Thrombocythemia 2

Summary

Thrombocythemia 2 (MONDO:0011173) is a disease caused by MPL (GenCC Definitive), with 3 cohort genes.

At a glance

• Causal gene: MPL (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 63

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	thrombocythemia 2
Mondo ID	MONDO:0011173
OMIM	601977
UMLS	C3275998
MedGen	477629
GARD	0024778
Is cancer (heuristic)	no

Also known as: familial thrombocytosis caused by mutation in MPL · MPL familial thrombocytosis · THCYT2 · thrombocythemia 2 · thrombocythemia 2, autosomal dominant, somatic mutation · thrombocythemia type 2

Data availability: 63 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › hematologic disorder › blood platelet disease › thrombocytosis disease › familial thrombocytosis › thrombocythemia 2

Related subtypes (2): thrombocythemia 1, thrombocythemia 3

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

63 retrieved; paginated sample, class counts are floors:

20 likely pathogenic, 15 uncertain significance, 15 pathogenic/likely pathogenic, 9 pathogenic, 2 benign/likely benign, 2 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
1069689	NM_005373.3(MPL):c.273C>A (p.Tyr91Ter)	MPL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1069872	NM_005373.3(MPL):c.230del (p.Cys77fs)	MPL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1075094	NM_005373.3(MPL):c.308del (p.Leu103fs)	MPL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1301356	NM_005373.3(MPL):c.367C>T (p.Arg123Ter)	MPL	Pathogenic	criteria provided, multiple submitters, no conflicts
134822	NM_005373.3(MPL):c.235_236del (p.Leu79fs)	MPL	Pathogenic	criteria provided, multiple submitters, no conflicts
135563	NM_005373.3(MPL):c.79+2T>A	MPL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
14154	NM_005373.3(MPL):c.556C>T (p.Gln186Ter)	MPL	Pathogenic	criteria provided, multiple submitters, no conflicts
14156	NM_005373.3(MPL):c.769C>T (p.Arg257Cys)	MPL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
14157	NM_005373.3(MPL):c.1904C>T (p.Pro635Leu)	MPL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
14158	NM_005373.3(MPL):c.305G>C (p.Arg102Pro)	MPL	Pathogenic	criteria provided, multiple submitters, no conflicts
14163	NM_005373.3(MPL):c.1514G>A (p.Ser505Asn)	MPL	Pathogenic	criteria provided, multiple submitters, no conflicts
1453832	NM_005373.3(MPL):c.1431G>A (p.Trp477Ter)	MPL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1504060	NM_005373.3(MPL):c.460T>C (p.Trp154Arg)	MPL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
265248	NM_005373.3(MPL):c.317C>T (p.Pro106Leu)	MPL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
265249	NM_005373.3(MPL):c.378del (p.Phe126fs)	MPL	Pathogenic	criteria provided, multiple submitters, no conflicts
2928056	NM_005373.3(MPL):c.1033C>T (p.Gln345Ter)	MPL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3340285	NM_005373.3(MPL):c.1545G>A (p.Trp515Ter)	MPL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
371574	NM_005373.3(MPL):c.127C>T (p.Arg43Ter)	MPL	Pathogenic	criteria provided, multiple submitters, no conflicts
435886	NM_005373.3(MPL):c.972del (p.Arg325fs)	MPL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
458369	NM_005373.3(MPL):c.1744_1745del (p.Leu582fs)	MPL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
631607	NM_005373.3(MPL):c.1774C>T (p.Arg592Ter)	MPL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
632897	NM_005373.3(MPL):c.1653+1del	MPL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
956954	NM_005373.3(MPL):c.268C>T (p.Arg90Ter)	MPL	Pathogenic	criteria provided, multiple submitters, no conflicts
9579	NC_012920.1(MT-TK):m.8344A>G	MT-TK	Pathogenic	reviewed by expert panel
1379348	NM_005373.3(MPL):c.407C>A (p.Pro136His)	MPL	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1492963	NM_005373.3(MPL):c.1566-1G>A	MPL	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1523230	NM_005373.3(MPL):c.1166-1G>C	MPL	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2445438	NM_005373.3(MPL):c.407C>G (p.Pro136Arg)	MPL	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3584214	NM_005373.3(MPL):c.256del (p.His86fs)	MPL	Likely pathogenic	criteria provided, single submitter
3584273	NM_005373.3(MPL):c.690+1G>A	MPL	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 10 · Orphanet: 8 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
MPL	Definitive	Autosomal dominant	thrombocythemia 2	10

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MPL	Orphanet:3318	Essential thrombocythemia
MPL	Orphanet:3319	Congenital amegakaryocytic thrombocytopenia
MPL	Orphanet:397692	Hereditary isolated aplastic anemia
MPL	Orphanet:71493	Familial thrombocytosis
MPL	Orphanet:824	Primary myelofibrosis
MT-TK	Orphanet:1349	Mitochondrial DNA-related cardiomyopathy and hearing loss
MT-TK	Orphanet:255210	Mitochondrial DNA-associated Leigh syndrome
MT-TK	Orphanet:551	MERRF

Cohort genes → proteins

3 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
MPL	HGNC:7217	ENSG00000117400	P40238	Thrombopoietin receptor	gencc,clinvar
MPIG6B	HGNC:13937	ENSG00000204420	O95866	Megakaryocyte and platelet inhibitory receptor G6b	clinvar
MT-TK	HGNC:7489	ENSG00000210156		mitochondrially encoded tRNA-Lys (AAA/G)	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MPL	Thrombopoietin receptor	Receptor for thrombopoietin that regulates hematopoietic stem cell renewal, megakaryocyte differentiation, and platelet formation.
MPIG6B	Megakaryocyte and platelet inhibitory receptor G6b	Inhibitory receptor that acts as a critical regulator of hematopoietic lineage differentiation, megakaryocyte function and platelet production.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.33

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Antibody/Immunoglobulin	1	9.7×	0.199
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MPL	Antibody/Immunoglobulin	yes		Long_hematopoietin_rcpt_CS, FN3_dom, Ig-like_fold
MPIG6B	Other/Unknown	no		G6B, G6B_V-set
MT-TK	Other/Unknown	no

Expression context

Cohort genes with no expression data: 0.

2 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
monocyte	2
male germ line stem cell (sensu Vertebrata) in testis	1
mononuclear cell	1
blood	1
leukocyte	1
caudate nucleus	1
skeletal muscle tissue	1
sural nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MPL	166	tissue_specific	marker	male germ line stem cell (sensu Vertebrata) in testis, mononuclear cell, monocyte
MPIG6B	125	tissue_specific	marker	monocyte, leukocyte, blood
MT-TK	118		yes	sural nerve, skeletal muscle tissue, caudate nucleus

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MPL	1,039
MPIG6B	360
MT-TK	0

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MPL	P40238	1
MPIG6B	O95866	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. Enrichment computed across 3 evidence-associated genes (2 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Platelet Aggregation (Plug Formation)	1	219.6×	0.006	MPL
GPVI-mediated activation cascade	1	154.3×	0.006	MPIG6B

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
platelet formation	2	702.2×	3e-05	MPL, MPIG6B
basophil homeostasis	1	8426.0×	9e-04	MPL
positive regulation of platelet formation	1	4213.0×	0.001	MPL
monocyte homeostasis	1	2808.7×	0.001	MPL
eosinophil homeostasis	1	2808.7×	0.001	MPL
thrombopoietin-mediated signaling pathway	1	1053.2×	0.002	MPL
positive regulation of lymphocyte proliferation	1	936.2×	0.002	MPL
neutrophil homeostasis	1	766.0×	0.002	MPL
megakaryocyte differentiation	1	601.9×	0.003	MPIG6B
megakaryocyte development	1	351.1×	0.004	MPIG6B
negative regulation of signal transduction	1	187.2×	0.007	MPIG6B
erythrocyte differentiation	1	133.8×	0.009	MPIG6B
blood coagulation	1	86.9×	0.013	MPIG6B
integrin-mediated signaling pathway	1	80.2×	0.013	MPIG6B
cellular response to hypoxia	1	60.6×	0.016	MPL

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 2

Druggability breadth: 1 of 3 evidence-associated genes (33%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
MPL	LUSUTROMBOPAG

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MPL	2	4
MPIG6B	0	0
MT-TK	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
LUSUTROMBOPAG	4	MPL
ELTROMBOPAG	4	MPL

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
MPL	23	Functional:15, Binding:7, ADMET:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

2 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
LUSUTROMBOPAG	4	MPL
ELTROMBOPAG	4	MPL

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	MPL
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	MPIG6B, MT-TK

Undrugged target profiles

2 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
MPIG6B	0	—
MT-TK	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.