THPO

Summary

THPO (thrombopoietin, HGNC:11795) is a protein-coding gene on chromosome 3q27.1, encoding Thrombopoietin (P40225). Lineage-specific cytokine affecting the proliferation and maturation of megakaryocytes from their committed progenitor cells.

Megakaryocytopoiesis is the cellular development process that leads to platelet production. The main functional protein encoded by this gene is a humoral growth factor that is necessary for megakaryocyte proliferation and maturation, as well as for thrombopoiesis. This protein is the ligand for MLP/C_MPL, the product of myeloproliferative leukemia virus oncogene. Mutations in this gene are the cause of thrombocythemia 1. Alternative promoter usage and differential splicing result in multiple transcript variants differing in the 5’ UTR and/or coding region. Multiple AUG codons upstream of the main open reading frame (ORF) have been identified, and these upstream AUGs inhibit translation of the main ORF at different extent.

Source: NCBI Gene 7066 — RefSeq curated summary.

At a glance

• Gene–disease (curated): congenital amegakaryocytic thrombocytopenia (Definitive, ClinGen) — +5 more curated relationships
• GWAS associations: 24
• Clinical variants (ClinVar): 242 total — 7 pathogenic, 9 likely-pathogenic
• Phenotypes (HPO): 81
• Druggable target: yes — 103 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_000460

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11795
Approved symbol	THPO
Name	thrombopoietin
Location	3q27.1
Locus type	gene with protein product
Status	Approved
Aliases	TPO, MPLLG
Ensembl gene	ENSG00000090534
Ensembl biotype	protein_coding
OMIM	600044
Entrez	7066

Gene structure

Transcript identifiers

Ensembl transcripts: 15 — 13 protein_coding, 1 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000421442, ENST00000445696, ENST00000477594, ENST00000645603, ENST00000647395, ENST00000648612, ENST00000649095, ENST00000650229, ENST00000876539, ENST00000876540, ENST00000876541, ENST00000876542, ENST00000876543, ENST00000876544, ENST00000962183

RefSeq mRNA: 10 — MANE Select: NM_000460 NM_000460, NM_001177597, NM_001177598, NM_001289997, NM_001289998, NM_001290003, NM_001290022, NM_001290026, NM_001290027, NM_001290028

CCDS: CCDS3265, CCDS54693, CCDS77867, CCDS93431, CCDS93432

Canonical transcript exons

ENST00000647395 — 6 exons

Exon	Start	End
ENSE00000781177	184375515	184375601
ENSE00000781178	184373415	184373582
ENSE00001056827	184376247	184376404
ENSE00001079331	184375888	184376015
ENSE00001288988	184371935	184373178
ENSE00003827644	184378075	184378207

Expression profiles

Bgee: expression breadth ubiquitous, 157 present calls, max score 91.67.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.4646 / max 68.0802, expressed in 125 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
45892	0.2796	73
45894	0.1427	51
45893	0.0383	23
45891	0.0040	2

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right lobe of liver	UBERON:0001114	91.67	gold quality
liver	UBERON:0002107	79.83	gold quality
right hemisphere of cerebellum	UBERON:0014890	76.11	gold quality
right frontal lobe	UBERON:0002810	75.89	gold quality
cerebellar hemisphere	UBERON:0002245	75.48	gold quality
cerebellar cortex	UBERON:0002129	75.18	gold quality
cerebellum	UBERON:0002037	72.12	gold quality
body of uterus	UBERON:0009853	71.83	gold quality
cingulate cortex	UBERON:0003027	71.01	gold quality
anterior cingulate cortex	UBERON:0009835	70.86	gold quality
Brodmann (1909) area 9	UBERON:0013540	69.78	gold quality
endocervix	UBERON:0000458	68.69	gold quality
right adrenal gland	UBERON:0001233	68.69	gold quality
right ovary	UBERON:0002118	68.55	gold quality
left adrenal gland	UBERON:0001234	68.34	gold quality
apex of heart	UBERON:0002098	68.26	gold quality
gastrocnemius	UBERON:0001388	68.20	gold quality
right adrenal gland cortex	UBERON:0035827	68.15	gold quality
left adrenal gland cortex	UBERON:0035825	67.99	gold quality
left ovary	UBERON:0002119	67.87	gold quality
amygdala	UBERON:0001876	67.67	gold quality
muscle of leg	UBERON:0001383	67.48	gold quality
hindlimb stylopod muscle	UBERON:0004252	67.46	gold quality
adult mammalian kidney	UBERON:0000082	67.23	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	67.22	gold quality
prefrontal cortex	UBERON:0000451	66.21	gold quality
adrenal cortex	UBERON:0001235	66.09	gold quality
metanephros cortex	UBERON:0010533	65.89	gold quality
omental fat pad	UBERON:0010414	65.32	gold quality
peritoneum	UBERON:0002358	65.25	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	2.09

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): HIF1A, IRF2, JUN, MYC, SPI1

miRNA regulators (miRDB)

58 targeting THPO, 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-8075	99.97	67.20	962
HSA-MIR-30A-3P	99.87	69.74	2928
HSA-MIR-30D-3P	99.87	69.92	2917
HSA-MIR-30E-3P	99.87	69.68	2942
HSA-LET-7A-2-3P	99.87	70.53	1921
HSA-LET-7G-3P	99.85	70.43	1929
HSA-MIR-544A	99.84	68.66	1965
HSA-MIR-204-5P	99.79	71.62	2439
HSA-MIR-211-5P	99.79	71.65	2440
HSA-MIR-6764-5P	99.75	67.89	2304
HSA-MIR-5006-3P	99.71	70.26	2728
HSA-MIR-12124	99.68	69.17	2700
HSA-MIR-3202	99.66	67.70	2737
HSA-MIR-3158-5P	99.65	67.51	1763
HSA-MIR-4502	99.65	66.99	1021
HSA-MIR-10394-5P	99.65	66.83	1852
HSA-MIR-1205	99.65	66.76	1826
HSA-MIR-6832-5P	99.58	64.82	1132
HSA-MIR-1915-3P	99.58	66.79	1988
HSA-MIR-4328	99.57	71.06	4094
HSA-MIR-6832-3P	99.52	70.44	1726
HSA-MIR-513C-5P	99.50	68.42	1730
HSA-MIR-514B-5P	99.50	68.19	1766
HSA-MIR-3123	99.47	67.15	2693
HSA-MIR-21-5P	99.46	70.54	1035
HSA-MIR-4251	99.40	69.19	3363
HSA-MIR-6839-3P	99.39	68.86	1301
HSA-MIR-1276	99.36	68.18	1642
HSA-MIR-6507-5P	99.36	70.46	2524
HSA-MIR-3678-3P	99.31	67.10	1432

Literature-anchored findings (GeneRIF, showing 40)

• Jak-Stat and PI 3-kinase activation pathways regulate the TPO-induced survival of megakaryocytic cells via Bcl-xL gene expression. (PMID:11756417)
• Mutations in the 5’ untranslated region of the TPO gene are not the cause of the normal or elevated TPO levels in acquired essential thrombocythemia. (PMID:11860444)
• Overexpreeeion of human thrombopoietin increased the platelet level in the transfected mice. (PMID:11877062)
• REVIEW: central role in the pathogenesis of idiopathic thrombocytopenic purpura (ITP), andother immune-mediated thrombocytopenias. (PMID:11913997)
• While there is increased platelet turnover in patients with chronic renal failure, the kidney does not seem to play a major role in the overall Tpo production in the body. (PMID:11960394)
• binding to platelet thrombopoietin receptor is directly involved in human thrombopoietin plasma level regulation (PMID:11961237)
• Flt3/Flk-2-ligand in synergy with thrombopoietin may slow down megakaryocyte development by causing increased proliferation of megakaryocyte progenitor cells. (PMID:11983110)
• In the presence of EPO and SCF and/or IL-3, TPO enhances bone marrow erythropoiesis in cell cultures derived from patients with Diamond-Blackfan anemia. (PMID:12041668)
• Thrombopoietin activates MAPKp42/44, AKT, and STAT proteins in normal human CD34+ cells, megakaryocytes, and platelets. (PMID:12135673)
• The endogenous levels of TPO, IL-6 and IL-8 are elevated in the thrombocytopenic patients with AML and MDS. (PMID:12187073)
• induces megakaryocyte-specific glycoprotein VI promoter and its regulation by GATA-1, Fli-1, and Sp1 (PMID:12359731)
• no difference was found in the cord blood level of thrombopoietin between infants born to mothers with pregnancy-induced hypertension and those without (PMID:12381927)
• Platelet signaling pathways activated by thrombopoietin may affect mitochondrial transcription via activation of mitochondrial STAT3 (PMID:12389630)
• review of TPO role in thrombopoiesis, signal transduction, cellular proliferative and anti-apoptotic mechanisms increasing megakaryocyte numbers (PMID:12430879)
• levels in children with acute and chronic idiopathic thrombocytopenic purpura and its relationship with mega-dose methylprednisolone therapy (PMID:12468916)
• Tpo concentrations in plasma samples taken concurrently from the right ventricle, the pulmonary artery, and the left ventricle showed there were positive correlations between the Tpo levels and pulmonary artery systolic pressure. (PMID:12487786)
• TPO stimulation of a megakaryocyte cell line activated lyn kinase, shown to be involved in the transduction pathway of the TPO proliferative signal. (PMID:12495897)
• Production of this protein in human hepatic cell cultures is not affected by IFN-alpha, IFN-beta, and IFN-gamma. (PMID:12581491)
• c-mpl mutations are the cause not only for the hypomegakaryocytic thrombocytopenia, but also for the development of an aplastic anemia (AA) in patients with CAMT (PMID:12799278)
• Hematopoietic stem cell self-renewal and expansion is reduced 10-20-fold after transplantation of normal stem cells into thrombopoietin null mice (PMID:12799280)
• identification of a potential “silencer” sequence in intron 5 of the TPO gene (PMID:12829024)
• results suggest that one mechanism of thrombocytopenia in patients with cGVHD is low TPO production by BM cells (PMID:12879435)
• Thrombopoietin cooperates with FLT3-L, inducing CD34+ HPCs to undergo a 400-fold expansion in cell numbers. (PMID:14670916)
• Increased serum TPO levels in patients with thrombocytosis in lung cancer which may be related to the activity of neoplasms. (PMID:14689068)
• structure-function relationships in TPO and the activation scheme of c-Mpl (PMID:14769915)
• IL-1beta up-regulates the expression of TPO in megakaryocytic cells. (PMID:14966463)
• The maximal promoter activity of c-mpl was obtained 24 hr after pretreatment with TPO for 3 hr (PMID:14995067)
• Decreased production of platelets by megakaryocytes due to low thrombopoietin concentration could be a possible cause of thrombocytopenia in liver cirrhosis. (PMID:15239259)
• Thrombopoietin induces HOXA9 nuclear transport in immature hematopoietic cells (PMID:15254242)
• Altered regulation of the TPO gene might be involved in the pathogenesis of familial thrombocytosis. (PMID:15282677)
• The Thrombopoietin altered expression provide an opportunity to diagnose and identify subpopulations of MPD patients. (PMID:15572213)
• expression of TPO receptor on platelets until 1 month after birth cause a decreased TPO clearance and keep a high level of free TPO in blood, resulting in the subsequent thrombocytosis in preterm infants. (PMID:15647951)
• mechanisms by which THPO can influence stem cell development (PMID:15705785)
• The effect of THPO on HuMCs in the presence of rhSCF varies, depending on the relative concentration of each growth factor, while THPO alone or in combination with rhSCF supports a unique population of CD117low/CD110+ HuMCs. (PMID:15781331)
• TPO integrates G(i), but not G(q), stimulation, supports integrin alpha(IIb)beta(3) activation platelet aggregation independently of phospholipase C but requires PI3-kinase and Rap1B (PMID:15863506)
• Data describe coculture of human peripheral blood cells and mouse stromal cells transfected with c-kit ligand, thrombopoietin, flt-3/flk2 ligand, and granulocyte-macrophage-CSF or with weekly addition of these cytokines. (PMID:16305336)
• in patients with AML, inadequate TPO levels are secondary to TPO clearing by functional c-mpl receptor myeloid blast cells and that TPO may serve as an in vivo myeloid leukemic growth factor (PMID:16317100)
• Preoperative serum thrombopoietin levels are higher in patients with ovarian cancer than with benign cysts (PMID:16359773)
• in HIV infected patients, both the serum thrombopoietin (TPO) levels and the TPO-c-Mpl complexes on the platelet surface were significantly elevated (PMID:16454716)
• FISH study showed no cytogenetic abnormalities in any of the analyzed cases. (PMID:16682284)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	thpo	ENSDARG00000079158
mus_musculus	Thpo	ENSMUSG00000022847
rattus_norvegicus	Thpo	ENSRNOG00000046850

Protein

Protein identifiers

Thrombopoietin — P40225 (reviewed: P40225)

Alternative names: C-mpl ligand, Megakaryocyte colony-stimulating factor, Megakaryocyte growth and development factor, Myeloproliferative leukemia virus oncogene ligand

All UniProt accessions (5): P40225, A0A2R8Y734, A0A3B3ITS0, F8W6L1, Q5FBX8

UniProt curated annotations — full annotation on UniProt →

Function. Lineage-specific cytokine affecting the proliferation and maturation of megakaryocytes from their committed progenitor cells. It acts at a late stage of megakaryocyte development. It may be the major physiological regulator of circulating platelets.

Subunit / interactions. Interacts with MPL/TPOR.

Subcellular location. Secreted.

Disease relevance. Thrombocythemia 1 (THCYT1) [MIM:187950] A myeloproliferative disorder characterized by excessive platelet production, resulting in increased numbers of circulating platelets. It can be associated with spontaneous hemorrhages and thrombotic episodes. The disease is caused by variants affecting the gene represented in this entry. Amegakaryocytic thrombocytopenia, congenital, 2 (CAMT2) [MIM:620481] A form of congenital amegakaryocytic thrombocytopenia, a hematologic disorder characterized by severe reduction of megakaryocytes and platelets at birth, and evolving into generalized bone marrow aplasia during childhood. CAMT2 is an autosomal recessive form. Most patients present with thrombocytopenia that progresses to pancytopenia. The disease is caused by variants affecting the gene represented in this entry. Thrombocytopenia 9 (THC9) [MIM:620478] A form of thrombocytopenia, a hematologic disorder defined by a decrease in the number of platelets in circulating blood, resulting in the potential for increased bleeding and decreased ability for clotting. THC9 is an autosomal dominant form characterized by low platelet counts in the absence of significant bleeding tendency. Some individuals may have mild mucocutaneous bleeding, whereas others may be asymptomatic. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. Two-domain structure with an erythropoietin-like N-terminal and a Ser/Pro/Thr-rich C-terminal.

Similarity. Belongs to the EPO/TPO family.

Isoforms (3)

UniProt ID	Names	Canonical?
P40225-1	1	yes
P40225-2	2, TPO-2
P40225-3	3, Truncated

RefSeq proteins (10): NP_000451, NP_001171068, NP_001171069, NP_001276926, NP_001276927, NP_001276932, NP_001276951, NP_001276955, NP_001276956, NP_001276957 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001323	EPO_TPO	Family
IPR003978	Thrombopoietin	Family
IPR009079	4_helix_cytokine-like_core	Homologous_superfamily
IPR019767	EPO/TPO_CS	Conserved_site

Pfam: PF00758

UniProt features (55 total): glycosylation site 14, helix 11, sequence variant 7, sequence conflict 6, strand 5, compositionally biased region 3, disulfide bond 2, splice variant 2, turn 2, signal peptide 1, chain 1, region of interest 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
1V7M	X-RAY DIFFRACTION	2.51
1V7N	X-RAY DIFFRACTION	3.3
8G04	ELECTRON MICROSCOPY	3.4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P40225-F1	61.61	0.22

Antibody-complex structures (SAbDab): 2 — 1V7M, 1V7N

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 (2): 28–172, 50–106

Glycosylation sites (14): 180, 184, 197, 206, 213, 234, 255, 265, 340, 348, 22, 58, 131, 179

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-76009	Platelet Aggregation (Plug Formation)

MSigDB gene sets: 416 (showing top): BROWNE_HCMV_INFECTION_30MIN_DN, GOBP_MYELOID_CELL_DIFFERENTIATION, GOBP_PHENOL_CONTAINING_COMPOUND_METABOLIC_PROCESS, GOBP_EMBRYONIC_HEMOPOIESIS, chr2p25, GOBP_REGULATION_OF_PHOSPHORYLATION, GOBP_MYELOID_CELL_DEVELOPMENT, GOMF_OXIDOREDUCTASE_ACTIVITY_ACTING_ON_PAIRED_DONORS_WITH_INCORPORATION_OR_REDUCTION_OF_MOLECULAR_OXYGEN, GOBP_RESPONSE_TO_PEPTIDE, REACTOME_PLATELET_AGGREGATION_PLUG_FORMATION, REACTOME_PLATELET_ACTIVATION_SIGNALING_AND_AGGREGATION, GCANCTGNY_MYOD_Q6, GOBP_HYDROGEN_PEROXIDE_CATABOLIC_PROCESS, MODULE_64, GOBP_POSITIVE_REGULATION_OF_MAPK_CASCADE

GO Biological Process (13): positive regulation of protein phosphorylation (GO:0001934), cell population proliferation (GO:0008283), positive regulation of cell population proliferation (GO:0008284), megakaryocyte differentiation (GO:0030219), megakaryocyte development (GO:0035855), thrombopoietin-mediated signaling pathway (GO:0038163), positive regulation of MAPK cascade (GO:0043410), positive regulation of megakaryocyte differentiation (GO:0045654), positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction (GO:0051897), positive regulation of ERK1 and ERK2 cascade (GO:0070374), cell surface receptor signaling pathway via STAT (GO:0097696), positive regulation of hematopoietic stem cell proliferation (GO:1902035), signal transduction (GO:0007165)

GO Molecular Function (4): signaling receptor binding (GO:0005102), cytokine activity (GO:0005125), hormone activity (GO:0005179), growth factor activity (GO:0008083)

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

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Platelet activation, signaling and aggregation	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
receptor ligand activity	3
cellular process	2
megakaryocyte differentiation	2
positive regulation of intracellular signal transduction	2
regulation of protein phosphorylation	1
protein phosphorylation	1
positive regulation of protein modification process	1
positive regulation of phosphorylation	1
cell population proliferation	1
regulation of cell population proliferation	1
positive regulation of cellular process	1
myeloid cell differentiation	1
myeloid cell development	1
chemokine-mediated signaling pathway	1
MAPK cascade	1
regulation of MAPK cascade	1
positive regulation of myeloid cell differentiation	1
regulation of megakaryocyte differentiation	1
phosphatidylinositol 3-kinase/protein kinase B signal transduction	1
regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	1
positive regulation of MAPK cascade	1
ERK1 and ERK2 cascade	1
regulation of ERK1 and ERK2 cascade	1
cell surface receptor signaling pathway	1
hematopoietic stem cell proliferation	1
regulation of hematopoietic stem cell proliferation	1
positive regulation of stem cell proliferation	1
cell communication	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
protein binding	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1360 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
THPO	MPL	P40238	999
THPO	KITLG	P21583	974
THPO	IL3	P08700	971
THPO	FLT3LG	P49771	968
THPO	EPO	P01588	925
THPO	JAK2	O60674	919
THPO	EPOR	P19235	918
THPO	CD34	P28906	904
THPO	CSF3	P09919	855
THPO	TEK	Q02763	794
THPO	SH2B3	Q9UQQ2	790
THPO	ITGA2B	P08514	766
THPO	KIT	P10721	756
THPO	CSF3R	Q99062	734
THPO	CXCL12	P48061	732

IntAct

9 interactions, top by confidence:

A	B	Type	Score
MPL	THPO	psi-mi:“MI:0407”(direct interaction)	0.600
THPO	MPL	psi-mi:“MI:0407”(direct interaction)	0.600
THPO	EP300	psi-mi:“MI:0915”(physical association)	0.370
NUMBL	THPO	psi-mi:“MI:0915”(physical association)	0.370
APH1A	THPO	psi-mi:“MI:0915”(physical association)	0.370
ECE1	THPO	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (6): S100P (Reconstituted Complex), THPO (Positive Genetic), S100A6 (Reconstituted Complex), THPO (Two-hybrid), THPO (Two-hybrid), THPO (Two-hybrid)

ESM2 similar proteins: A0A1B0GV85, A2ALI5, A2APT9, B0BN44, B1ARY8, B6ZI38, O14836, O35188, O55145, O60279, O60667, P07141, P09603, P0C8S2, P28906, P40225, P40226, P42705, P78423, Q06154, Q08DV9, Q13261, Q1ERP8, Q28270, Q2TB54, Q3UY90, Q4V9H3, Q4W8E7, Q5F267, Q5R770, Q60819, Q64314, Q6PAL1, Q6PCP7, Q6UXB8, Q80XI1, Q8BLK9, Q8CAE9, Q8CBC4, Q8JZQ0

Diamond homologs: P40225, P40226, P42705, P42706, P49745, Q5IGQ0, A3FFS8, P01588, P07321, P07865, P29676, P33707, P33708, P33709, P48617, P49157, Q0Z956, Q28513, Q2XNF5, Q4T554, Q6H8S9, Q6H8T0, Q6H8T1, Q6H8T2, Q6JV22, Q867B1, Q9GKA2

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
THPO	up-regulates	MPL	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	7
Likely pathogenic	9
Uncertain significance	130
Likely benign	62
Benign	12

Top pathogenic / likely-pathogenic (16)

Variant ID	HGVS	Classification
1298946	NM_000460.4(THPO):c.469C>T (p.Arg157Ter)	Pathogenic
1684405	NM_000460.4(THPO):c.825del (p.Ser276fs)	Pathogenic
2070998	NM_000460.4(THPO):c.295C>T (p.Arg99Trp)	Pathogenic
3062220	NM_000460.4(THPO):c.-324C>T	Pathogenic
3659127	NM_000460.4(THPO):c.13+1G>T	Pathogenic
520806	NM_000460.4(THPO):c.112C>T (p.Arg38Cys)	Pathogenic
872935	NM_000460.4(THPO):c.-47del	Pathogenic
1703805	NM_000460.4(THPO):c.91C>T (p.Arg31Ter)	Likely pathogenic
2504918	NM_000460.4(THPO):c.355C>T (p.Arg119Cys)	Likely pathogenic
3256569	NM_000460.4(THPO):c.-64_-63dup	Likely pathogenic
3342160	NM_000460.4(THPO):c.754del (p.Glu252fs)	Likely pathogenic
3380981	NM_000460.4(THPO):c.530dup (p.Pro178fs)	Likely pathogenic
3380982	NM_000460.4(THPO):c.262_265del (p.Val88fs)	Likely pathogenic
372983	NM_000460.4(THPO):c.247G>A (p.Asp83Asn)	Likely pathogenic
9510	NM_000460.4(THPO):c.-31G>T	Likely pathogenic
975832	NM_000460.4(THPO):c.13+2T>C	Likely pathogenic

SpliceAI

5321 predictions. Top by Δscore:

Variant	Effect	Δscore
2:1414500:GGG:G	donor_gain	1.0000
2:1414501:GG:G	donor_gain	1.0000
2:1414501:GGG:G	donor_gain	1.0000
2:1414502:GG:G	donor_gain	1.0000
2:1414503:G:GA	donor_loss	1.0000
2:1414504:TAA:T	donor_loss	1.0000
2:1423125:CAGAG:C	donor_loss	1.0000
2:1423126:AGAGG:A	donor_loss	1.0000
2:1423127:GAG:G	donor_gain	1.0000
2:1423127:GAGGT:G	donor_loss	1.0000
2:1423128:AGGTG:A	donor_loss	1.0000
2:1423129:GG:G	donor_loss	1.0000
2:1423131:T:G	donor_loss	1.0000
2:1433428:T:TA	acceptor_gain	1.0000
2:1433433:CATAG:C	acceptor_loss	1.0000
2:1433436:A:AG	acceptor_gain	1.0000
2:1433437:G:GG	acceptor_gain	1.0000
2:1433437:GAA:G	acceptor_gain	1.0000
2:1433606:GG:G	donor_gain	1.0000
2:1433607:GG:G	donor_gain	1.0000
2:1456072:CCAGG:C	acceptor_loss	1.0000
2:1456073:CA:C	acceptor_loss	1.0000
2:1456283:G:GG	donor_gain	1.0000
2:1456284:T:G	donor_loss	1.0000
2:1484851:GGAG:G	donor_gain	1.0000
2:1484852:GAG:G	donor_gain	1.0000
2:1484852:GAGG:G	donor_gain	1.0000
2:1484854:GG:G	donor_loss	1.0000
2:1484855:GTGA:G	donor_gain	1.0000
2:1484856:T:G	donor_loss	1.0000

AlphaMissense

2206 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:184375527:C:A	W72C	0.998
3:184375527:C:G	W72C	0.998
3:184375529:A:G	W72R	0.991
3:184375529:A:T	W72R	0.991
3:184373129:A:C	F149C	0.989
3:184373089:G:C	F162L	0.983
3:184373089:G:T	F162L	0.983
3:184373091:A:G	F162L	0.983
3:184375595:A:G	C50R	0.983
3:184373129:A:G	F149S	0.982
3:184375542:A:C	F67L	0.981
3:184375542:A:T	F67L	0.981
3:184375544:A:G	F67L	0.981
3:184373098:C:A	K159N	0.980
3:184373098:C:G	K159N	0.980
3:184373111:A:G	L155P	0.980
3:184373571:C:A	K80N	0.979
3:184373571:C:G	K80N	0.979
3:184373128:G:C	F149L	0.977
3:184373128:G:T	F149L	0.977
3:184373130:A:G	F149L	0.977
3:184375594:C:G	C50S	0.977
3:184375595:A:T	C50S	0.977
3:184375543:A:C	F67C	0.975
3:184373539:A:G	L91P	0.972
3:184375543:A:G	F67S	0.969
3:184373470:A:G	L114P	0.968
3:184375528:C:G	W72S	0.968
3:184375564:A:T	V60D	0.967
3:184373099:T:A	K159M	0.965

dbSNP variants (sampled 300 via entrez): RS1000148320 (3:184377146 G>A), RS1000518529 (3:184377364 C>T), RS1000875801 (3:184381657 G>C), RS1000897943 (3:184374159 C>T), RS1001202096 (3:184377759 T>A), RS1001266588 (3:184373938 T>A,C,G), RS1001485133 (3:184371521 A>C), RS1001527193 (3:184376758 T>A), RS1001551582 (3:184375764 G>A,C), RS1001852498 (3:184371758 C>T), RS1002536924 (3:184378174 A>G), RS1002635142 (3:184372238 C>G,T), RS1002879158 (3:184379020 C>T), RS1003014024 (3:184371857 A>T), RS1003558136 (3:184372828 C>A,G)

Disease associations

OMIM: gene MIM:600044 | disease phenotypes: MIM:187950, MIM:620481, MIM:620478

GenCC curated gene-disease

Disease	Classification	Inheritance
thrombocythemia 1	Strong	Autosomal dominant
thrombocytopenia 9	Strong	Autosomal dominant
hereditary thrombocytosis with transverse limb defect	Supportive	Autosomal dominant
congenital amegakaryocytic thrombocytopenia	Supportive	Autosomal recessive
hereditary isolated aplastic anemia	Supportive	Autosomal dominant
familial thrombocytosis	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (2)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
congenital amegakaryocytic thrombocytopenia	Definitive	SD
thrombocythemia 1	Definitive	AD

Mondo (8): thrombocythemia 1 (MONDO:0008554), thrombocytopenia (MONDO:0002049), amegakaryocytic thrombocytopenia, congenital, 2 (MONDO:0957575), thrombocytopenia 9 (MONDO:0957572), hereditary thrombocytosis with transverse limb defect (MONDO:0018000), (MONDO:0011469), (MONDO:0018340), familial thrombocytosis (MONDO:0019111)

Orphanet (0):

HPO phenotypes

81 total (30 of 81 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000158	Macroglossia
HP:0000270	Delayed cranial suture closure
HP:0000280	Coarse facial features
HP:0000282	Facial edema
HP:0000407	Sensorineural hearing impairment
HP:0000470	Short neck
HP:0000821	Hypothyroidism
HP:0000851	Congenital hypothyroidism
HP:0000853	Goiter
HP:0000975	Hyperhidrosis
HP:0000989	Pruritus
HP:0000995	Melanocytic nevus
HP:0001123	Visual field defect
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001254	Lethargy
HP:0001260	Dysarthria
HP:0001265	Hyporeflexia
HP:0001279	Syncope
HP:0001537	Umbilical hernia
HP:0001662	Bradycardia
HP:0001671	Abnormal cardiac septum morphology
HP:0001744	Splenomegaly
HP:0001824	Weight loss
HP:0001873	Thrombocytopenia
HP:0001875	Decreased total neutrophil count
HP:0001876	Pancytopenia

GWAS associations

24 associations (top):

Study	Trait	p-value
GCST000580_3	Platelet count	5.000000e-11
GCST001337_56	Platelet count	6.000000e-08
GCST002875_76	Diisocyanate-induced asthma	3.000000e-06
GCST004603_259	Platelet count	5.000000e-63
GCST004603_260	Platelet count	7.000000e-65
GCST004603_261	Platelet count	4.000000e-51
GCST004603_262	Platelet count	2.000000e-50
GCST004607_263	Plateletcrit	4.000000e-74
GCST004607_264	Plateletcrit	5.000000e-71
GCST004607_265	Plateletcrit	9.000000e-63
GCST004607_266	Plateletcrit	4.000000e-65
GCST005991_5	Platelet count	7.000000e-50
GCST006101_12	Cardiometabolic and hematological traits	2.000000e-50
GCST90002397_91	Mean spheric corpuscular volume	4.000000e-10
GCST90002400_413	Plateletcrit	1.000000e-168
GCST90002400_414	Plateletcrit	3.000000e-43
GCST90002400_415	Plateletcrit	1.000000e-85
GCST90002400_416	Plateletcrit	1.000000e-14
GCST90002400_417	Plateletcrit	9.000000e-109
GCST90002402_664	Platelet count	2.000000e-138
GCST90002402_665	Platelet count	7.000000e-45
GCST90002402_666	Platelet count	1.000000e-67
GCST90002402_667	Platelet count	2.000000e-13
GCST90002402_668	Platelet count	4.000000e-82

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004309	platelet count
EFO:0006995	response to diisocyanate
EFO:0007985	platelet crit

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D013921	Thrombocytopenia	C15.378.140.855; C15.378.243.937

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL1293256 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

103 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 783,375 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL103	PROGESTERONE	4	162,141
CHEMBL104	CLOTRIMAZOLE	4	56,325
CHEMBL107	COLCHICINE	4	93,932
CHEMBL1082607	SALMETEROL XINAFOATE	4	15,201
CHEMBL1095292	BRETYLIUM TOSYLATE	4	3,061
CHEMBL1109	SULFAPHENAZOLE	4	4,065
CHEMBL1113	AMOXAPINE	4	20,128
CHEMBL1123	DICYCLOMINE	4	8,691
CHEMBL1200326	NICARDIPINE HYDROCHLORIDE	4	3,903
CHEMBL1201236	CARBIDOPA ANHYDROUS	4	25,180
CHEMBL1256958	EPINEPHRINE BITARTRATE	4	2,257
CHEMBL1370	BUDESONIDE	4	72,936
CHEMBL1371	CHLORZOXAZONE	4	16,752
CHEMBL1423	PIMOZIDE	4	17,310
CHEMBL1448	NICLOSAMIDE	4	14,322
CHEMBL1489	AZACITIDINE	4	97,123
CHEMBL15023	TRIFLUPERIDOL	4	2,646
CHEMBL1560	CAPTOPRIL	4	66,415
CHEMBL157101	KETOCONAZOLE	4	75,361
CHEMBL1590	PSEUDOEPHEDRINE	4	25,626
CHEMBL1626	CLEMASTINE	4
CHEMBL1643	RIBAVIRIN	4
CHEMBL1709	SERTRALINE HYDROCHLORIDE	4
CHEMBL17157	TERFENADINE	4
CHEMBL185	FLUOROURACIL	4
CHEMBL193	NIFEDIPINE	4
CHEMBL2	PRAZOSIN	4
CHEMBL21731	MAPROTILINE	4
CHEMBL267936	MECAMYLAMINE	4
CHEMBL276832	HYDRALAZINE	4

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

ChEMBL bioactivities

542 potent at pChembl≥5 of 834 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.40	Potency	4	nM	CHEMBL1448979
8.40	Potency	4	nM	CHEMBL1406446
8.00	Potency	10	nM	BUDESONIDE
8.00	Potency	10	nM	CHEMBL1435477
7.90	Potency	12.6	nM	FLUOROURACIL
7.90	Potency	12.6	nM	NOCODAZOLE
7.60	Potency	25.1	nM	CHEMBL1515691
7.60	Potency	25.1	nM	MITOXANTRONE
7.50	Potency	31.6	nM	CHEMBL1518927
7.40	Potency	39.8	nM	CHEMBL1330659
7.40	Potency	39.8	nM	HYDRALAZINE
7.40	Potency	39.8	nM	DIPHENYLENEIODONIUM
7.30	Potency	50.1	nM	CHEMBL1355952
7.20	Potency	63.1	nM	CHEMBL1435868
7.20	Potency	63.1	nM	DIPHENHYDRAMINE
7.20	Potency	63.1	nM	CHEMBL296455
7.10	Potency	79.4	nM	CHEMBL405358
7.00	Potency	100	nM	NICLOSAMIDE
7.00	Potency	100	nM	CHEMBL1255755
6.90	Potency	125.9	nM	CHEMBL156747
6.90	Potency	125.9	nM	HYDRAZINECARBOXAMIDE
6.90	Potency	125.9	nM	CHLORZOXAZONE
6.90	Potency	125.9	nM	CAMPTOTHECIN
6.80	Potency	158.5	nM	CHEMBL1437221
6.80	Potency	158.5	nM	KENPAULLONE
6.70	Potency	199.5	nM	CHEMBL322970
6.60	Potency	251.2	nM	CHEMBL355496
6.60	Potency	251.2	nM	CHEMBL1397711
6.60	Potency	251.2	nM	SOBUZOXANE
6.60	Potency	251.2	nM	CHEMBL1472903
6.50	Potency	316.2	nM	CHEMBL1553718
6.50	Potency	316.2	nM	RUTAECARPINE
6.50	Potency	316.2	nM	DEXPROPRANOLOL
6.40	Potency	398.1	nM	DISULFIRAM
6.40	Potency	398.1	nM	CHEMBL1315323
6.40	Potency	398.1	nM	CHEMBL35482
6.30	Potency	501.2	nM	COLCHICINE
6.30	Potency	501.2	nM	CHEMBL1365553
6.30	Potency	501.2	nM	OLEOYL DOPAMINE
6.30	Potency	501.2	nM	APIGENIN
6.20	Potency	631	nM	CHEMBL1255867
6.10	Potency	794.3	nM	CHEMBL1441136
6.10	Potency	794.3	nM	IMETIT
6.00	Potency	1000	nM	CHEMBL66654
6.00	Potency	1000	nM	CHEMBL297784
6.00	Potency	1000	nM	LINOPIRDINE
6.00	Potency	1000	nM	CHEMBL56543
6.00	Potency	1000	nM	CHEMBL1315342
6.00	Potency	1000	nM	CHEMBL101168
6.00	Potency	1000	nM	SANGUINARIUM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression	5
Acetaminophen	affects expression, decreases expression	2
Benzo(a)pyrene	affects methylation, decreases expression	2
dicrotophos	increases expression	1
diphenyleneiodonium	decreases reaction, increases phosphorylation	1
6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid	decreases reaction, increases abundance, increases expression	1
testosterone undecanoate	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
sodium arsenite	decreases expression	1
anagrelide	decreases reaction, increases expression	1
nickel chloride	affects cotreatment, increases secretion	1
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one	decreases reaction, increases expression	1
CGP 52608	affects binding, increases reaction	1
alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide	increases expression, decreases reaction	1
U 0126	increases expression, decreases reaction	1
entinostat	increases expression	1
pyrazolanthrone	increases expression, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
StemRegenin 1	affects cotreatment, increases activity	1
10-(4’-(N-diethylamino)butyl)-2-chlorophenoxazine	decreases reaction, increases expression	1
Resveratrol	affects cotreatment, increases activity	1
Gemcitabine	increases expression	1
Acetylcysteine	decreases reaction, increases abundance, increases expression	1
Cadmium	decreases expression	1
Calcitriol	decreases expression	1
Dioxins	increases expression	1
Lipopolysaccharides	affects cotreatment, increases secretion	1
Methamphetamine	increases expression	1
Tetradecanoylphorbol Acetate	affects cotreatment, affects expression	1

ChEMBL screening assays

2 unique, capped per target: 2 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1614034	Functional	PUBCHEM_BIOASSAY: qHTS Assay for Identification of Small Molecule Antagonists for Thrombopoietin (TPO) Signaling Pathway. (Class of assay: confirmatory) [Related pubchem assays: 917 ]	PubChem BioAssay data set

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00039858	PHASE4	COMPLETED	Evaluation of Argatroban Injection in Pediatric Patients Requiring Anticoagulant Alternatives to Heparin
NCT00239733	PHASE4	TERMINATED	Anti-D for Treating Thrombocytopenia in Adults Infected With Hepatitis C Virus With or Without HIV Co-Infection
NCT00907478	PHASE4	COMPLETED	Study on Bone Marrow Morphology in Adults Receiving Romiplostim for Treatment of Thrombocytopenia Associated With Immune Thrombocytopenia Purpura (ITP)
NCT01727401	PHASE4	TERMINATED	Thromboprophylaxis of Venous Thromboembolism in Acutely-ill Medical Inpatients With Thrombocytopenia
NCT02032134	PHASE4	TERMINATED	Protocol for the Infusion of Buffy Coat-derived Cryopreserved Platelets in Patients With Severe Thrombocytopenia
NCT02267993	PHASE4	COMPLETED	Efficacy and Safety of rhTPO for the Treatment of Thrombocytopenia After Chemotherapy in AML Patients
NCT03633019	PHASE4	UNKNOWN	High-dose Use of rhTPO in CIT Patients
NCT03688191	PHASE4	UNKNOWN	Study of Sirolimus in CTD-TP in China
NCT04906083	PHASE4	UNKNOWN	Avatrombopag in Patients With End-stage Liver Disease and Thrombocytopenia
NCT05217719	PHASE4	UNKNOWN	Effects of Recombinant Human Thrombopoietin on Platelet Levels in ICU Patients
NCT05255003	PHASE4	RECRUITING	STrategies for Anticoagulation in Patients With thRombocytopenia and Cancer-associated Thrombosis
NCT05382013	PHASE4	UNKNOWN	Efficacy and Safety of Avatrombopag for Treating TCP in HBV-ACLF Patients Receiving ALSS Treatment
NCT05944458	PHASE4	COMPLETED	Efficacy of Intravenous N-Acetylcysteine in Preventing Linezolid-Induced Thrombocytopenia in Critically Ill Patients
NCT06562738	PHASE4	RECRUITING	Clinical Study on Efficacy and Safety of Hetrombopag in the Preoperative Patients of Thrombocytopenia
NCT00037791	PHASE3	COMPLETED	Safety and Efficacy of (PN-152,243)/PN-196,444 in the Prevention of Thrombocytopenia
NCT00039910	PHASE3	COMPLETED	Safety and Efficacy of (PN-152,243)/PN-196,444 in the Prevention of Thrombocytopenia
NCT00073580	PHASE3	COMPLETED	Angiomax in Patients With HIT/HITTS Type II Undergoing Off-Pump Coronary Artery Bypass Grafting (CABG) (CHOOSE)
NCT00102323	PHASE3	COMPLETED	AMG 531 Treatment of Thrombocytopenic Subjects With Immune (Idiopathic) Thrombocytopenic Purpura (ITP) Refractory to Splenectomy
NCT00102336	PHASE3	COMPLETED	AMG 531 Treatment of Thrombocytopenic Subjects With Immune (Idiopathic) Thrombocytopenic Purpura (ITP) Prior to Splenectomy
NCT00116688	PHASE3	COMPLETED	Open Label Extension Study of Romiplostim (AMG 531) in Thrombocytopenic Patients With Immune (Idiopathic) Thrombocytopenic Purpura (ITP)
NCT00128713	PHASE3	COMPLETED	Optimal Platelet Dose Strategy for Management of Thrombocytopenia
NCT00151866	PHASE3	COMPLETED	Efficacy of Transfusions With Platelets Stored in Platelet Additive Solution II Versus Plasma
NCT00261924	PHASE3	COMPLETED	Efficacy and Safety Study of Platelets Treated for Pathogen Inactivation and Stored for Up to Seven Days
NCT00415532	PHASE3	COMPLETED	Romiplostim (AMG 531) Versus Medical Standard of Care for Immune (Idiopathic) Thrombocytopenic Purpura
NCT00420914	PHASE3	TERMINATED	Strategies for Transfusion of Platelets (SToP)
NCT00501345	PHASE3	TERMINATED	Aspirin in Patients With Myocardial Infarction and Thrombocytopenia
NCT00508820	PHASE3	COMPLETED	An Open Label Study of Romiplostim in Adult Thrombocytopenic Subjects With ITP
NCT00678587	PHASE3	TERMINATED	Eltrombopag To Reduce The Need For Platelet Transfusion In Subjects With Chronic Liver Disease And Thrombocytopenia Undergoing Elective Invasive Procedures
NCT01438840	PHASE3	COMPLETED	Efficacy and Safety of Oral E5501 Plus Standard of Care for the Treatment of Thrombocytopenia in Adults With Chronic Immune Thrombocytopenia (Amendment 02)
NCT01444417	PHASE3	COMPLETED	Safety and Efficacy Study of Romiplostim to Treat Immune Thrombocytopenia (ITP) in Pediatric Patients
NCT01805648	PHASE3	UNKNOWN	Efficacy and Safety Study of Maintenance Treatment With rhTPO in Thrombocytopenic Subjects With ITP
NCT02244658	PHASE3	UNKNOWN	Recombinant Human Thrombopoietin (rhTPO) in Management of Chemotherapy-induced Thrombocytopenia in Acute Myelocytic Leukemia
NCT02389621	PHASE3	COMPLETED	Safety and Efficacy Study of Lusutrombopag for Thrombocytopenia in Patients With Chronic Liver Disease Undergoing Elective Invasive Procedures
NCT02444728	PHASE3	TERMINATED	Cyclophosphamide and Hydroxychloroquine for Thrombocytopenia in SLE
NCT02487563	PHASE3	COMPLETED	Prospective Study of Patients With Thrombocytopenia Following HSCT
NCT02578901	PHASE3	COMPLETED	American Trial Using Tranexamic Acid in Thrombocytopenia
NCT03326843	PHASE3	TERMINATED	Avatrombopag for the Treatment of Thrombocytopenia in Adults Scheduled for a Surgical Procedure
NCT03515096	PHASE3	COMPLETED	Eltrombopag vs. rhTPO to Increase Platelet Level After HSCT
NCT05563064	PHASE3	UNKNOWN	Effect of Herbal Formulation on Thrombocytes Count
NCT07442513	PHASE3	RECRUITING	Comparison of Etamsylate Versus Placebo to Prevent Bleeding in HSCT