GNAS

Summary

GNAS (GNAS complex locus, HGNC:4392) is a protein-coding gene on chromosome 20q13.32, encoding Neuroendocrine secretory protein 55 (O95467). In precision oncology, GNAS c.393T>C is associated with resistance to Gefitinib + Erlotinib in Lung Non-small Cell Carcinoma (CIViC Level B); 4 further curated variant–drug associations are listed below. It is haploinsufficient (ClinGen: sufficient evidence).

This locus has a highly complex imprinted expression pattern. It gives rise to maternally, paternally, and biallelically expressed transcripts that are derived from four alternative promoters and 5’ exons. Some transcripts contain a differentially methylated region (DMR) at their 5’ exons, and this DMR is commonly found in imprinted genes and correlates with transcript expression. An antisense transcript is produced from an overlapping locus on the opposite strand. One of the transcripts produced from this locus, and the antisense transcript, are paternally expressed noncoding RNAs, and may regulate imprinting in this region. In addition, one of the transcripts contains a second overlapping ORF, which encodes a structurally unrelated protein - Alex. Alternative splicing of downstream exons is also observed, which results in different forms of the stimulatory G-protein alpha subunit, a key element of the classical signal transduction pathway linking receptor-ligand interactions with the activation of adenylyl cyclase and a variety of cellular reponses. Multiple transcript variants encoding different isoforms have been found for this gene. Mutations in this gene result in pseudohypoparathyroidism type 1a, pseudohypoparathyroidism type 1b, Albright hereditary osteodystrophy, pseudopseudohypoparathyroidism, McCune-Albright syndrome, progressive osseus heteroplasia, polyostotic fibrous dysplasia of bone, and some pituitary tumors.

Source: NCBI Gene 2778 — RefSeq curated summary.

At a glance

• Gene–disease (curated): pseudohypoparathyroidism type 1A (Definitive, GenCC) — +6 more curated relationships
• GWAS associations: 45
• Clinical variants (ClinVar): 1,316 total — 149 pathogenic, 70 likely-pathogenic
• Phenotypes (HPO): 216
• Precision-oncology evidence (CIViC): 5 curated variant–drug associations
• Cancer driver (intOGen): activating (oncogene-like) across 8 cancer types
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_000516

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4392
Approved symbol	GNAS
Name	GNAS complex locus
Location	20q13.32
Locus type	gene with protein product
Status	Approved
Aliases	NESP55, NESP, GNASXL, GPSA, SCG6, SgVI
Ensembl gene	ENSG00000087460
Ensembl biotype	protein_coding
OMIM	139320
Entrez	2778

Gene structure

Transcript identifiers

Ensembl transcripts: 77 — 49 protein_coding, 22 retained_intron, 4 nonsense_mediated_decay, 2 protein_coding_CDS_not_defined

ENST00000265620, ENST00000306090, ENST00000306120, ENST00000313949, ENST00000338783, ENST00000349036, ENST00000354359, ENST00000371075, ENST00000371081, ENST00000371085, ENST00000371095, ENST00000371098, ENST00000371099, ENST00000371100, ENST00000371102, ENST00000419558, ENST00000423897, ENST00000453292, ENST00000461152, ENST00000462499, ENST00000464624, ENST00000464788, ENST00000464960, ENST00000467227, ENST00000467321, ENST00000468895, ENST00000469431, ENST00000470512, ENST00000472183, ENST00000475610, ENST00000476196, ENST00000476935, ENST00000477931, ENST00000478585, ENST00000479025, ENST00000480232, ENST00000480975, ENST00000481039, ENST00000481768, ENST00000482112, ENST00000483387, ENST00000484504, ENST00000485673, ENST00000487862, ENST00000487981, ENST00000488546, ENST00000488652, ENST00000490374, ENST00000491348, ENST00000492907, ENST00000493744, ENST00000493958, ENST00000494081, ENST00000496934, ENST00000603546, ENST00000604005, ENST00000656419, ENST00000657090, ENST00000663479, ENST00000667293, ENST00000676826, ENST00000682092, ENST00000682134, ENST00000682411, ENST00000682590, ENST00000682680, ENST00000682803, ENST00000682829, ENST00000682917, ENST00000682986, ENST00000683015, ENST00000683632, ENST00000683932, ENST00000684284, ENST00000684466, ENST00000684644, ENST00000684761

RefSeq mRNA: 13 — MANE Select: NM_000516 NM_000516, NM_001077488, NM_001077489, NM_001077490, NM_001309840, NM_001309842, NM_001309861, NM_001309883, NM_001410912, NM_001410913, NM_016592, NM_080425, NM_080426

CCDS: CCDS13471, CCDS13472, CCDS42892, CCDS46622, CCDS46623, CCDS46624, CCDS82633, CCDS93063, CCDS93066, CCDS93068

Canonical transcript exons

ENST00000371085 — 13 exons

Exon	Start	End
ENSE00001869532	58891421	58891865
ENSE00003480754	58895612	58895684
ENSE00003500528	58909521	58909579
ENSE00003513281	58909684	58909804
ENSE00003564247	58910334	58910401
ENSE00003576231	58909951	58910081
ENSE00003586723	58898941	58898985
ENSE00003621596	58909162	58909216
ENSE00003658282	58910683	58911192
ENSE00003666581	58903672	58903791
ENSE00003690843	58903531	58903585
ENSE00003785267	58909350	58909423
ENSE00003788021	58905383	58905480

Expression profiles

Bgee: expression breadth ubiquitous, 312 present calls, max score 99.99.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 677.4314 / max 10356.3596, expressed in 1828 samples.

FANTOM5 promoters (38 alternative TSS)

Promoter ID	TPM avg	Samples expressed
185543	304.5771	1826
185542	170.7387	1827
185538	75.2905	1799
185548	28.1920	1806
185541	18.1413	1814
185546	12.4628	1772
185551	12.2570	1766
185537	10.8641	1750
185549	9.5005	1755
185547	4.6940	1660

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
type B pancreatic cell	CL:0000169	99.99	gold quality
postcentral gyrus	UBERON:0002581	99.97	gold quality
Brodmann (1909) area 46	UBERON:0006483	99.97	gold quality
pituitary gland	UBERON:0000007	99.96	gold quality
adenohypophysis	UBERON:0002196	99.96	gold quality
lateral nuclear group of thalamus	UBERON:0002736	99.96	gold quality
islet of Langerhans	UBERON:0000006	99.95	gold quality
prefrontal cortex	UBERON:0000451	99.95	gold quality
parietal lobe	UBERON:0001872	99.95	gold quality
entorhinal cortex	UBERON:0002728	99.95	gold quality
endometrium epithelium	UBERON:0004811	99.95	gold quality
Brodmann (1909) area 10	UBERON:0013541	99.95	gold quality
left lobe of thyroid gland	UBERON:0001120	99.94	gold quality
parotid gland	UBERON:0001831	99.94	gold quality
superior frontal gyrus	UBERON:0002661	99.94	gold quality
frontal pole	UBERON:0002795	99.94	gold quality
paraflocculus	UBERON:0005351	99.94	gold quality
right lobe of thyroid gland	UBERON:0001119	99.93	gold quality
thyroid gland	UBERON:0002046	99.93	gold quality
cerebellar hemisphere	UBERON:0002245	99.93	gold quality
middle temporal gyrus	UBERON:0002771	99.93	gold quality
hypothalamus	UBERON:0001898	99.92	gold quality
substantia nigra pars compacta	UBERON:0001965	99.92	gold quality
orbitofrontal cortex	UBERON:0004167	99.92	gold quality
superior vestibular nucleus	UBERON:0007227	99.92	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	99.92	gold quality
right hemisphere of cerebellum	UBERON:0014890	99.92	gold quality
pons	UBERON:0000988	99.91	gold quality
heart right ventricle	UBERON:0002080	99.91	gold quality
right frontal lobe	UBERON:0002810	99.91	gold quality

Single-cell (SCXA)

Detected in 27 experiment(s), a significant marker in 19.

Experiment	Marker?	Max mean expression
E-GEOD-114530	yes	3683.96
E-HCAD-10	yes	3407.86
E-GEOD-124472	yes	2910.15
E-MTAB-8205	yes	2230.97
E-HCAD-13	yes	829.00
E-MTAB-8142	yes	43.24
E-HCAD-35	yes	41.03
E-GEOD-137537	yes	31.83
E-HCAD-4	yes	29.41
E-GEOD-81547	yes	25.89
E-MTAB-9221	yes	24.58
E-CURD-46	yes	17.22
E-MTAB-7316	yes	16.82
E-HCAD-25	yes	11.74
E-CURD-114	yes	11.69

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AP1, ARID4A, ATF3, ATF5, BCL11B, BCL3, CDX2, CEBPA, CEBPB, CEBPG, CREB1, CREM, CTCF, DLX4, DLX5, DNMT1, E2F1, E2F3, E2F4, EGR1, EGR2, ENO1, EPAS1, ESR1, ESR2, ESRRA, ETS1, ETS2, FOS, FOXC1, FOXD2, FOXM1, FUBP1, GATA1, GATA4, GATA6, HAND2, HNF1A, HNF1B, HNF4A

miRNA regulators (miRDB)

41 targeting GNAS, 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-6748-5P	100.00	65.81	1057
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-218-5P	99.93	72.22	2103
HSA-MIR-205-3P	99.92	69.92	3165
HSA-MIR-338-5P	99.92	72.34	2951
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-579-3P	99.86	71.66	3628
HSA-MIR-664B-3P	99.84	71.65	3590
HSA-MIR-4799-5P	99.82	70.60	2663
HSA-MIR-636	99.80	69.58	1500
HSA-MIR-3202	99.66	67.70	2737
HSA-MIR-5003-5P	99.61	69.13	1624
HSA-MIR-2053	99.57	69.15	1635
HSA-MIR-513A-3P	99.39	70.63	3620
HSA-MIR-513C-3P	99.39	70.63	3620
HSA-MIR-155-5P	99.35	70.16	1509
HSA-MIR-7515	99.31	68.22	1795
HSA-MIR-16-2-3P	99.29	70.60	1954
HSA-MIR-195-3P	99.29	70.61	1954
HSA-MIR-3160-5P	99.28	69.07	1938
HSA-MIR-4724-5P	98.87	67.75	1324
HSA-MIR-6769B-5P	98.73	64.91	1092
HSA-MIR-1178-3P	98.57	67.09	890
HSA-MIR-4720-3P	98.50	68.88	988
HSA-MIR-6864-5P	98.38	66.59	1079
HSA-MIR-3179	98.22	65.90	1445

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• Genetic variaion of the extra-large stimulatory G protein alpha subunit leads to GS hyperfunction in platelets and is a risk factor for bleeding. (PMID:11583302)
• GTP-binding proteins G(salpha), G(ialpha), and Ran identified in mitochondria of human placenta (PMID:11779226)
• Paternally inherited inactivating GNAS1 mutations cause progessive osseous heteroplasia (POH). (PMID:11784876)
• Polymorphisms of genes encoding Gs protein alpha-subunit as risk factors for orthostatic hypotension. (PMID:11910300)
• mutational analysis of the GNAS1 gene is a strong supportive tool for the diagnosis of pseudohypoparathyroidism type 1a (PMID:11926205)
• These data provide new evidence that involves the helical domain as a regulator of Gs(alpha) function, in this case the alphaA helix, which is not directly involved with the nucleotide binding site nor the interdomain interface. (PMID:11968001)
• beta1-adrenoceptor and beta2-adrenoceptor couple to Gs-proteins to activate adenylyl cyclase (PMID:12106601)
• mutations and imprinting defects in disease -review (PMID:12119276)
• McCune-Albright syndrome is a rare disease caused by somatic postzygotic mutations at Arg201 in the GNAS1 gene that encodes for the Gsalpha protein (PMID:12199346)
• Association of GNAS1 gene variant with hypertension depending on smoking status (PMID:12215464)
• evidence for a predominant maternal origin of GNAS1 transcripts in different human adult endocrine tissues, particularly thyroid, ovary, and pituitary (PMID:12364467)
• Pseudohypoparathyroidism type Ib with disturbed imprinting in the GNAS1 cluster and Gsalpha deficiency in platelets. (PMID:12374764)
• linkage at 20q13.3 in pseudohypoparathyroidism type 1b (PMID:12619926)
• wide mutation heterogeneity of pseudohypoparathyroidism and pseudohypoparathyroidism type-Ia. (PMID:12621129)
• Overlapping transcripts of this protein identify the parental origin of mutations in patients with sporadic Albright hereditary osteodystrophy. (PMID:12624854)
• gnas1 gene mutations were identified in subjects with fibrous dysplasia of bone (PMID:12756386)
• Neuroendocrine secretory protein 55 is found in a subset of neuroendocrine tumours showing differentiation towards adrenal chromaffin cells and pancreatic islets cells and not in ileal carcinoids (PMID:12771991)
• allelic expression and methylation of CpG islands within exon 1A of GNAS1 in patients with sporadic pseudohypoparathyroidism type 1b, consistent with a maternal imprinting defect (PMID:12858292)
• a significant interaction between GNAS1 polymorphism and drinking status in the association with pulse pressure, reflected by a significant association between the T393C polymorphism and pulse pressure in moderate to heavy drinkers (PMID:12862199)
• patients with pseudohypoparathyroidism Ia display variable degrees of growth hormone-releasing hormone resistance, consistent with Gs alpha imprinting in human pituitary (PMID:12970263)
• the stimulatory G protein alpha-subunit Gs alpha is imprinted in human thyroid glands which has: implications for thyroid function in pseudohypoparathyroidism types 1A and 1B (PMID:12970307)
• molecular analysis revealed that foci of malignancy and adjacent areas of hyperplasia and some areas of normal thyroid harbored activating mutations of Arg(201) in the GNAS1 gene (PMID:12970318)
• GNAS1 mutated stromal cells produce IL-6 at a basal magnitude and rate that are significantly higher than in the cognate wild-type cells (PMID:13678786)
• findings show that signaling via the erythrocyte beta2-adrenergic receptor and heterotrimeric guanine nucleotide-binding protein (Galphas) regulated the entry of the human malaria parasite Plasmodium falciparum (PMID:14500986)
• Transgenic mice expressing an active form of Gs alpha exhibit selective deficits in prepulse inhibition (PPI) without exhibiting alterations in the startle response. (PMID:14694347)
• Disturbances of post-receptor trans-membrane signalling in Alzheimer’s disease can be attributed to functional changes of G(salpha), independent of alterations in levels in normal aging. (PMID:14991457)
• Iloprost stimulation (1 microM, 2 h) of IP prostanoid receptor expressed in HEK293 cells resulted in specific decrease of endogenous G(s)alpha protein in detergent-insensitive, caveolin-enriched, membrane domains (PMID:15053924)
• Cluster analysis in subjects with the same genotypes did not generally show a genotype/phenotype correlation. (PMID:15070926)
• Missense point mutations in the GNAS1 gene, located on the long arm of chromosome 20 and encoding for the alpha subunited of G(s)(the G protein that stimulated cyclic AMP) of transmembrane glycoprotein receptors, have been identified. (PMID:15112914)
• Mutation in 33% of the 39 cases of isolated peripheral precocious puberty. (PMID:15126527)
• Data report that the XL exon of Gsalpha is longer than presumed an additional 139 codons to XLalphas. (PMID:15148396)
• isolated hyperfunctioning thyroid and adrenal adenomas displayed the mutation on the maternal and paternal alleles, respectively (PMID:15181091)
• G alpha S has a role in thyroid-stimulating hormone receptor activation of cAMP production and inositol 1,4,5-trisphosphate turnover (PMID:15234971)
• Expression of sensitization of adenyl cyclase 1 involves Galpha(s)-adenylyl cyclase interactions. (PMID:15361543)
• Structure analysis showed that disruption of the salt bridge between R165 and E168 by the introduced mutations in Galpha subunits, caused important structural changes in the helical domain at the alphaD-alphaE loop (residues 160-175) (PMID:15368366)
• suggested that the GNAS1 T393C polymorphism is associated with ANS activity in youth and may be useful as a genetic marker for hypertension (PMID:15479166)
• Familial and sporadic forms of Pseudohypoparathyroidism type IB have distinct GNAS imprinting patterns that occur through different defects in the imprinting mechanism. (PMID:15537666)
• GNAS T393C (rs7121) localizes to a recombination hotspot not in linkage disequilibrium with the rest of GNAS gene locus (PMID:15564881)
• GSPalpha mutations have a role in progression of acromegaly in Mexican patients (PMID:15701569)
• Pseudohypoparathyroidism is caused by heterozygous inactivating mutations in exons of GNAS encoding alpha subunit of Gsalpha. Autosomal dominant form caused by heterozygous mutations disrupting long-range imprinting control element of GNAS. (Review) (PMID:15711092)

Cross-species orthologs

21 orthologs

Organism	Symbol	Gene ID
danio_rerio	gnas	ENSDARG00000043094
mus_musculus	Gnas	ENSMUSG00000027523
rattus_norvegicus	Gnas	ENSRNOG00000047374
drosophila_melanogaster	cta	FBGN0000384
drosophila_melanogaster	Galphai	FBGN0001104
drosophila_melanogaster	Galphaf	FBGN0010223
drosophila_melanogaster	CG17760	FBGN0033756
drosophila_melanogaster	CG30054	FBGN0050054
caenorhabditis_elegans		WBGENE00001664
caenorhabditis_elegans		WBGENE00001665
caenorhabditis_elegans		WBGENE00001666
caenorhabditis_elegans		WBGENE00001667
caenorhabditis_elegans		WBGENE00001668
caenorhabditis_elegans		WBGENE00001670
caenorhabditis_elegans		WBGENE00001671
caenorhabditis_elegans		WBGENE00001673
caenorhabditis_elegans		WBGENE00001674
caenorhabditis_elegans		WBGENE00001675
caenorhabditis_elegans	gpa-14	WBGENE00001676
caenorhabditis_elegans	gpa-16	WBGENE00001678
caenorhabditis_elegans	gsa-1	WBGENE00001745

Paralogs (15): GNA15 (ENSG00000060558), GNAI3 (ENSG00000065135), GNAO1 (ENSG00000087258), GNA11 (ENSG00000088256), GNAT1 (ENSG00000114349), GNAI2 (ENSG00000114353), GNA13 (ENSG00000120063), GNAI1 (ENSG00000127955), GNAZ (ENSG00000128266), GNAT2 (ENSG00000134183), GNAL (ENSG00000141404), GNA12 (ENSG00000146535), GNA14 (ENSG00000156049), GNAQ (ENSG00000156052), GNAT3 (ENSG00000214415)

Protein

Protein identifiers

Neuroendocrine secretory protein 55 — O95467 (reviewed: O95467, P63092, P84996, Q5JWF2)

All UniProt accessions (27): O95467, P63092, Q5JWF2, A0A0A0MR13, A0A0S2Z3H8, A0A0S2Z3S5, A0A590UJ46, A0A590UJ47, A0A590UJC9, A0A590UJF0, A0A590UJQ9, A0A590UJS2, A0A590UJX3, A0A590UJX6, A0A590UJY2, A0A590UK00, A0A590UK28, A0A7I2V5R6, A0A804HIH4, A0A8I5F5B5, A2A2R6, A2A2S1, B0AZR9, H0Y7E8, H0Y7Z6, Q5JWD1, Q5JWE9

UniProt curated annotations — full annotation on UniProt →

Subcellular location. Cytoplasmic vesicle. Secretory vesicle. Secreted.

Post-translational modifications. Binds keratan sulfate chains. May be proteolytically processed to give rise to a number of active peptides.

Disease relevance. 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. The disease is caused by variants affecting the gene represented in this entry. 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. The disease is caused by variants 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. Genetic variation affecting the GNAS locus is associated with GNAS hyperfunction, a condition characterized by increased trauma-related bleeding tendency, prolonged bleeding time, brachydactyly and intellectual disability. 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.

Miscellaneous. This protein is produced by a bicistronic gene which also produces the ALEX protein from an overlapping reading frame. The GNAS locus is imprinted in a complex manner, giving rise to distinct paternally, maternally and biallelically expressed proteins. The XLas isoforms are paternally derived, the Gnas isoforms are biallelically derived and the Nesp55 isoforms are maternally derived. Shares no sequence similarity with other isoforms due to a novel first exon containing the entire reading frame spliced to shared exon 2 so that exons 2-13 make up the 3’-UTR.

Similarity. Belongs to the NESP55 family.

Isoforms (8)

UniProt ID	Names	Canonical?
O95467-1	Nesp55	yes
Q5JWF2-1	XLas-1
Q5JWF2-2	XLas-2
Q5JWF2-3	XLas-3
P63092-1	Gnas-1, Alpha-S2, GNASl, Alpha-S-long
P63092-2	Gnas-2, Alpha-S1, GNASs, Alpha-S-short
P63092-3	3
P63092-4	4

RefSeq proteins (13): NP_000507, NP_001070956, NP_001070957, NP_001070958, NP_001296769, NP_001296771, NP_001296790, NP_001296812, NP_001397841, NP_001397842, NP_057676, NP_536350, NP_536351 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR009434	NESP55	Family
IPR000367	Gprotein_alpha_S	Family
IPR001019	Gprotein_alpha_su	Family
IPR011025	GproteinA_insert	Homologous_superfamily
IPR027417	P-loop_NTPase	Homologous_superfamily

Pfam: PF00503, PF06390

Catalyzed reactions (Rhea), 1 shown:

• GTP + H2O = GDP + phosphate + H(+) (RHEA:19669)

UniProt features (201 total): sequence variant 38, helix 31, strand 24, region of interest 22, compositionally biased region 21, sequence conflict 15, binding site 14, splice variant 8, turn 5, chain 4, modified residue 4, mutagenesis site 4, peptide 2, domain 2, lipid moiety-binding region 2, coiled-coil region 2, signal peptide 1, initiator methionine 1, cross-link 1

Structure

Experimental structures (PDB)

490 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
7BPH	X-RAY DIFFRACTION	1.57
6AU6	X-RAY DIFFRACTION	1.7
8F0K	ELECTRON MICROSCOPY	1.9
7E5E	X-RAY DIFFRACTION	1.95
7MBX	ELECTRON MICROSCOPY	1.95
8F0J	ELECTRON MICROSCOPY	2
8F2B	ELECTRON MICROSCOPY	2
9XXT	ELECTRON MICROSCOPY	2
6X18	ELECTRON MICROSCOPY	2.1
6X19	ELECTRON MICROSCOPY	2.1
7RTB	ELECTRON MICROSCOPY	2.14
7TYF	ELECTRON MICROSCOPY	2.2
8F2A	ELECTRON MICROSCOPY	2.2
9BP3	ELECTRON MICROSCOPY	2.2
9MZE	ELECTRON MICROSCOPY	2.2
9N05	ELECTRON MICROSCOPY	2.2
6UVA	ELECTRON MICROSCOPY	2.3
6WZG	ELECTRON MICROSCOPY	2.3
8E3X	ELECTRON MICROSCOPY	2.3
8E3Y	ELECTRON MICROSCOPY	2.3
9BUB	ELECTRON MICROSCOPY	2.3
9N04	ELECTRON MICROSCOPY	2.3
9N0E	ELECTRON MICROSCOPY	2.3
9BYO	ELECTRON MICROSCOPY	2.31
7WCM	ELECTRON MICROSCOPY	2.33
8ZVZ	ELECTRON MICROSCOPY	2.35
6UUS	ELECTRON MICROSCOPY	2.4
7TZF	ELECTRON MICROSCOPY	2.4
7UTZ	ELECTRON MICROSCOPY	2.4
7XKD	ELECTRON MICROSCOPY	2.4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O95467-F1	59.47	0.04
AF-P63092-F1	91.76	0.79
AF-P84996-F1	43.60	0.00
AF-Q5JWF2-F1	58.58	0.30

Antibody-complex structures (SAbDab): 355 — 5UZ7, 5VAI, 6B3J, 6E3Y, 6GDG, 6LI3, 6LMK, 6LPB, 6M1H, 6M1I, 6NI3, 6NIY, 6P9X, 6P9Y, 6PB0, 6PB1, 6UUN, 6UUS, 6UVA, 6VCB, 6VN7, 6WHC, 6WI9, 6WPW, 6WZG (+330 more)

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

P63092

Ligand- & substrate-binding residues (7): 47–55; 54; 197–204; 204; 223–227; 292–295; 366

Post-translational modifications (5): 201, 352, 2, 3, 300

Mutagenesis-validated functional residues (4):

Position	Phenotype
170	increases gdp release but does not affect receptor-mediated activation.
227	increases binding to gas2l2; when associated with n-295.
258	increases gdp release and impairs receptor-mediated activation; markedly elevated intrinsic gtpase rate which will lead
295	increases binding to gas2l2; when associated with l-227.

Q5JWF2

Ligand- & substrate-binding residues (7): 690–698; 697; 840–847; 847; 866–870; 935–938; 1009

Post-translational modifications (2): 844, 995

Function

Pathways and Gene Ontology

Reactome pathways

13 pathways

ID	Pathway
R-HSA-163359	Glucagon signaling in metabolic regulation
R-HSA-164378	PKA activation in glucagon signalling
R-HSA-381676	Glucagon-like Peptide-1 (GLP1) regulates insulin secretion
R-HSA-392851	Prostacyclin signalling through prostacyclin receptor
R-HSA-418555	G alpha (s) signalling events
R-HSA-418594	G alpha (i) signalling events
R-HSA-418597	G alpha (z) signalling events
R-HSA-420092	Glucagon-type ligand receptors
R-HSA-432040	Vasopressin regulates renal water homeostasis via Aquaporins
R-HSA-5610787	Hedgehog ‘off’ state
R-HSA-9634597	GPER1 signaling
R-HSA-9660821	ADORA2B mediated anti-inflammatory cytokines production
R-HSA-9856530	High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells

MSigDB gene sets: 1013 (showing top): BIOCARTA_GCR_PATHWAY, RNGTGGGC_UNKNOWN, BEGUM_TARGETS_OF_PAX3_FOXO1_FUSION_UP, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_EPITHELIUM_DEVELOPMENT, REACTOME_GLUCAGON_TYPE_LIGAND_RECEPTORS, GOBP_REGULATION_OF_INFLAMMATORY_RESPONSE_TO_ANTIGENIC_STIMULUS, GOBP_COGNITION, LU_IL4_SIGNALING, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, GOBP_RESPONSE_TO_PROSTAGLANDIN_E, GOBP_INFLAMMATORY_RESPONSE, GOBP_CELLULAR_RESPONSE_TO_LIPID, GOBP_REGULATION_OF_DEVELOPMENTAL_GROWTH, GOBP_RESPONSE_TO_FLUID_SHEAR_STRESS

GO Biological Process (35): female pregnancy (GO:0007565), protein secretion (GO:0009306), negative regulation of multicellular organism growth (GO:0040015), response to parathyroid hormone (GO:0071107), positive regulation of cold-induced thermogenesis (GO:0120162), intracellular glucose homeostasis (GO:0001678), negative regulation of inflammatory response to antigenic stimulus (GO:0002862), renal water homeostasis (GO:0003091), G protein-coupled receptor signaling pathway (GO:0007186), adenylate cyclase-activating G protein-coupled receptor signaling pathway (GO:0007189), activation of adenylate cyclase activity (GO:0007190), adenylate cyclase-activating dopamine receptor signaling pathway (GO:0007191), adenylate cyclase-activating serotonin receptor signaling pathway (GO:0007192), sensory perception of smell (GO:0007608), regulation of skeletal muscle contraction (GO:0014819), positive regulation of insulin secretion (GO:0032024), response to prostaglandin E (GO:0034695), positive regulation of insulin secretion involved in cellular response to glucose stimulus (GO:0035774), adenylate cyclase-activating G protein-coupled bile acid receptor signaling pathway (GO:0038184), intracellular transport (GO:0046907), developmental growth (GO:0048589), cognition (GO:0050890), bone development (GO:0060348), hair follicle placode formation (GO:0060789), platelet aggregation (GO:0070527), cellular response to glucagon stimulus (GO:0071377), cellular response to prostaglandin E stimulus (GO:0071380), cellular response to acidic pH (GO:0071468), cellular response to catecholamine stimulus (GO:0071870), adenylate cyclase-activating adrenergic receptor signaling pathway (GO:0071880), vascular endothelial cell response to laminar fluid shear stress (GO:0097700), regulation of signal transduction (GO:0009966), sensory perception of chemical stimulus (GO:0007606), signal transduction (GO:0007165), regulation of insulin secretion (GO:0050796)

GO Molecular Function (17): GTPase activity (GO:0003924), G protein activity (GO:0003925), GTP binding (GO:0005525), adenylate cyclase activator activity (GO:0010856), G-protein beta/gamma-subunit complex binding (GO:0031683), D1 dopamine receptor binding (GO:0031748), metal ion binding (GO:0046872), insulin-like growth factor receptor binding (GO:0005159), beta-2 adrenergic receptor binding (GO:0031698), mu-type opioid receptor binding (GO:0031852), ionotropic glutamate receptor binding (GO:0035255), corticotropin-releasing hormone receptor 1 binding (GO:0051430), nucleotide binding (GO:0000166), protein binding (GO:0005515), adenylate cyclase regulator activity (GO:0010854), hydrolase activity (GO:0016787), guanyl nucleotide binding (GO:0019001)

GO Cellular Component (14): extracellular region (GO:0005576), nucleus (GO:0005634), cytoplasm (GO:0005737), transport vesicle (GO:0030133), perinuclear region of cytoplasm (GO:0048471), cytosol (GO:0005829), heterotrimeric G-protein complex (GO:0005834), plasma membrane (GO:0005886), membrane (GO:0016020), trans-Golgi network membrane (GO:0032588), extracellular exosome (GO:0070062), ruffle (GO:0001726), apical plasma membrane (GO:0016324), cytoplasmic vesicle (GO:0031410)

Reactome top-level categories

Rollup of top-11 pathways:

Category	Pathways
GPCR downstream signalling	3
Integration of energy metabolism	1
Glucagon signaling in metabolic regulation	1
Regulation of insulin secretion	1
Platelet homeostasis	1
Class B/2 (Secretin family receptors)	1
Aquaporin-mediated transport	1
Signaling by Hedgehog	1
G alpha (s) signalling events	1
Anti-inflammatory response favouring Leishmania parasite infection	1
Response of endothelial cells to shear stress	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
adenylate cyclase-activating G protein-coupled receptor signaling pathway	3
cytoplasm	3
intracellular anatomical structure	2
adenylate cyclase activity	2
multi-organism reproductive process	1
multi-multicellular organism process	1
protein transport	1
secretion by cell	1
establishment of protein localization to extracellular region	1
protein localization to extracellular region	1
multicellular organism growth	1
regulation of multicellular organism growth	1
negative regulation of developmental growth	1
negative regulation of multicellular organismal process	1
response to hormone	1
positive regulation of multicellular organismal process	1
cold-induced thermogenesis	1
regulation of cold-induced thermogenesis	1
glucose homeostasis	1
intracellular chemical homeostasis	1
inflammatory response to antigenic stimulus	1
regulation of inflammatory response to antigenic stimulus	1
negative regulation of inflammatory response	1
negative regulation of immune response	1
renal system process	1
multicellular organismal-level water homeostasis	1
G protein-coupled receptor activity	1
signal transduction	1
adenylate cyclase-modulating G protein-coupled receptor signaling pathway	1
adenylate cyclase activator activity	1
positive regulation of adenylate cyclase activity	1
G protein-coupled dopamine receptor signaling pathway	1
serotonin receptor signaling pathway	1
sensory perception of chemical stimulus	1
skeletal muscle contraction	1
regulation of striated muscle contraction	1
insulin secretion	1
positive regulation of protein secretion	1
regulation of insulin secretion	1

Protein interactions and networks

STRING

0 interactions, top by confidence (×1000):

IntAct

37 interactions, top by confidence:

A	B	Type	Score
GNG8	GNB5	psi-mi:“MI:0914”(association)	0.640
GNG5	GNB5	psi-mi:“MI:0914”(association)	0.620
GNB2	PFDN6	psi-mi:“MI:0914”(association)	0.530
GNG10	GNAS	psi-mi:“MI:0914”(association)	0.530
GNG2	GNB5	psi-mi:“MI:0914”(association)	0.530
GNG5	GNAS	psi-mi:“MI:0914”(association)	0.530
POP4	RPP40	psi-mi:“MI:0914”(association)	0.530
P		psi-mi:“MI:0914”(association)	0.350
CUL3	KIF21B	psi-mi:“MI:0914”(association)	0.350
GNG8	POTEF	psi-mi:“MI:0914”(association)	0.350
CERS2	VPS37C	psi-mi:“MI:0914”(association)	0.350
GNG2	FAM171A2	psi-mi:“MI:0914”(association)	0.350
OCIAD1	BTAF1	psi-mi:“MI:0914”(association)	0.350
GNAS	RANBP6	psi-mi:“MI:0914”(association)	0.350
GNG3	GNAS	psi-mi:“MI:0914”(association)	0.350
GNG4	GNAS	psi-mi:“MI:0914”(association)	0.350
GNGT1	GNAS	psi-mi:“MI:0914”(association)	0.350
RIC8B	GNAS	psi-mi:“MI:0914”(association)	0.350
RANBP6	IPO5	psi-mi:“MI:0914”(association)	0.350
CMIP	INPPL1	psi-mi:“MI:0914”(association)	0.350
OCIAD1	NME2P1	psi-mi:“MI:0914”(association)	0.350
GNAS	CPT2	psi-mi:“MI:0914”(association)	0.350
GNAS	GNG11	psi-mi:“MI:0914”(association)	0.350
GNB1	MYO9A	psi-mi:“MI:0914”(association)	0.350
GSDME	DDX39A	psi-mi:“MI:0914”(association)	0.350
OCIAD1	DCTN6	psi-mi:“MI:0914”(association)	0.350
KRAS		psi-mi:“MI:0914”(association)	0.350

BioGRID (373): GNAS (Affinity Capture-MS), GNAS (Affinity Capture-Western), AXIN1 (Affinity Capture-Western), AXIN1 (Reconstituted Complex), PANX1 (Reconstituted Complex), GNAS (Reconstituted Complex), GNAS (Reconstituted Complex), GNAS (Affinity Capture-MS), GNAS (Affinity Capture-MS), GNAS (Affinity Capture-MS), GNAL (Affinity Capture-MS), GNG4 (Affinity Capture-MS), TRO (Affinity Capture-MS), MAGED2 (Affinity Capture-MS), GNB1 (Affinity Capture-MS)

ESM2 similar proteins: A6QL29, A7XCC9, B3FWS0, F5HDE4, G4RT11, O18979, O95467, P03186, P03203, P03204, P03234, P06923, P0C765, P0C766, P0C798, P0C799, P10233, P14379, P34347, P54092, P54093, P68337, P69484, P69485, P89474, Q06428, Q196V0, Q1HVC7, Q1HVG4, Q1HVH9, Q2HR63, Q2HR64, Q3KSP9, Q3KST0, Q3KST1, Q3KSU8, Q4QFD3, Q58CN7, Q5U2Y8, Q69138

Diamond homologs: O18979, O95467, Q792G6, Q9Z0F1

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 45 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
G beta:gamma signalling through BTK	11	211.5×	1e-22
Prostacyclin signalling through prostacyclin receptor	11	200.3×	2e-22
G beta:gamma signalling through PLC beta	11	190.3×	2e-22
G beta:gamma signalling through CDC42	11	190.3×	2e-22
Presynaptic function of Kainate receptors	11	181.3×	3e-22
ADP signalling through P2Y purinoceptor 12	11	165.5×	9e-22
G-protein activation	11	158.6×	1e-21
Thromboxane signalling through TP receptor	11	158.6×	1e-21

GO biological processes:

GO term	Partners	Fold	FDR
G protein-coupled receptor signaling pathway	12	10.6×	2e-07

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: activating (oncogene-like) across 8 cancer types — BRCA, COADREAD, ESCA, HCC, LUAD, MBL, PAAD, PANCREAS.

Clinical variants and AI predictions

ClinVar

1316 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	149
Likely pathogenic	70
Uncertain significance	560
Likely benign	349
Benign	60

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1028314	NM_000516.7(GNAS):c.432+1G>T	Pathogenic
1033065	NM_000516.7(GNAS):c.1107_1108del (p.Asn371fs)	Pathogenic
1065880	NM_000516.7(GNAS):c.124C>A (p.Arg42Ser)	Pathogenic
1065881	NM_000516.7(GNAS):c.127C>G (p.Leu43Val)	Pathogenic
1065882	NM_000516.7(GNAS):c.1150C>G (p.Gln384Glu)	Pathogenic
1065883	NM_000516.7(GNAS):c.489C>G (p.Tyr163Ter)	Pathogenic
1065884	NM_000516.7(GNAS):c.507C>A (p.Tyr169Ter)	Pathogenic
1065885	NM_000516.7(GNAS):c.595C>T (p.Arg199Cys)	Pathogenic
1065886	NM_000516.7(GNAS):c.682C>T (p.Arg228Cys)	Pathogenic
1065888	NM_000516.7(GNAS):c.773G>T (p.Arg258Leu)	Pathogenic
1065890	NM_000516.7(GNAS):c.917C>T (p.Ser306Leu)	Pathogenic
1065891	NM_000516.7(GNAS):c.1025G>A (p.Arg342Gln)	Pathogenic
1065892	NM_000516.7(GNAS):c.1040G>C (p.Arg347Thr)	Pathogenic
1065894	NM_000516.7(GNAS):c.1067G>A (p.Arg356His)	Pathogenic
1065895	NM_000516.7(GNAS):c.1115T>C (p.Ile372Thr)	Pathogenic
1071844	NM_000516.7(GNAS):c.139+1G>A	Pathogenic
1212	GNAS, 4.7-KB DEL	Pathogenic
1216795	NM_000516.7(GNAS):c.432+2_432+15del	Pathogenic
1216872	NM_000516.7(GNAS):c.139+2T>C	Pathogenic
1217738	NM_000516.7(GNAS):c.91C>T (p.Gln31Ter)	Pathogenic
1332852	NM_000516.7(GNAS):c.3G>T (p.Met1Ile)	Pathogenic
1338331	NM_000516.7(GNAS):c.283del (p.Ile95fs)	Pathogenic
1338608	NM_000516.7(GNAS):c.1012_1013insT (p.Lys338fs)	Pathogenic
1354053	NM_000516.7(GNAS):c.312+5G>A	Pathogenic
1354948	NM_000516.7(GNAS):c.348del (p.Val117fs)	Pathogenic
1366207	NM_000516.7(GNAS):c.928del (p.Asp310fs)	Pathogenic
1406415	NM_000516.7(GNAS):c.21dup (p.Lys8Ter)	Pathogenic
1441448	NM_000516.7(GNAS):c.1068dup (p.His357fs)	Pathogenic
1452493	NM_000516.7(GNAS):c.157A>G (p.Lys53Glu)	Pathogenic
1455100	NM_000516.7(GNAS):c.432+2T>G	Pathogenic

SpliceAI

1279 predictions. Top by Δscore:

Variant	Effect	Δscore
20:58891861:GCTGG:G	donor_gain	1.0000
20:58891864:GG:G	donor_gain	1.0000
20:58891865:GG:G	donor_gain	1.0000
20:58895683:GA:G	donor_gain	1.0000
20:58895685:G:GG	donor_gain	1.0000
20:58903518:A:AG	acceptor_gain	1.0000
20:58903519:A:G	acceptor_gain	1.0000
20:58903586:G:GG	donor_gain	1.0000
20:58903671:GACC:G	acceptor_gain	1.0000
20:58903787:CTCCC:C	donor_gain	1.0000
20:58903788:TCCC:T	donor_gain	1.0000
20:58903789:CCC:C	donor_gain	1.0000
20:58903790:CC:C	donor_gain	1.0000
20:58903791:CG:C	donor_loss	1.0000
20:58903792:G:GG	donor_gain	1.0000
20:58903792:GT:G	donor_loss	1.0000
20:58905375:A:AG	acceptor_gain	1.0000
20:58905376:C:G	acceptor_gain	1.0000
20:58905378:TTCA:T	acceptor_loss	1.0000
20:58905379:TCAG:T	acceptor_loss	1.0000
20:58905381:A:AG	acceptor_gain	1.0000
20:58905381:AG:A	acceptor_gain	1.0000
20:58905382:G:GA	acceptor_gain	1.0000
20:58905382:GG:G	acceptor_gain	1.0000
20:58905382:GGA:G	acceptor_gain	1.0000
20:58905382:GGAA:G	acceptor_gain	1.0000
20:58905382:GGAAT:G	acceptor_gain	1.0000
20:58905476:CAGTA:C	donor_gain	1.0000
20:58905478:GTA:G	donor_gain	1.0000
20:58905479:TA:T	donor_gain	1.0000

AlphaMissense

2646 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
20:58895612:G:A	G690D	1.000
20:58895612:G:T	G690V	1.000
20:58895617:G:A	G692R	1.000
20:58895617:G:C	G692R	1.000
20:58895618:G:A	G692E	1.000
20:58895626:G:A	G695S	1.000
20:58895626:G:C	G695R	1.000
20:58895626:G:T	G695C	1.000
20:58895627:G:A	G695D	1.000
20:58895627:G:T	G695V	1.000
20:58895630:A:T	K696I	1.000
20:58895632:A:C	S697R	1.000
20:58895634:C:A	S697R	1.000
20:58895634:C:G	S697R	1.000
20:58895639:T:A	I699N	1.000
20:58895651:T:C	M703T	1.000
20:58895651:T:G	M703R	1.000
20:58895660:T:C	L706P	1.000
20:58903569:T:C	L742P	1.000
20:58903577:G:C	A745P	1.000
20:58905408:T:C	L796P	1.000
20:58905410:T:A	W797R	1.000
20:58905410:T:C	W797R	1.000
20:58905462:T:C	L814P	1.000
20:58909164:T:C	F821S	1.000
20:58909167:T:C	L822P	1.000
20:58909354:T:C	L840P	1.000
20:58909357:T:C	L841P	1.000
20:58909360:G:C	R842P	1.000
20:58909362:T:C	C843R	1.000

dbSNP variants (sampled 300 via entrez): RS1000027145 (20:58908489 A>G), RS1000059573 (20:58872008 G>A), RS1000111099 (20:58850573 T>C), RS1000121475 (20:58908825 AAAAAT>A), RS1000139961 (20:58875293 C>T), RS1000232981 (20:58846628 C>T), RS1000265420 (20:58846374 T>C), RS1000271340 (20:58903012 A>G), RS1000299927 (20:58898002 C>G), RS1000332076 (20:58898223 A>G), RS1000358866 (20:58845090 C>T), RS1000396278 (20:58891362 C>G,T), RS1000438228 (20:58865653 T>C), RS1000451515 (20:58870123 A>G,T), RS1000493323 (20:58852622 G>A)

Disease associations

OMIM: gene MIM:139320 | disease phenotypes: MIM:174800, MIM:612463, MIM:103580, MIM:166350, MIM:603233, MIM:612462, MIM:219080, MIM:617686, MIM:182601, MIM:126800, MIM:102200

GenCC curated gene-disease

Disease	Classification	Inheritance
pseudohypoparathyroidism type 1A	Definitive	Autosomal dominant
progressive osseous heteroplasia	Definitive	Autosomal dominant
McCune-Albright syndrome	Definitive	Autosomal dominant
pseudohypoparathyroidism type 1B	Definitive	Autosomal dominant
pseudopseudohypoparathyroidism	Strong	Autosomal dominant
pseudohypoparathyroidism type 1C	Strong	Autosomal dominant
disorder of GNAS inactivation	Strong	Autosomal dominant

Mondo (19): McCune-Albright syndrome (MONDO:0018919), pseudohypoparathyroidism (MONDO:0019992), pseudopseudohypoparathyroidism (MONDO:0012912), pseudohypoparathyroidism type 1A (MONDO:0007078), progressive osseous heteroplasia (MONDO:0008153), pseudohypoparathyroidism type 1B (MONDO:0011301), pseudohypoparathyroidism type 1C (MONDO:0012911), ACTH-independent macronodular adrenal hyperplasia 1 (MONDO:0020735), pituitary adenoma 3, multiple types (MONDO:0054665), Cushing syndrome (MONDO:0018912), hereditary spastic paraplegia 4 (MONDO:0008438), sex cord-stromal tumor (MONDO:0006055), Duane retraction syndrome (MONDO:0007473), disorder of GNAS inactivation (MONDO:0800466), obesity disorder (MONDO:0011122)

Orphanet (18): McCune-Albright syndrome (Orphanet:562), Pseudohypoparathyroidism type 1A (Orphanet:79443), Pseudohypoparathyroidism (Orphanet:97593), Pseudopseudohypoparathyroidism (Orphanet:79445), Progressive osseous heteroplasia (Orphanet:2762), Pseudohypoparathyroidism type 1C (Orphanet:79444), Pseudohypoparathyroidism type 1B (Orphanet:94089), Cushing syndrome due to bilateral macronodular adrenocortical disease (Orphanet:189427), Autosomal dominant spastic paraplegia type 4 (Orphanet:100985), Duane retraction syndrome (Orphanet:233), Obesity due to melanocortin 4 receptor deficiency (Orphanet:71529), Primary bone dysplasia (Orphanet:364526), Familial isolated pituitary adenoma (Orphanet:314777), Acromegaly (Orphanet:963), Albright hereditary osteodystrophy (Orphanet:665)

HPO phenotypes

216 total (30 of 216 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000035	Abnormal testis morphology
HP:0000053	Macroorchidism
HP:0000117	Renal phosphate wasting
HP:0000124	Renal tubular dysfunction
HP:0000135	Hypogonadism
HP:0000138	Ovarian cyst
HP:0000144	Decreased fertility
HP:0000271	Abnormality of the face
HP:0000293	Full cheeks
HP:0000311	Round face
HP:0000324	Facial asymmetry
HP:0000365	Hearing impairment
HP:0000407	Sensorineural hearing impairment
HP:0000470	Short neck
HP:0000486	Strabismus
HP:0000509	Conjunctivitis
HP:0000518	Cataract
HP:0000572	Visual loss
HP:0000585	Band keratopathy
HP:0000618	Blindness
HP:0000639	Nystagmus
HP:0000684	Delayed eruption of teeth
HP:0000689	Dental malocclusion
HP:0000709	Psychosis
HP:0000712	Emotional lability
HP:0000713	Agitation
HP:0000716	Depression
HP:0000725	Psychotic episodes
HP:0000737	Irritability

GWAS associations

45 associations (top):

Study	Trait	p-value
GCST000857_2	Event-related brain oscillations	6.000000e-06
GCST001227_14	Systolic blood pressure	4.000000e-23
GCST001228_16	Diastolic blood pressure	6.000000e-23
GCST001235_12	Blood pressure	2.000000e-06
GCST001236_15	Blood pressure	2.000000e-12
GCST001238_10	Hypertension	4.000000e-14
GCST001610_6	Renal function-related traits (BUN)	9.000000e-09
GCST002058_11	DNA methylation (variation)	5.000000e-09
GCST002067_1	Response to diuretic therapy in hypertension	6.000000e-08
GCST003264_157	Post bronchodilator FEV1/FVC ratio	2.000000e-06
GCST003264_836	Post bronchodilator FEV1/FVC ratio	9.000000e-07
GCST003336_9	Waist circumference adjusted for body mass index	4.000000e-08
GCST004616_153	Platelet distribution width	5.000000e-54
GCST004776_27	Systolic blood pressure	4.000000e-13
GCST004777_58	Diastolic blood pressure	2.000000e-15
GCST004781_11	Sulfasalazine-induced agranulocytosis	2.000000e-07
GCST005978_18	Diastolic blood pressure	6.000000e-09
GCST006010_30	Mean arterial pressure	4.000000e-08
GCST006187_45	Diastolic blood pressure (cigarette smoking interaction)	7.000000e-37
GCST006188_15	Systolic blood pressure (cigarette smoking interaction)	3.000000e-22
GCST006258_57	Diastolic blood pressure	5.000000e-24
GCST006259_17	Systolic blood pressure	3.000000e-22
GCST007552_3	Colorectal cancer	2.000000e-08
GCST007704_122	Diastolic blood pressure	9.000000e-06
GCST007876_127	Estimated glomerular filtration rate	4.000000e-08
GCST007916_12	Hyperuricemia	2.000000e-16
GCST007917_15	Estimated glomerular filtration rate	2.000000e-16
GCST007918_25	Serum uric acid levels	2.000000e-16
GCST007919_4	Creatinine levels	2.000000e-16
GCST008058_296	Estimated glomerular filtration rate	2.000000e-11

EFO canonical traits (18, from GWAS)

EFO ID	Trait name
EFO:0004358	event-related brain oscillation
EFO:0006335	systolic blood pressure
EFO:0006336	diastolic blood pressure
EFO:0005763	pulse pressure measurement
EFO:0006340	mean arterial pressure
EFO:0022599	DNA methylation
EFO:0004713	FEV/FVC ratio
EFO:0007789	BMI-adjusted waist circumference
EFO:0007984	platelet component distribution width
EFO:0006527	smoking status measurement
EFO:0009104	hyperuricemia
EFO:0004761	uric acid measurement
EFO:0004344	birth weight
EFO:0004531	urate measurement
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0009819	comparative body size at age 10, self-reported
EFO:0008039	BMI-adjusted hip circumference
EFO:0004980	appendicular lean mass

MeSH disease descriptors (9)

Descriptor	Name	Tree numbers
D059327	Brachydactyly	C05.660.585.262; C16.131.621.585.262
D003480	Cushing Syndrome	C19.053.800.367
D004370	Duane Retraction Syndrome	C10.292.562.700.375.500; C11.270.235; C11.590.436.400.500; C16.320.290.235
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D011547	Pseudohypoparathyroidism	C05.116.198.709; C16.320.565.618.815; C18.452.104.709; C18.452.174.766; C18.452.648.618.815
D011556	Pseudopseudohypoparathyroidism	C05.116.198.709.628; C16.320.565.618.815.815; C18.452.104.709.628; C18.452.174.766.815; C18.452.648.618.815.815
C562735	Osseous Heteroplasia, Progressive (supp.)
C548076	Pseudohypoparathyroidism Type 1C (supp.)
C536865	Spastic paraplegia 4, autosomal dominant (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

Clinical evidence (CIViC)

Drug × variant × indication: 5 predictive associations from 5 curated evidence items; also 8 prognostic.

Variant	Therapy	Indication	Effect	Level	CIViC
GNAS c.393T>C	Gefitinib + Erlotinib	Lung Non-small Cell Carcinoma	Resistance	CIViC B	EID1995
GNAS c.393T>C	Cisplatin + Fluorouracil	Esophageal Cancer	Resistance	CIViC B	EID2895
GNAS R201H	Radioactive Iodine	Follicular Thyroid Carcinoma	Sensitivity/Response	CIViC C	EID3045
GNAS R201H	Trametinib	Appendix Cancer	Sensitivity/Response	CIViC C	EID8676
BRAF V600E AND GNAS R201C	Vemurafenib + Irinotecan + Cetuximab	Colorectal Cancer	Resistance	CIViC C	EID1906

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

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs62205366	Efficacy	3	dobutamine

PharmGKB variants

2 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs7121	GNAS		0.00	0
rs62205366	GNAS	3	2.25	1	dobutamine

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	increases expression, affects expression, affects cotreatment, decreases methylation	6
Valproic Acid	affects cotreatment, increases expression, affects expression	6
sodium arsenite	decreases expression, increases abundance, increases expression	4
trichostatin A	affects cotreatment, increases expression	3
bisphenol F	increases expression	2
perfluorooctanoic acid	affects cotreatment, affects expression, increases expression	2
perfluorooctane sulfonic acid	affects expression, affects cotreatment, increases expression	2
entinostat	increases expression, affects cotreatment	2
bisphenol S	increases expression	2
(+)-JQ1 compound	decreases response to substance, decreases expression	2
Panobinostat	affects cotreatment, increases expression	2
Cyclic AMP	increases abundance, increases activity, increases reaction, increases response to substance	2
Cisplatin	increases cleavage, decreases response to substance, decreases reaction, increases expression	2
Doxorubicin	decreases response to substance, increases expression, affects expression	2
Lead	affects expression, affects splicing, increases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression, affects expression	2
Tobacco Smoke Pollution	increases expression, affects expression	2
FR900359	increases phosphorylation	1
ammonium 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)-propanoate	affects cotreatment, affects expression	1
methylmercuric chloride	increases expression	1
alpha phellandrene	increases expression	1
alpha-pinene	affects cotreatment, decreases expression, increases abundance	1
propylparaben	increases expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, affects localization, decreases expression, increases expression	1
2,4,5,2’,4’,5’-hexachlorobiphenyl	increases expression	1
beta-lapachone	decreases expression, increases expression	1
arsenite	affects methylation	1
methylparaben	increases expression	1
3,3’-diindolylmethane	decreases expression, decreases reaction	1
11-nor-delta(9)-tetrahydrocannabinol-9-carboxylic acid	affects methylation, increases abundance	1

Cellosaurus cell lines

8 cell lines: 6 cancer cell line, 2 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_0626	SK-CO-1	Cancer cell line	Male
CVCL_A2GL	Nips-B2 GNAS R201H/+ clone 1	Induced pluripotent stem cell	Female
CVCL_A2GM	Nips-B2 GNAS R201H/+ clone 2	Induced pluripotent stem cell	Female
CVCL_E0DV	Ubigene HeLa GNAS KO	Cancer cell line	Female
CVCL_LD67	HCT 116 GNAS (R201C/+)	Cancer cell line	Male
CVCL_LD78	SW48 GNAS (R201C/+)	Cancer cell line	Female
CVCL_YN87	UWG02CTC	Cancer cell line	Male
CVCL_YP13	PDXPC1	Cancer cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05966064	PHASE4	RECRUITING	DEnosumab for the Treatment of FIbrous Dysplasia/McCune-Albright Syndrome in Adults (DeFiD)
NCT03718403	PHASE4	RECRUITING	Effect of Theophylline in Pseudohypoparathyroidism
NCT01959711	PHASE4	COMPLETED	Randomized Clinical Trial of Posterior Retroperitoneoscopic Adrenalectomy Versus Lateral Laparoscopic Adrenalectomy
NCT01990560	PHASE4	COMPLETED	Glucocorticoid Receptor Blockade With Mifepristone in Patients With Mild Adrenal Hypercortisolism
NCT05772169	PHASE4	COMPLETED	Study to Determine the Prevalence of Hypercortisolism in Patients With Type 2 Diabetes and Treatment With Korlym® (Mifepristone) (CATALYST)
NCT06801249	PHASE4	RECRUITING	Effect of Metyrapone on Cardiovascular Risk Factors in Patients With Adrenal Incidentalomas and Cushing’s Syndrome
NCT07247162	PHASE4	NOT_YET_RECRUITING	Osilodrostat in Patients With Hypertension Caused by Hypercortisolaemia Due to Cushing’s Syndrome
NCT00076362	PHASE4	COMPLETED	Pediatric Hypothalamic Obesity
NCT00079547	PHASE4	COMPLETED	The Safety and Effectiveness of Low and High Carbohydrate Diets
NCT00115063	PHASE4	TERMINATED	LOSS- Louisiana Obese Subjects Study
NCT00134303	PHASE4	COMPLETED	Trial Comparing Metformin Versus Placebo in Non Alcoholic Steatohepatitis (NASH) Patients Receiving Bariatric Surgery for Obesity
NCT00143936	PHASE4	COMPLETED	The Safety and Efficacy of Low and High Carbohydrate Diets
NCT00143962	PHASE4	COMPLETED	Comparison of Two Approaches to Weight Loss Follow-Up Study
NCT00152360	PHASE4	COMPLETED	The Effect of Xenical on Weight and Risk Factors
NCT00176306	PHASE4	COMPLETED	Levofloxacin Pharmacokinetics (PK) in the Severely Obese
NCT00203450	PHASE4	COMPLETED	Zonegran for the Treatment of Weight Gain Associated With Psychotropic Medication Use: A Placebo-Controlled Trial
NCT00205504	PHASE4	COMPLETED	Oral Contraceptives in the Metabolic Syndrome
NCT00229229	PHASE4	TERMINATED	Comparison of 4 Diets in the Management of Overweight Patients With Vascular Disease
NCT00234988	PHASE4	COMPLETED	A Phase IV, Multi-Center, Open-Label Trial of Sibutramine in Combination With a Hypocaloric Diet in Obese and Overweight Thai Subjects.
NCT00264589	PHASE4	COMPLETED	Exercise Training and Cardiovascular Function in Obesity and in Type 2 Diabetes
NCT00288873	PHASE4	COMPLETED	Characterization of Hyperparathyroidism and Vitamin D Deficiency in Obesity
NCT00298857	PHASE4	TERMINATED	A Pharmacokinetic Study to Compare the Dosing of Valproic Acid in Subjects With Different Body Weights
NCT00315146	PHASE4	COMPLETED	Optimizing Body Composition for Function in Older Adults
NCT00319202	PHASE4	TERMINATED	Clinical Trial to Assess the Effects of Candesartan on the Carbohydrate Metabolism of Obese Subjects
NCT00327912	PHASE4	UNKNOWN	Laparoscopic Roux-en-Y Gastric Bypass Versus Laparoscopic Biliopancreatic Diversion (BPD)- Duodenal Switch for Superobesity
NCT00352287	PHASE4	COMPLETED	Study to Determine the Effects of Human Growth Hormone and Pioglitazone in Overweight, Prediabetic Adults
NCT00353054	PHASE4	COMPLETED	Effect of Calcium/Vitamin D Supplementation on Body Weight and Fat Loss.
NCT00390637	PHASE4	COMPLETED	Diet, Obesity and Genes (DiOGenes)
NCT00415688	PHASE4	COMPLETED	Lifestyle Modification for Obesity-Related Type 2 Diabetes
NCT00433641	PHASE4	COMPLETED	Weight Loss in Response to Sibutramine (MERIDIA) is Influenced by the Inherited Genes
NCT00440375	PHASE4	COMPLETED	Effects of Rosiglitazone on Bone in Postmenopausal Diabetic Women
NCT00453557	PHASE4	COMPLETED	Mechanism of Growth Hormone Effects on Adipose Tissue
NCT00456885	PHASE4	COMPLETED	The Effect of Exenatide on Weight and Hunger in Obese, Healthy Women
NCT00463112	PHASE4	COMPLETED	Effect of Diet Plus Sibutramine on Hormonal and Metabolic Features in Overweight and Obese Women With PCOS
NCT00512187	PHASE4	COMPLETED	Moderate Weight Loss Makes Obese Patients With Severe Chronic Plaque Psoriasis Responsive to Sub-Optimal Dose of Cyclosporine: an Investigator Blinded, Controlled, Randomized Clinical Trial
NCT00516919	PHASE4	COMPLETED	Study of Behavioral Weight Loss Therapy for Obesity and Binge Eating in Monolingual Hispanic Persons
NCT00522470	PHASE4	COMPLETED	Effects of Rosiglitazone on Serum Ghrelin and Peptide YY Levels
NCT00537810	PHASE4	COMPLETED	Treatment of Binge Eating in Obese Patients in Primary Care
NCT00538486	PHASE4	COMPLETED	A Randomized, Double-Blind, Active Control Trial Comparing Effects of Telmisartan, Candesartan and Amlodipine, Alone or Plus Metformin, on Non-Diabetic, Obese Hypertensive Patients
NCT00584389	PHASE4	TERMINATED	The Effect of Rimonabant on Energy Expenditure, Fat Metabolism and Body Composition