GNAS

GNAS complex locus, the group of Granins|G protein subunits alpha, group s

Basic information

Region (hg38): 20:58839717-58911192

Previous symbols: [ "GNAS1" ]

Links

ENSG00000087460 ∙ NCBI:2778 ∙ OMIM:139320 ∙ HGNC:4392 ∙ Uniprot:O95467, P63092, P84996, Q5JWF2 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• pseudohypoparathyroidism type 1B (Definitive), mode of inheritance: Autosomal dominant inheritance with paternal imprinting
• ACTH-independent macronodular adrenal hyperplasia 1 (Definitive), mode of inheritance: Somatic mosaicism
• pseudohypoparathyroidism type 1A (Definitive), mode of inheritance: AD
• pseudohypoparathyroidism type 1A (Strong), mode of inheritance: AD
• pseudohypoparathyroidism type 1B (Strong), mode of inheritance: AD
• pseudohypoparathyroidism type 1C (Strong), mode of inheritance: AD
• McCune-Albright syndrome (Strong), mode of inheritance: Unknown
• progressive osseous heteroplasia (No Known Disease Relationship), mode of inheritance: AD
• pseudohypoparathyroidism type 1A (Definitive), mode of inheritance: AD
• pseudopseudohypoparathyroidism (Moderate), mode of inheritance: AD
• McCune-Albright syndrome (Definitive), mode of inheritance: Somatic mosaicism
• progressive osseous heteroplasia (Supportive), mode of inheritance: AD
• pseudohypoparathyroidism type 1A (Supportive), mode of inheritance: AD
• pseudohypoparathyroidism type 1C (Supportive), mode of inheritance: AD
• pseudopseudohypoparathyroidism (Supportive), mode of inheritance: AD
• pseudohypoparathyroidism type 1B (Supportive), mode of inheritance: AD
• McCune-Albright syndrome (Definitive), mode of inheritance: AD
• pseudohypoparathyroidism type 1A (Definitive), mode of inheritance: Mitochondrial
• pseudopseudohypoparathyroidism (Definitive), mode of inheritance: Mitochondrial
• pseudohypoparathyroidism type 1C (Definitive), mode of inheritance: Mitochondrial
• pseudohypoparathyroidism type 1B (Definitive), mode of inheritance: AD
• McCune-Albright syndrome (Strong), mode of inheritance: AD
• progressive osseous heteroplasia (Strong), mode of inheritance: AD
• pseudohypoparathyroidism type 1A (Strong), mode of inheritance: AD
• pseudopseudohypoparathyroidism (Strong), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Pseudohypoparathyroidism, type IA; Pseudohypoparathyroidism, type IB; Pseudohypoparathyroidism, type IC; Progressive osseous heteroplasia; McCune-Albright syndrome	AD	Endocrine; Oncologic; Renal	In Pseudohypoparathyroidism, medical treatment (eg, with calcium and vitamin D therapy) of electrolyte abnormalities and related complications such as osteitis fibrosa cystica can be effective, and complications; Surveillance and early treatment of endocrinological manifestations (eg, hypothyroidism, hypogonadism) can be beneficial; In McCune-Albright syndrome, medical (eg, related to estrogen production, hyperthyroidism, growth hormone production) and surgical (eg, to treat adrenal pathology, hyperthyroidism) treatment of endocrinopathies may be beneficial, and surveillance and early and specific treatment for manifestations such as a number of types of neoplasms, including GH-producing tumors (eg, with long-acting octreotide, GHR antagonists) can be beneficial, as well as surveillance for and treatment of Cushing syndrome (some patients require adrenalectomy)	Dermatologic; Endocrine; Musculoskeletal; Oncologic; Renal	13005676; 5906056; 1083395; 198661; 219790; 431133; 6265935; 3126297; 2829196; 2273209; 2109828; 3093862; 2122458; 1955519; 1944469; 1400888; 1621772; 1424186; 1594625; 1346061; 8421479; 7980957; 8126048; 8126161; 7739708; 7671486; 9226216; 9506752; 0614538; 10356155; 10190480; 11073544; 10646121; 11067869; 11095461; 10998448; 11600516; 11406605; 11297617; 11583302; 11397863; 11029463; 12414879; 12024004; 12407707; 11788646; 11784876; 14561710; 12605446; 12727968; 12858292; 14557424; 12624854; 15001590; 15126527; 15711092; 16060910; 15537666; 16984995; 17405850; 17651445; 18553568; 18416659; 18397987; 20480732; 19858129; 21816789; 21488135; 21357941; 22640971
Mosaic variants have been described; PPHP occurs with paternal inheritance

ClinVar

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

• not provided (411 variants)
• GNAS-related condition (80 variants)
• not specified (57 variants)
• 8 conditions (53 variants)
• Pseudohypoparathyroidism type I A (44 variants)
• Inborn genetic diseases (28 variants)
• Pseudopseudohypoparathyroidism (19 variants)
• Pseudohypoparathyroidism (18 variants)
• Pseudohypoparathyroidism type 1B (14 variants)
• McCune-Albright syndrome (7 variants)
• Pseudohypoparathyroidism type 1B;Pseudohypoparathyroidism type I A;Pseudohypoparathyroidism type 1C;Pseudopseudohypoparathyroidism (6 variants)
• Pseudohypoparathyroidism type 1C (6 variants)
• Progressive osseous heteroplasia (6 variants)
• Disorders of GNAS Inactivation (3 variants)
• Adrenal cortex carcinoma (2 variants)
• Neoplasm of uterine cervix (2 variants)
• Hepatocellular carcinoma (2 variants)
• Lung adenocarcinoma (2 variants)
• Pancreatic adenocarcinoma (2 variants)
• Pseudohypoparathyroidism;Pseudopseudohypoparathyroidism (2 variants)
• Neoplasm of the large intestine (2 variants)
• Sex cord-stromal tumor (2 variants)
• Pituitary adenoma 3, multiple types (2 variants)
• Pseudohypoparathyroidism type 1B;Pseudohypoparathyroidism type 1C;Pseudohypoparathyroidism type I A (2 variants)
• Cushing syndrome (2 variants)
• Gastric adenocarcinoma (2 variants)
• Neoplasm (2 variants)
• Squamous cell carcinoma of the head and neck (2 variants)
• Malignant melanoma of skin (2 variants)
• Breast neoplasm (2 variants)
• Hereditary spastic paraplegia 4 (1 variants)
• GNAS-related disorder (1 variants)
• Pseudohypoparathyroidism type 1C;Pseudopseudohypoparathyroidism;Pseudohypoparathyroidism type 1B;Pseudohypoparathyroidism type I A (1 variants)
• Pseudohypoparathyroidism;Pseudohypoparathyroidism type 1C (1 variants)
• See cases (1 variants)
• Pseudohypoparathyroidism type I A;Pseudohypoparathyroidism type 1B;Pseudopseudohypoparathyroidism;Pseudohypoparathyroidism type 1C (1 variants)
• Intellectual disability (1 variants)
• Pseudohypoparathyroidism type 1C;Pseudohypoparathyroidism type I A;Pseudohypoparathyroidism type 1B;Pseudopseudohypoparathyroidism;Progressive osseous heteroplasia (1 variants)
• Pseudohypoparathyroidism type 1B;Pseudohypoparathyroidism type I A;Progressive osseous heteroplasia;Pseudohypoparathyroidism type 1C (1 variants)
• Pseudohypoparathyroidism type 1B;Pseudohypoparathyroidism type I A;Pseudohypoparathyroidism type 1C;Progressive osseous heteroplasia;Pseudopseudohypoparathyroidism (1 variants)
• Pseudohypoparathyroidism type 1C;Pseudohypoparathyroidism type 1B;Pseudopseudohypoparathyroidism;Pseudohypoparathyroidism type I A (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the GNAS 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			20	62	11	93
missense	23	27	159	11	2	222
nonsense	22	3	2			27
start loss	3	2	1	2		8
frameshift	30	7	12			49
inframe indel	1	3	17		3	24
splice donor/acceptor (+/-2bp)	14	6				20
splice region	1	2	15	12		30
non coding			2	40	36	78
Total	93	48	213	115	52

Highest pathogenic variant AF is 0.0000131

Variants in GNAS

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

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

Position	Type	Phenotype	Significance	ClinVar
20-58839812-C-G			Benign (Nov 16, 2018)
20-58840055-A-G			Benign (Oct 16, 2018)
20-58840109-G-A			Likely pathogenic (Sep 16, 2018)
20-58840110-G-A			Uncertain significance (Mar 01, 2023)
20-58840113-C-G		Pseudohypoparathyroidism type 1C;Pseudohypoparathyroidism type 1B;Pseudohypoparathyroidism type I A • GNAS-related disorder	Conflicting classifications of pathogenicity (Apr 08, 2022)
20-58840113-C-T		Pseudohypoparathyroidism type I A	Uncertain significance (Oct 18, 2021)
20-58840116-A-G		not specified • GNAS-related disorder	Uncertain significance (Jan 08, 2024)
20-58840129-A-C		GNAS-related disorder	Uncertain significance (Dec 12, 2023)
20-58840133-G-A		GNAS-related disorder	Likely benign (Mar 09, 2021)
20-58840150-A-G		GNAS-related disorder	Uncertain significance (Mar 29, 2023)
20-58840162-A-AC		GNAS-related disorder	Uncertain significance (Dec 15, 2023)
20-58840178-A-G		GNAS-related disorder	Uncertain significance (Oct 10, 2023)
20-58840232-C-T		GNAS-related disorder	Likely benign (Jan 10, 2020)
20-58840233-C-T		GNAS-related disorder	Uncertain significance (Nov 13, 2023)
20-58840294-GCTTC-G			Uncertain significance (Dec 29, 2022)
20-58840312-A-T		GNAS-related disorder	Likely benign (Jun 22, 2022)
20-58840368-C-CA		Inborn genetic diseases	Pathogenic (Jan 14, 2016)
20-58840370-CGAG-C			Uncertain significance (Feb 14, 2022)
20-58840372-A-G		GNAS-related disorder	Likely benign (Dec 21, 2023)
20-58840392-T-G		GNAS-related disorder	Uncertain significance (Nov 01, 2023)
20-58840400-C-T		not specified	Benign/Likely benign (-)
20-58840404-T-C			Uncertain significance (Sep 22, 2022)
20-58840409-A-G		GNAS-related disorder	Likely benign (Feb 10, 2022)
20-58840410-G-C		Duane retraction syndrome	Uncertain significance (Feb 27, 2024)
20-58840415-C-T		GNAS-related disorder	Likely benign (Mar 16, 2020)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
GNAS	protein_coding	protein_coding	ENST00000371100	13	71475

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.681	0.319	124575	1	38	124614	0.000157

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	2.65	460	651	0.707	0.0000436	6674
Missense in Polyphen		42	196.77	0.21345		2112
Synonymous	-0.174	275	271	1.01	0.0000211	2131
Loss of Function	4.59	8	38.9	0.206	0.00000209	426

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000158	0.000156
Ashkenazi Jewish	0.00	0.00
East Asian	0.000224	0.000223
Finnish	0.00	0.00
European (Non-Finnish)	0.000256	0.000239
Middle Eastern	0.000224	0.000223
South Asian	0.000171	0.000131
Other	0.000166	0.000165

dbNSFP

Source: dbNSFP

• Disease: DISEASE: ACTH-independent macronodular adrenal hyperplasia 1 (AIMAH1) [MIM:219080]: A rare adrenal defect characterized by multiple, bilateral, non-pigmented, benign, adrenocortical nodules. It results in excessive production of cortisol leading to ACTH-independent Cushing syndrome. Clinical manifestations of Cushing syndrome include facial and truncal obesity, abdominal striae, muscular weakness, osteoporosis, arterial hypertension, diabetes. {ECO:0000269|PubMed:12727968}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Pseudohypoparathyroidism 1B (PHP1B) [MIM:603233]: A disorder characterized by end-organ resistance to parathyroid hormone, hypocalcemia and hyperphosphatemia. Patients affected with PHP1B lack developmental defects characteristic of Albright hereditary osteodystrophy, and typically show no other endocrine abnormalities besides resistance to PTH. {ECO:0000269|PubMed:11029463, ECO:0000269|PubMed:11067869, ECO:0000269|PubMed:11294659, ECO:0000269|PubMed:12858292, ECO:0000269|PubMed:14561710, ECO:0000269|PubMed:15592469, ECO:0000269|PubMed:15800843}. Note=The disease is caused by mutations affecting the gene represented in this entry. Most affected individuals have defects in methylation of the gene. In some cases microdeletions involving the STX16 appear to cause loss of methylation at exon A/B of GNAS, resulting in PHP1B. Paternal uniparental isodisomy have also been observed.; DISEASE: GNAS hyperfunction (GNASHYP) [MIM:139320]: This condition is characterized by increased trauma-related bleeding tendency, prolonged bleeding time, brachydactyly and mental retardation. Both the XLas isoforms and the ALEX protein are mutated which strongly reduces the interaction between them and this may allow unimpeded activation of the XLas isoforms. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Inflammatory mediator regulation of TRP channels - Homo sapiens (human);Platelet activation - Homo sapiens (human);Cortisol synthesis and secretion - Homo sapiens (human);Relaxin signaling pathway - Homo sapiens (human);Aldosterone synthesis and secretion - Homo sapiens (human);Regulation of lipolysis in adipocytes - Homo sapiens (human);Oxytocin signaling pathway - Homo sapiens (human);Serotonergic synapse - Homo sapiens (human);Dopaminergic synapse - Homo sapiens (human);Glutamatergic synapse - Homo sapiens (human);Cushing,s syndrome - Homo sapiens (human);Dilated cardiomyopathy (DCM) - Homo sapiens (human);Thyroid hormone synthesis - Homo sapiens (human);Long-term depression - Homo sapiens (human);GnRH signaling pathway - Homo sapiens (human);Bile secretion - Homo sapiens (human);Vasopressin-regulated water reabsorption - Homo sapiens (human);Gap junction - Homo sapiens (human);Gastric acid secretion - Homo sapiens (human);Circadian entrainment - Homo sapiens (human);Amoebiasis - Homo sapiens (human);Thermogenesis - Homo sapiens (human);Glucagon signaling pathway - Homo sapiens (human);Adrenergic signaling in cardiomyocytes - Homo sapiens (human);Chagas disease (American trypanosomiasis) - Homo sapiens (human);Calcium signaling pathway - Homo sapiens (human);cAMP signaling pathway - Homo sapiens (human);Estrogen signaling pathway - Homo sapiens (human);Vascular smooth muscle contraction - Homo sapiens (human);Endocrine and other factor-regulated calcium reabsorption - Homo sapiens (human);Renin secretion - Homo sapiens (human);Vibrio cholerae infection - Homo sapiens (human);Rap1 signaling pathway - Homo sapiens (human);Salivary secretion - Homo sapiens (human);Pancreatic secretion - Homo sapiens (human);Phospholipase D signaling pathway - Homo sapiens (human);Amphetamine addiction - Homo sapiens (human);Pathways in cancer - Homo sapiens (human);Morphine addiction - Homo sapiens (human);Alcoholism - Homo sapiens (human);Cocaine addiction - Homo sapiens (human);Ovarian steroidogenesis - Homo sapiens (human);Insulin secretion - Homo sapiens (human);Melanogenesis - Homo sapiens (human);Human papillomavirus infection - Homo sapiens (human);Proton Pump Inhibitor Pathway, Pharmacodynamics;Platelet Aggregation Inhibitor Pathway, Pharmacodynamics;Selective Serotonin Reuptake Inhibitor Pathway, Pharmacodynamics;Beta-agonist/Beta-blocker Pathway, Pharmacodynamics;Excitatory Neural Signalling Through 5-HTR 4 and Serotonin;Intracellular Signalling Through Adenosine Receptor A2b and Adenosine;Intracellular Signalling Through Adenosine Receptor A2a and Adenosine;Intracellular Signalling Through Prostacyclin Receptor and Prostacyclin;Corticotropin Activation of Cortisol Production;Excitatory Neural Signalling Through 5-HTR 7 and Serotonin ;Excitatory Neural Signalling Through 5-HTR 6 and Serotonin ;Vasopressin Regulation of Water Homeostasis;Intracellular Signalling Through PGD2 receptor and Prostaglandin D2;Intracellular Signalling Through LHCGR Receptor and Luteinizing Hormone/Choriogonadotropin;Intracellular Signalling Through FSH Receptor and Follicle Stimulating Hormone;Intracellular Signalling Through Histamine H2 Receptor and Histamine;Dopamine Activation of Neurological Reward System;Human Thyroid Stimulating Hormone (TSH) signaling pathway;Endothelin Pathways;Corticotropin-releasing hormone signaling pathway;Common Pathways Underlying Drug Addiction;Myometrial Relaxation and Contraction Pathways;G Protein Signaling Pathways;Calcium Regulation in the Cardiac Cell;Estrogen signaling pathway;Serotonin Receptor 4-6-7 and NR3C Signaling;Signaling by GPCR;Signal Transduction;phospholipase c-epsilon pathway;gata3 participate in activating the th2 cytokine genes expression;transcription factor creb and its extracellular signals;regulation of ck1/cdk5 by type 1 glutamate receptors;corticosteroids and cardioprotection;cystic fibrosis transmembrane conductance regulator (cftr) and beta 2 adrenergic receptor (b2ar) pathway;ion channels and their functional role in vascular endothelium;ccr3 signaling in eosinophils;activation of csk by camp-dependent protein kinase inhibits signaling through the t cell receptor;chrebp regulation by carbohydrates and camp;signaling pathway from g-protein families;how progesterone initiates the oocyte maturation;attenuation of gpcr signaling;role of -arrestins in the activation and targeting of map kinases;activation of camp-dependent protein kinase pka;Glucagon signaling in metabolic regulation;GPCR Dopamine D1like receptor;GPCR Adenosine A2A receptor;GPCR signaling-cholera toxin;GPCR signaling-pertussis toxin;Metabolism;G alpha (s) signalling events;Transport of small molecules;Glucagon-like Peptide-1 (GLP1) regulates insulin secretion;Regulation of insulin secretion;roles of arrestin dependent recruitment of src kinases in gpcr signaling;CRH;regulation of spermatogenesis by crem;Glucagon-type ligand receptors;Class B/2 (Secretin family receptors);GPCR ligand binding;GPCR signaling-G alpha s Epac and ERK;Hedgehog ,off, state;GPCR signaling-G alpha s PKA and ERK;Signaling by Hedgehog;Hemostasis;-arrestins in gpcr desensitization;Rapid glucocorticoid signaling;G alpha (i) signalling events;G alpha (z) signalling events;PKA activation in glucagon signalling;GPCR signaling-G alpha i;Vasopressin regulates renal water homeostasis via Aquaporins;Aquaporin-mediated transport;TSH;Prostacyclin signalling through prostacyclin receptor;Integration of energy metabolism;Platelet homeostasis;GPCR downstream signalling;LPA4-mediated signaling events;Plasma membrane estrogen receptor signaling;Endothelins (Consensus)

Recessive Scores

• pRec: 0.800

Intolerance Scores

• loftool: 0.00834
• rvis_EVS: -0.02
• rvis_percentile_EVS: 52.32

Haploinsufficiency Scores

• pHI: 0.484
• hipred: Y
• hipred_score: 0.704
• ghis: 0.566

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: N
• gene_indispensability_score: 0.387

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Gnas
• Phenotype: craniofacial phenotype; muscle phenotype; cellular phenotype; homeostasis/metabolism phenotype; adipose tissue phenotype (the observable morphological and physiological characteristics of mammalian fat tissue that are manifested through development and lifespan); endocrine/exocrine gland phenotype; 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); 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); growth/size/body region phenotype; hematopoietic system phenotype; 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); limbs/digits/tail phenotype; hearing/vestibular/ear 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); renal/urinary system phenotype; skeleton phenotype; immune system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); liver/biliary system phenotype; respiratory system phenotype; neoplasm

Gene ontology

• Biological process: tissue homeostasis;endochondral ossification;energy reserve metabolic process;DNA methylation;adenylate cyclase-modulating G protein-coupled receptor signaling pathway;adenylate cyclase-activating G protein-coupled receptor signaling pathway;adenylate cyclase-activating dopamine receptor signaling pathway;embryonic hindlimb morphogenesis;multicellular organism growth;post-embryonic body morphogenesis;response to drug;positive regulation of catalytic activity;skin development;positive regulation of osteoblast differentiation;positive regulation of osteoclast differentiation;developmental growth;embryonic cranial skeleton morphogenesis;cartilage development;bone development;platelet aggregation;genetic imprinting;positive regulation of cold-induced thermogenesis;regulation of parathyroid hormone secretion
• Cellular component: cytosol;heterotrimeric G-protein complex;membrane;apical plasma membrane;dendrite;extracellular exosome
• Molecular function: G protein-coupled receptor binding;GTPase activity;insulin-like growth factor receptor binding;protein binding;GTP binding;adenylate cyclase activator activity;G-protein beta/gamma-subunit complex binding;beta-2 adrenergic receptor binding;D1 dopamine receptor binding;mu-type opioid receptor binding;ionotropic glutamate receptor binding;metal ion binding;corticotropin-releasing hormone receptor 1 binding