GPHA2

Summary

GPHA2 (glycoprotein hormone subunit alpha 2, HGNC:18054) is a protein-coding gene on chromosome 11q13.1, encoding Glycoprotein hormone alpha-2 (Q96T91). Functions as a heterodimeric glycoprotein hormone with GPHB5 able to bind and activate the thyroid-stimulating hormone receptor (TSHR), leading to increased cAMP production.

GPHA2 is a cystine knot-forming polypeptide and a subunit of the dimeric glycoprotein hormone family (Hsu et al., 2002 [PubMed 12089349]).

Source: NCBI Gene 170589 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 23 total
• MANE Select transcript: NM_130769

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:18054
Approved symbol	GPHA2
Name	glycoprotein hormone subunit alpha 2
Location	11q13.1
Locus type	gene with protein product
Status	Approved
Aliases	GPA2, ZSIG51, A2, MGC126572
Ensembl gene	ENSG00000149735
Ensembl biotype	protein_coding
OMIM	609651
Entrez	170589

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 3 protein_coding

ENST00000279168, ENST00000532246, ENST00000533257

RefSeq mRNA: 1 — MANE Select: NM_130769 NM_130769

CCDS: CCDS8086

Canonical transcript exons

ENST00000279168 — 4 exons

Exon	Start	End
ENSE00000992191	64935358	64935460
ENSE00000992192	64934991	64935175
ENSE00001063425	64935834	64935893
ENSE00001334540	64934471	64934874

Expression profiles

Bgee: expression breadth ubiquitous, 136 present calls, max score 93.91.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.2656 / max 112.8767, expressed in 71 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
120511	0.2656	71

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
oocyte	CL:0000023	93.91	gold quality
body of pancreas	UBERON:0001150	91.94	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	91.13	gold quality
gall bladder	UBERON:0002110	86.59	gold quality
kidney epithelium	UBERON:0004819	86.54	gold quality
secondary oocyte	CL:0000655	85.30	gold quality
left ventricle myocardium	UBERON:0006566	84.47	gold quality
cardiac muscle of right atrium	UBERON:0003379	84.45	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	82.30	gold quality
right testis	UBERON:0004534	80.60	gold quality
epithelial cell of pancreas	CL:0000083	80.56	gold quality
upper arm skin	UBERON:0004263	80.54	gold quality
pituitary gland	UBERON:0000007	79.84	gold quality
pancreas	UBERON:0001264	79.13	gold quality
myocardium	UBERON:0002349	79.05	gold quality
left testis	UBERON:0004533	78.99	gold quality
adenohypophysis	UBERON:0002196	77.76	gold quality
testis	UBERON:0000473	76.85	gold quality
gingival epithelium	UBERON:0001949	74.17	gold quality
superficial temporal artery	UBERON:0001614	71.53	gold quality
gingiva	UBERON:0001828	71.17	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	70.32	gold quality
nasal cavity epithelium	UBERON:0005384	69.40	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	68.10	gold quality
vastus lateralis	UBERON:0001379	67.81	gold quality
quadriceps femoris	UBERON:0001377	67.37	gold quality
biceps brachii	UBERON:0001507	66.69	gold quality
tibia	UBERON:0000979	66.24	gold quality
jejunal mucosa	UBERON:0000399	66.19	gold quality
jejunum	UBERON:0002115	64.78	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	21.20

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): THRB

miRNA regulators (miRDB)

20 targeting GPHA2, 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-6825-5P	99.96	69.81	3431
HSA-MIR-145-5P	99.92	71.13	1836
HSA-MIR-5195-3P	99.92	70.92	1877
HSA-MIR-200A-5P	99.76	69.10	949
HSA-MIR-200B-5P	99.76	69.05	948
HSA-MIR-3679-3P	99.64	69.88	1599
HSA-MIR-1207-5P	99.49	69.11	2983
HSA-MIR-1272	99.34	68.79	878
HSA-MIR-4763-3P	99.10	67.83	2649
HSA-MIR-9500	98.62	66.54	1845
HSA-MIR-548AO-5P	98.55	69.57	1362
HSA-MIR-548AX	98.55	69.58	1362
HSA-MIR-6873-5P	98.45	66.14	1417
HSA-MIR-4704-3P	98.28	69.33	1300
HSA-MIR-509-3P	98.12	67.25	612
HSA-MIR-6824-5P	97.41	68.43	583
HSA-MIR-7973	96.48	65.54	502
HSA-MIR-2909	96.36	67.30	562
HSA-MIR-4278	95.28	65.49	351
HSA-MIR-6789-5P	94.05	66.19	285

Literature-anchored findings (GeneRIF, showing 7)

• identification and characterization of GPA2 genes (PMID:12089349)
• GPA2, and another beta-subunit, GPB5, in human, are capable of forming heterodimers to activate TSH receptors. (PMID:15890769)
• cloning and functional analysis of the promoter of the thyrostimulin A2 subunit (PMID:16376481)
• Sudy illustrated that GPA2 is positively regulated by isl-1, suggesting that this protein associates with endocrine systems including the pituitary and pancreas. (PMID:17363077)
• Dual site-disrupted GPA2 and the GPB5 mutant were not expressed in either the conditioned medium or cell lysate. (PMID:18433898)
• expressed in osteoblasts and osteoclasts (PMID:26018249)
• Glycoprotein hormone subunit alpha 2 (GPHA2): A pituitary stem cell-expressed gene associated with NOTCH2 signaling. (PMID:38246572)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	gpha2	ENSDARG00000075403
mus_musculus	Gpha2	ENSMUSG00000024784
rattus_norvegicus	Gpha2	ENSRNOG00000021020
drosophila_melanogaster		FBGN0261386
caenorhabditis_elegans		WBGENE00001466

Protein

Protein identifiers

Glycoprotein hormone alpha-2 — Q96T91 (reviewed: Q96T91)

Alternative names: Putative secreted protein Zsig51, Thyrostimulin subunit alpha

All UniProt accessions (3): Q96T91, A0A024R579, E9PLQ0

UniProt curated annotations — full annotation on UniProt →

Function. Functions as a heterodimeric glycoprotein hormone with GPHB5 able to bind and activate the thyroid-stimulating hormone receptor (TSHR), leading to increased cAMP production. Plays a central role in controlling thyroid cell metabolism.

Subunit / interactions. Heterodimer with GPHB5; this heterodimer interacts with thyroid-stimulating hormone receptor (TSHR), and hence stimulates cAMP production.

Subcellular location. Secreted.

Tissue specificity. Found in a variety of tissues.

Post-translational modifications. Glycosylated.

Similarity. Belongs to the glycoprotein hormones subunit alpha family.

RefSeq proteins (1): NP_570125* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000476	Glyco_hormone	Family
IPR006207	Cys_knot_C	Domain
IPR029034	Cystine-knot_cytokine	Homologous_superfamily
IPR052680	Glyco_Hormone_Alpha	Family

UniProt features (8 total): disulfide bond 4, glycosylation site 2, signal peptide 1, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96T91-F1	88.95	0.70

Functional residue map

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

Disulfide bonds (4): 31–89, 48–103, 57–119, 61–121

Glycosylation sites (2): 37, 81

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-375281	Hormone ligand-binding receptors
R-HSA-418555	G alpha (s) signalling events

MSigDB gene sets: 42 (showing top): GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_UP, chr11q13, GOBP_ADENYLATE_CYCLASE_MODULATING_G_PROTEIN_COUPLED_RECEPTOR_SIGNALING_PATHWAY, LIU_VAV3_PROSTATE_CARCINOGENESIS_DN, REACTOME_HORMONE_LIGAND_BINDING_RECEPTORS, GOMF_G_PROTEIN_COUPLED_RECEPTOR_BINDING, GATA4_Q3, GOMF_SIGNALING_RECEPTOR_BINDING, GOBP_ADENYLATE_CYCLASE_ACTIVATING_G_PROTEIN_COUPLED_RECEPTOR_SIGNALING_PATHWAY, GOMF_HORMONE_RECEPTOR_BINDING, GOMF_PROTEIN_HETERODIMERIZATION_ACTIVITY, GOMF_PROTEIN_DIMERIZATION_ACTIVITY, GOMF_PEPTIDE_HORMONE_RECEPTOR_BINDING, GOMF_HORMONE_ACTIVITY

GO Biological Process (3): cell surface receptor signaling pathway (GO:0007166), adenylate cyclase-activating G protein-coupled receptor signaling pathway (GO:0007189), signal transduction (GO:0007165)

GO Molecular Function (4): hormone activity (GO:0005179), thyrotropin-releasing hormone receptor binding (GO:0031531), protein heterodimerization activity (GO:0046982), protein binding (GO:0005515)

GO Cellular Component (2): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Class A/1 (Rhodopsin-like receptors)	1
GPCR downstream signalling	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
signal transduction	1
adenylate cyclase-modulating G protein-coupled receptor signaling pathway	1
adenylate cyclase activator activity	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
receptor ligand activity	1
G protein-coupled receptor binding	1
peptide hormone receptor binding	1
protein dimerization activity	1
binding	1
cellular anatomical structure	1

Protein interactions and networks

STRING

804 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GPHA2	GPHB5	Q86YW7	997
GPHA2	CMKLR2	P46091	987
GPHA2	CGA	P01215	955
GPHA2	PPP2R5B	Q15173	791
GPHA2	TSHB	P01222	768
GPHA2	FSHR	P23945	712
GPHA2	LHCGR	P22888	652
GPHA2	GIT2	Q14161	549
GPHA2	FSHB	P01225	508
GPHA2	C12orf43	Q96C57	479
GPHA2	GPHRA	B7ZAQ6	475
GPHA2	PRL	P01236	460
GPHA2	KLHL28	Q9NXS3	455
GPHA2	TSHR	P16473	452
GPHA2	AOC3	Q16853	445

IntAct

11 interactions, top by confidence:

A	B	Type	Score
GPHB5	GPHA2	psi-mi:“MI:0915”(physical association)	0.580
GPHA2	PLXNA2	psi-mi:“MI:0914”(association)	0.530
ngl	GPHA2	psi-mi:“MI:2280”(deamidation reaction)	0.440
CGB5	GPHA2	psi-mi:“MI:0915”(physical association)	0.370
FSHB	GPHA2	psi-mi:“MI:0915”(physical association)	0.370
TSHB	GPHA2	psi-mi:“MI:0915”(physical association)	0.370
LHB	GPHA2	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (46): LAMB2 (Affinity Capture-MS), FAT1 (Affinity Capture-MS), FRAS1 (Affinity Capture-MS), GFPT2 (Affinity Capture-MS), PPP6R3 (Affinity Capture-MS), ZMYM3 (Affinity Capture-MS), GPR98 (Affinity Capture-MS), ADAM9 (Affinity Capture-MS), PLXNA2 (Affinity Capture-MS), C17orf70 (Affinity Capture-MS), CNTNAP3 (Affinity Capture-MS), LNPEP (Affinity Capture-MS), CBWD1 (Affinity Capture-MS), MANBA (Affinity Capture-MS), MOXD1 (Affinity Capture-MS)

ESM2 similar proteins: A0A0F7YZI5, A1BN60, A1BN61, C0K3N2, O13050, O46430, O73824, P01225, P01226, P01227, P01228, P04837, P10257, P12656, P18427, P30971, P30972, P37240, P48250, P48252, P52584, Q08127, Q2PUH2, Q330K6, Q3HRV4, Q3YC02, Q52R90, Q60687, Q6EV79, Q6IY73, Q6SI68, Q6SV86, Q6U830, Q7ZZV4, Q8HY83, Q8HY84, Q8WN19, Q925Q4, Q925Q5, Q95J82

Diamond homologs: A0A0F7Z3J2, Q925Q4, Q925Q5, Q96T91

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
GPHA2	up-regulates	TSHR	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	20
Likely benign	2
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

293 predictions. Top by Δscore:

Variant	Effect	Δscore
11:64935174:GGCTA:G	acceptor_loss	1.0000
11:64935175:GCTAG:G	acceptor_loss	1.0000
11:64935176:C:CC	acceptor_gain	1.0000
11:64935176:CTA:C	acceptor_loss	1.0000
11:64935356:A:AC	donor_gain	1.0000
11:64935357:C:CC	donor_gain	1.0000
11:64935357:CGGTG:C	donor_gain	1.0000
11:64935171:GAAGG:G	acceptor_gain	0.9900
11:64935172:AAGG:A	acceptor_gain	0.9900
11:64935173:AGG:A	acceptor_gain	0.9900
11:64935174:GG:G	acceptor_gain	0.9900
11:64935349:GGTAC:G	donor_loss	0.9900
11:64935350:GTAC:G	donor_loss	0.9900
11:64935351:TAC:T	donor_loss	0.9900
11:64935352:AC:A	donor_loss	0.9900
11:64935354:TCA:T	donor_loss	0.9900
11:64935355:C:CG	donor_loss	0.9900
11:64935356:A:C	donor_loss	0.9900
11:64935357:C:T	donor_loss	0.9900
11:64935357:CG:C	donor_gain	0.9900
11:64935357:CGG:C	donor_gain	0.9900
11:64935357:CGGT:C	donor_gain	0.9900
11:64935838:T:TA	donor_gain	0.9900
11:64934990:CCTT:C	donor_gain	0.9800
11:64935074:G:T	acceptor_gain	0.9800
11:64935814:T:TA	donor_gain	0.9800
11:64935818:G:A	donor_gain	0.9800
11:64935833:CCA:C	donor_gain	0.9800
11:64934985:CCTCA:C	donor_loss	0.9700
11:64934986:CTCAC:C	donor_loss	0.9700

AlphaMissense

830 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:64935013:C:G	C89S	0.996
11:64935014:A:T	C89S	0.996
11:64935013:C:T	C89Y	0.994
11:64935097:C:G	C61S	0.994
11:64935098:A:T	C61S	0.994
11:64935012:G:C	C89W	0.993
11:64935014:A:G	C89R	0.993
11:64935016:C:G	C88S	0.993
11:64935017:A:T	C88S	0.993
11:64935082:A:C	F66C	0.993
11:64935097:C:T	C61Y	0.993
11:64935013:C:A	C89F	0.992
11:64935076:G:A	S68F	0.992
11:64934792:C:G	C124S	0.991
11:64934793:A:T	C124S	0.991
11:64935081:G:C	F66L	0.991
11:64935081:G:T	F66L	0.991
11:64935083:A:G	F66L	0.991
11:64935109:C:G	C57S	0.991
11:64935109:C:T	C57Y	0.991
11:64935110:A:T	C57S	0.991
11:64935017:A:G	C88R	0.990
11:64935104:C:A	G59C	0.990
11:64935369:C:G	C31S	0.990
11:64935370:A:T	C31S	0.990
11:64935097:C:A	C61F	0.989
11:64935110:A:G	C57R	0.989
11:64935076:G:T	S68Y	0.988
11:64935092:A:G	S63P	0.988
11:64934793:A:G	C124R	0.987

dbSNP variants (sampled 300 via entrez): RS1000353818 (11:64934432 T>G), RS1000415684 (11:64937327 G>A), RS1000750255 (11:64935662 G>A), RS1000782811 (11:64935288 G>A,C,T), RS1002760181 (11:64936308 G>T), RS1002944733 (11:64939101 T>A), RS1003248533 (11:64938001 G>A), RS1003324316 (11:64939390 C>A,G,T), RS1004319138 (11:64936802 A>G), RS1005334964 (11:64938372 C>A,T), RS1005349516 (11:64938056 C>G), RS1007174695 (11:64938643 G>A,C), RS1007737268 (11:64934268 C>G,T), RS1008324165 (11:64935334 C>T), RS1008687679 (11:64935634 T>C)

Disease associations

OMIM: gene MIM:609651 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

13 total (human), top 13 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects expression, decreases methylation	2
entinostat	increases expression, affects cotreatment	2
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
CGP 52608	affects binding, increases reaction	1
K 7174	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
jinfukang	decreases expression	1
Benzo(a)pyrene	increases methylation	1
Quercetin	decreases expression	1
Testosterone	increases expression	1
Cyclosporine	decreases expression	1
Aflatoxin B1	increases methylation	1

Clinical trials (associated diseases)

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