Thrombocythemia 3

Summary

Thrombocythemia 3 (MONDO:0013794) is a disease caused by JAK2 (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: JAK2 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 27

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	thrombocythemia 3
Mondo ID	MONDO:0013794
OMIM	614521
UMLS	C3281125
MedGen	482755
GARD	0024950
Is cancer (heuristic)	no

Also known as: familial thrombocytosis caused by mutation in JAK2 · JAK2 familial thrombocytosis · THCYT3 · thrombocythemia 3 · thrombocythemia 3, autosomal dominant, somatic mutation · thrombocythemia type 3

Data availability: 27 ClinVar variants · 3 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 3

Related subtypes (2): thrombocythemia 1, thrombocythemia 2

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

27 retrieved; paginated sample, class counts are floors:

14 uncertain significance, 7 conflicting classifications of pathogenicity, 2 benign/likely benign, 1 pathogenic/likely pathogenic, 1 pathogenic, 1 likely pathogenic, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
14662	NM_004972.4(JAK2):c.1849G>T (p.Val617Phe)	INSL6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
29763	NM_004972.4(JAK2):c.1849G>A (p.Val617Ile)	INSL6	Pathogenic	no assertion criteria provided
4813688	NM_004972.4(JAK2):c.2813G>A (p.Arg938Gln)	INSL6	Likely pathogenic	criteria provided, single submitter
1028834	NM_004972.4(JAK2):c.1641+6T>C	INSL6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1336051	NM_004972.4(JAK2):c.1711G>A (p.Gly571Ser)	INSL6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
134552	NM_004972.4(JAK2):c.2171T>C (p.Ile724Thr)	INSL6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
134557	NM_004972.4(JAK2):c.3323A>G (p.Asn1108Ser)	INSL6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2052244	NM_004972.4(JAK2):c.337C>G (p.Leu113Val)	INSL6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
367131	NM_004972.4(JAK2):c.2762-10_2762-9del	INSL6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1031487	NM_004972.4(JAK2):c.2175A>G (p.Glu725=)	JAK2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1712321	NM_004972.4(JAK2):c.2444T>C (p.Leu815Pro)	INSL6	Uncertain significance	criteria provided, single submitter
1803760	NM_004972.4(JAK2):c.1822C>G (p.His608Asp)	INSL6	Uncertain significance	criteria provided, single submitter
2432944	NM_004972.4(JAK2):c.2651T>G (p.Leu884Arg)	INSL6	Uncertain significance	criteria provided, single submitter
2585044	NM_004972.4(JAK2):c.3311A>C (p.Glu1104Ala)	INSL6	Uncertain significance	criteria provided, single submitter
2585137	NM_004972.4(JAK2):c.1054C>T (p.Leu352=)	INSL6	Uncertain significance	criteria provided, single submitter
2636010	NM_004972.4(JAK2):c.2768G>A (p.Arg923His)	INSL6	Uncertain significance	criteria provided, multiple submitters, no conflicts
2663979	NM_004972.4(JAK2):c.2755A>T (p.Ser919Cys)	INSL6	Uncertain significance	criteria provided, multiple submitters, no conflicts
2664166	NM_004972.4(JAK2):c.1057G>A (p.Glu353Lys)	INSL6	Uncertain significance	criteria provided, single submitter
2862680	NM_004972.4(JAK2):c.2390C>G (p.Ser797Cys)	INSL6	Uncertain significance	criteria provided, multiple submitters, no conflicts
3242123	NM_004972.4(JAK2):c.1340T>A (p.Ile447Asn)	INSL6	Uncertain significance	criteria provided, single submitter
3597474	NM_004972.4(JAK2):c.2768G>T (p.Arg923Leu)	INSL6	Uncertain significance	criteria provided, single submitter
4079032	NM_004972.4(JAK2):c.1819A>G (p.Lys607Glu)	INSL6	Uncertain significance	criteria provided, single submitter
4813146	NM_004972.4(JAK2):c.1674G>T (p.Lys558Asn)	INSL6	Uncertain significance	criteria provided, single submitter
2585138	NM_004972.4(JAK2):c.94A>G (p.Met32Val)	JAK2	Uncertain significance	criteria provided, multiple submitters, no conflicts
134559	NM_004972.4(JAK2):c.380G>A (p.Gly127Asp)	INSL6	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
585092	NM_004972.4(JAK2):c.2571+5A>C	INSL6	Likely benign	criteria provided, multiple submitters, no conflicts
134555	NM_004972.4(JAK2):c.3188G>A (p.Arg1063His)	JAK2	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 6 · 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
JAK2	Strong	Autosomal dominant	thrombocythemia 3	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
JAK2	Orphanet:131	Budd-Chiari syndrome
JAK2	Orphanet:3318	Essential thrombocythemia
JAK2	Orphanet:667662	Breast implant-associated anaplastic large cell lymphoma
JAK2	Orphanet:71493	Familial thrombocytosis
JAK2	Orphanet:729	Polycythemia vera
JAK2	Orphanet:824	Primary myelofibrosis

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
JAK2	HGNC:6192	ENSG00000096968	O60674	Tyrosine-protein kinase JAK2	gencc,clinvar
INSL6	HGNC:6089	ENSG00000120210	Q9Y581	Insulin-like peptide INSL6	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
JAK2	Tyrosine-protein kinase JAK2	Non-receptor tyrosine kinase involved in various processes such as cell growth, development, differentiation or histone modifications.
INSL6	Insulin-like peptide INSL6	May have a role in sperm development and fertilization.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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
Kinase	1	13.9×	0.142
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
JAK2	Kinase	yes	2.7.10.2	FERM_domain, Prot_kinase_dom, SH2
INSL6	Other/Unknown	no		Insulin-like, Insulin-like_pep_6, Insulin_CS

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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
blood vessel layer	1
calcaneal tendon	1
monocyte	1
left testis	1
male germ line stem cell (sensu Vertebrata) in testis	1
right testis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
JAK2	272	ubiquitous	marker	calcaneal tendon, monocyte, blood vessel layer
INSL6	152	tissue_specific	marker	male germ line stem cell (sensu Vertebrata) in testis, left testis, right testis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
JAK2	6,197
INSL6	509

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
JAK2	O60674	164

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
INSL6	Q9Y581	54.46

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 66. Enrichment computed across 2 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Erythropoietin activates Phospholipase C gamma (PLCG)	1	1631.4×	0.005	JAK2
Erythropoietin activates STAT5	1	1631.4×	0.005	JAK2
Interleukin-6 family signaling	1	1427.5×	0.005	JAK2
IFNG signaling activates MAPKs	1	1427.5×	0.005	JAK2
Interleukin-23 signaling	1	1268.9×	0.005	JAK2
MAPK1 (ERK2) activation	1	1142.0×	0.005	JAK2
Signaling by KIT in disease	1	1142.0×	0.005	JAK2
MAPK3 (ERK1) activation	1	1038.2×	0.005	JAK2
Signaling by Leptin	1	1038.2×	0.005	JAK2
Signaling by Erythropoietin	1	1038.2×	0.005	JAK2
Interleukin-27 signaling	1	1038.2×	0.005	JAK2
Interleukin-6 signaling	1	951.7×	0.005	JAK2
Interleukin-35 Signalling	1	951.7×	0.005	JAK2
Erythropoietin activates Phosphoinositide-3-kinase (PI3K)	1	951.7×	0.005	JAK2
Regulation of IFNG signaling	1	815.7×	0.005	JAK2
Prolactin receptor signaling	1	761.3×	0.005	JAK2
Erythropoietin activates RAS	1	761.3×	0.005	JAK2
RAF-independent MAPK1/3 activation	1	634.4×	0.005	JAK2
Interleukin-2 family signaling	1	634.4×	0.005	JAK2
IL-6-type cytokine receptor ligand interactions	1	634.4×	0.005	JAK2
Signaling by CSF3 (G-CSF)	1	571.0×	0.006	JAK2
Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants	1	519.1×	0.006	JAK2
Interleukin-12 family signaling	1	475.8×	0.006	JAK2
Growth hormone receptor signaling	1	475.8×	0.006	JAK2
Inactivation of CSF3 (G-CSF) signaling	1	439.2×	0.006	JAK2
Signaling by RAS mutants	1	423.0×	0.006	JAK2
Interleukin-20 family signaling	1	423.0×	0.006	JAK2
Interleukin-12 signaling	1	407.9×	0.006	JAK2
Interleukin receptor SHC signaling	1	407.9×	0.006	JAK2
G1 Phase	1	393.8×	0.006	JAK2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
nuclear receptor-mediated mineralocorticoid signaling pathway	1	16852.0×	0.002	JAK2
symbiont-induced defense-related programmed cell death	1	16852.0×	0.002	JAK2
interleukin-35-mediated signaling pathway	1	16852.0×	0.002	JAK2
response to interleukin-12	1	8426.0×	0.002	JAK2
positive regulation of growth factor dependent skeletal muscle satellite cell proliferation	1	8426.0×	0.002	JAK2
regulation of postsynapse to nucleus signaling pathway	1	8426.0×	0.002	JAK2
positive regulation of growth hormone receptor signaling pathway	1	5617.3×	0.002	JAK2
collagen-activated signaling pathway	1	4213.0×	0.002	JAK2
granulocyte-macrophage colony-stimulating factor signaling pathway	1	4213.0×	0.002	JAK2
activation of Janus kinase activity	1	4213.0×	0.002	JAK2
post-embryonic hemopoiesis	1	2808.7×	0.002	JAK2
cellular response to interleukin-3	1	2808.7×	0.002	JAK2
interleukin-5-mediated signaling pathway	1	2808.7×	0.002	JAK2
interleukin-23-mediated signaling pathway	1	2808.7×	0.002	JAK2
erythropoietin-mediated signaling pathway	1	2808.7×	0.002	JAK2
positive regulation of NK T cell proliferation	1	2808.7×	0.002	JAK2
positive regulation of leukocyte proliferation	1	2808.7×	0.002	JAK2
interleukin-3-mediated signaling pathway	1	2407.4×	0.002	JAK2
thrombopoietin-mediated signaling pathway	1	2106.5×	0.002	JAK2
interleukin-12-mediated signaling pathway	1	1872.4×	0.002	JAK2
mammary gland epithelium development	1	1872.4×	0.002	JAK2
response to hydroperoxide	1	1685.2×	0.002	JAK2
regulation of nitric oxide biosynthetic process	1	1685.2×	0.002	JAK2
growth hormone receptor signaling pathway via JAK-STAT	1	1532.0×	0.002	JAK2
negative regulation of protein localization to chromatin	1	1532.0×	0.002	JAK2
positive regulation of natural killer cell proliferation	1	1404.3×	0.002	JAK2
regulation of receptor signaling pathway via JAK-STAT	1	1404.3×	0.002	JAK2
positive regulation of T-helper 17 type immune response	1	1404.3×	0.002	JAK2
enzyme-linked receptor protein signaling pathway	1	1296.3×	0.002	JAK2
positive regulation of platelet activation	1	1296.3×	0.002	JAK2

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 evidence-associated genes (50%) 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
JAK2	FEDRATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
JAK2	100	4
INSL6	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
FEDRATINIB	4	JAK2
RUXOLITINIB	4	JAK2
TOFACITINIB	4	JAK2
UPADACITINIB	4	JAK2
MOMELOTINIB	4	JAK2
PONATINIB	4	JAK2
AXITINIB	4	JAK2
NICLOSAMIDE	4	JAK2
RUXOLITINIB PHOSPHATE	4	JAK2
INFIGRATINIB PHOSPHATE	4	JAK2
INFIGRATINIB	4	JAK2
ENTRECTINIB	4	JAK2
DABRAFENIB	4	JAK2
PACRITINIB	4	JAK2
TOFACITINIB CITRATE	4	JAK2
BARICITINIB	4	JAK2
CERITINIB	4	JAK2
BOSUTINIB	4	JAK2
PEFICITINIB	4	JAK2
LORLATINIB	4	JAK2
FILGOTINIB	4	JAK2
BRIGATINIB	4	JAK2
ABROCITINIB	4	JAK2
REPOTRECTINIB	4	JAK2
DEUCRAVACITINIB	4	JAK2
PRALSETINIB	4	JAK2
CRAVACITINIB	4	JAK2
PAZOPANIB	4	JAK2
NINTEDANIB	4	JAK2
SUNITINIB	4	JAK2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
JAK2	2,018	Binding:1911, Functional:51, ADMET:48, Unclassified:4, Toxicity:4

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
JAK2	2.7.10.2	non-specific protein-tyrosine kinase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
JAK2	2,018

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

30 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)
FEDRATINIB	4	JAK2
RUXOLITINIB	4	JAK2
TOFACITINIB	4	JAK2
UPADACITINIB	4	JAK2
MOMELOTINIB	4	JAK2
PONATINIB	4	JAK2
AXITINIB	4	JAK2
NICLOSAMIDE	4	JAK2
RUXOLITINIB PHOSPHATE	4	JAK2
INFIGRATINIB PHOSPHATE	4	JAK2
INFIGRATINIB	4	JAK2
ENTRECTINIB	4	JAK2
DABRAFENIB	4	JAK2
PACRITINIB	4	JAK2
TOFACITINIB CITRATE	4	JAK2
BARICITINIB	4	JAK2
CERITINIB	4	JAK2
BOSUTINIB	4	JAK2
PEFICITINIB	4	JAK2
LORLATINIB	4	JAK2
FILGOTINIB	4	JAK2
BRIGATINIB	4	JAK2
ABROCITINIB	4	JAK2
REPOTRECTINIB	4	JAK2
DEUCRAVACITINIB	4	JAK2
PRALSETINIB	4	JAK2
CRAVACITINIB	4	JAK2
PAZOPANIB	4	JAK2
NINTEDANIB	4	JAK2
SUNITINIB	4	JAK2

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	JAK2
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	1	INSL6

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
INSL6	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.