Homo sapiens (human);Transcriptional misregulation in cancer - Homo sapiens (human);Osteoclast differentiation - Homo sapiens (human);Thyroid cancer - Homo sapiens (human);Celecoxib Pathway, Pharmacodynamics;NHR;Energy Metabolism;Nuclear Receptors;Sterol Regulatory Element-Binding Proteins (SREBP) signalling;Transcriptional regulation of white adipocyte differentiation;White fat cell differentiation;Adipogenesis;HIF1A and PPARG regulation of glycolysis;Differentiation of white and brown adipocyte;Nuclear Receptors in Lipid Metabolism and Toxicity;Transcription factor regulation in adipogenesis;Wnt Signaling Pathway;NAD metabolism, sirtuins and aging;PPAR signaling pathway;Protein alkylation leading to liver fibrosis;Liver steatosis AOP;Steatosis AOP;White fat cell differentiation;Transcriptional cascade regulating adipogenesis;role of ppar-gamma coactivators in obesity and thermogenesis;Prostaglandin Synthesis and Regulation;Developmental Biology;Signal Transduction;Gene expression (Transcription);visceral fat deposits and the metabolic syndrome;Generic Transcription Pathway;basic mechanism of action of ppara pparb(d) and pparg and effects on gene expression;Nuclear Receptor transcription pathway;RNA Polymerase II Transcription;Ghrelin;Transcriptional regulation of white adipocyte differentiation;Regulation of PTEN gene transcription;PTEN Regulation;PIP3 activates AKT signaling;Noncanonical Wnt signaling pathway;Gastrin;RXR and RAR heterodimerization with other nuclear receptor;Intracellular signaling by second messengers;Calcineurin-regulated NFAT-dependent transcription in lymphocytes;Regulation of retinoblastoma protein;Signaling events mediated by HDAC Class I (Consensus)

Recessive Scores

• pRec: 0.974

Intolerance Scores

• loftool: 0.0635
• rvis_EVS: -0.31
• rvis_percentile_EVS: 31.93

Haploinsufficiency Scores

• pHI: 0.389
• hipred: Y
• hipred_score: 0.857
• ghis: 0.568

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: H
• gene_indispensability_pred: E
• gene_indispensability_score: 0.999

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium

Mouse Genome Informatics

• Gene name: Pparg
• Phenotype: cellular phenotype; homeostasis/metabolism phenotype; muscle phenotype; endocrine/exocrine gland phenotype; adipose tissue phenotype (the observable morphological and physiological characteristics of mammalian fat tissue that are manifested through development and lifespan); integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); growth/size/body region phenotype; embryo phenotype; renal/urinary system phenotype; skeleton phenotype; immune system phenotype; vision/eye phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); hearing/vestibular/ear phenotype; neoplasm; reproductive system phenotype; normal phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); hematopoietic system phenotype; liver/biliary system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan)

Zebrafish Information Network

• Gene name: pparg
• Affected structure: pancreatic B cell
• Phenotype tag: abnormal
• Phenotype quality: increased area

Gene ontology

• Biological process: negative regulation of transcription by RNA polymerase II;placenta development;negative regulation of acute inflammatory response;regulation of transcription by RNA polymerase II;transcription initiation from RNA polymerase II promoter;lipid metabolic process;fatty acid metabolic process;activation of cysteine-type endopeptidase activity involved in apoptotic process;signal transduction;G protein-coupled receptor signaling pathway;multicellular organism development;heart development;response to nutrient;regulation of blood pressure;response to cold;response to mechanical stimulus;hormone-mediated signaling pathway;macrophage derived foam cell differentiation;negative regulation of macrophage derived foam cell differentiation;negative regulation of receptor biosynthetic process;negative regulation of cholesterol storage;negative regulation of sequestering of triglyceride;long-chain fatty acid transport;negative regulation of angiogenesis;regulation of lipid metabolic process;fatty acid oxidation;cell differentiation;monocyte differentiation;negative regulation of cell growth;epithelial cell differentiation;response to caffeine;animal organ regeneration;response to retinoic acid;cellular response to insulin stimulus;negative regulation of collagen biosynthetic process;response to vitamin A;response to lipid;peroxisome proliferator activated receptor signaling pathway;response to immobilization stress;glucose homeostasis;response to starvation;regulation of circadian rhythm;lipoprotein transport;positive regulation of DNA binding;steroid hormone mediated signaling pathway;negative regulation of blood vessel endothelial cell migration;response to estrogen;innate immune response;cell fate commitment;positive regulation of fat cell differentiation;low-density lipoprotein particle receptor biosynthetic process;negative regulation of transcription, DNA-templated;positive regulation of transcription, DNA-templated;positive regulation of transcription by RNA polymerase II;positive regulation of fatty acid oxidation;cell maturation;rhythmic process;negative regulation of smooth muscle cell proliferation;positive regulation of oligodendrocyte differentiation;white fat cell differentiation;positive regulation of DNA-binding transcription factor activity;negative regulation of telomerase activity;lipid homeostasis;positive regulation of phagocytosis, engulfment;negative regulation of interferon-gamma-mediated signaling pathway;regulation of cholesterol transporter activity;regulation of transcription involved in cell fate commitment;negative regulation of gene silencing by miRNA;pri-miRNA transcription by RNA polymerase II;cellular response to retinoic acid;cellular response to vitamin E;cellular response to prostaglandin E stimulus;cellular response to low-density lipoprotein particle stimulus;cellular response to hyperoxia;response to metformin;negative regulation of vascular smooth muscle cell proliferation;positive regulation of vascular associated smooth muscle cell apoptotic process;negative regulation of vascular endothelial cell proliferation;negative regulation of pancreatic stellate cell proliferation
• Cellular component: nucleus;nucleoplasm;cytosol;protein-containing complex;intracellular membrane-bounded organelle;perinuclear region of cytoplasm;RNA polymerase II transcription factor complex
• Molecular function: transcription regulatory region sequence-specific DNA binding;RNA polymerase II regulatory region sequence-specific DNA binding;DNA-binding transcription factor activity, RNA polymerase II-specific;RNA polymerase II repressing transcription factor binding;DNA-binding transcription repressor activity, RNA polymerase II-specific;DNA binding;chromatin binding;double-stranded DNA binding;DNA-binding transcription factor activity;steroid hormone receptor activity;nuclear receptor activity;prostaglandin receptor activity;fatty acid binding;protein binding;protein C-terminus binding;transcription factor binding;drug binding;zinc ion binding;lipid binding;enzyme binding;protein phosphatase binding;estrogen receptor binding;nuclear receptor transcription coactivator activity;activating transcription factor binding;signaling receptor activity;peptide binding;identical protein binding;sequence-specific DNA binding;protein self-association;transcription regulatory region DNA binding;retinoid X receptor binding;protein heterodimerization activity;arachidonic acid binding;DBD domain binding;LBD domain binding;alpha-actinin binding;E-box binding