Acquired polycythemia vera

Summary

Acquired polycythemia vera (MONDO:0009891) is a disease with 4 cohort genes (8 GWAS associations across 6 studies) and 157 clinical trials. Molecularly, JAK2 V617F confers sensitivity to Peginterferon Alfa-2b in Polycythemia Vera (CIViC Level B); 1 further subtype–drug associations are mapped below. Top therapeutic interventions include ruxolitinib, hydroxyurea, and ropeginterferon alfa-2b.

At a glance

• Prevalence: 1-5 / 10 000 (Europe) [Orphanet-validated]
• Cohort genes: 4
• GWAS associations: 8
• ClinVar variants: 16
• Phenotypes (HPO): 35
• Clinical trials: 157
• Precision-medicine evidence (CIViC): 2 subtype–drug associations

Clinical features

Epidemiology

Prevalence records

3 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Annual incidence	1-9 / 100 000	1.9	Europe	Validated
Point prevalence	1-5 / 10 000	30	Europe	Validated
Point prevalence	1-5 / 10 000	30	Italy	Validated

Signs & symptoms

Clinical features (HPO)

35 HPO clinical features (Orphanet curated; top 35 by frequency):

HPO ID	Term	Frequency
HP:0000225	Gingival bleeding	Very frequent (80-99%)
HP:0000360	Tinnitus	Very frequent (80-99%)
HP:0000421	Epistaxis	Very frequent (80-99%)
HP:0000822	Hypertension	Very frequent (80-99%)
HP:0000978	Bruising susceptibility	Very frequent (80-99%)
HP:0001681	Angina pectoris	Very frequent (80-99%)
HP:0001744	Splenomegaly	Very frequent (80-99%)
HP:0001824	Weight loss	Very frequent (80-99%)
HP:0001901	Polycythemia	Very frequent (80-99%)
HP:0002027	Abdominal pain	Very frequent (80-99%)
HP:0002240	Hepatomegaly	Very frequent (80-99%)
HP:0002315	Headache	Very frequent (80-99%)
HP:0002321	Vertigo	Very frequent (80-99%)
HP:0002488	Acute leukemia	Very frequent (80-99%)
HP:0002863	Myelodysplasia	Very frequent (80-99%)
HP:0011974	Myelofibrosis	Very frequent (80-99%)
HP:0000504	Abnormality of vision	Frequent (30-79%)
HP:0002093	Respiratory insufficiency	Frequent (30-79%)
HP:0002829	Arthralgia	Frequent (30-79%)
HP:0003401	Paresthesia	Frequent (30-79%)
HP:0012378	Fatigue	Frequent (30-79%)
HP:0000989	Pruritus	Occasional (5-29%)
HP:0001297	Stroke	Occasional (5-29%)
HP:0001409	Portal hypertension	Occasional (5-29%)
HP:0001894	Thrombocytosis	Occasional (5-29%)
HP:0001974	Leukocytosis	Occasional (5-29%)
HP:0002204	Pulmonary embolism	Occasional (5-29%)
HP:0002239	Gastrointestinal hemorrhage	Occasional (5-29%)
HP:0002639	Budd-Chiari syndrome	Occasional (5-29%)
HP:0004417	Intermittent claudication	Occasional (5-29%)
HP:0004420	Arterial thrombosis	Occasional (5-29%)
HP:0004936	Venous thrombosis	Occasional (5-29%)
HP:0030242	Portal vein thrombosis	Occasional (5-29%)
HP:0032147	Erythromelalgia	Occasional (5-29%)
HP:0033842	Early satiety	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	acquired polycythemia vera
Mondo ID	MONDO:0009891
EFO	EFO:0002429
MeSH	D011087
OMIM	263300
Orphanet	729
DOID	DOID:8997
ICD-10-CM	D45
ICD-11	818364947
NCIT	C3336
UMLS	C0032463
MedGen	45996
GARD	0007422
MedDRA	10036057
Is cancer (heuristic)	no

Also known as: acquired primary erythrocytosis · Osler-Vaquez disease · polycythaemia rubra vera · polycythemia rubra vera · polycythemia vera · polycythemia vera, somatic · primary polycythemia · PRV · PV · Vaquez disease

Data availability: 16 ClinVar variants · 8 GWAS associations (6 studies) · 7 cell lines.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › familial polycythemia › acquired polycythemia vera

Related subtypes (7): primary familial polycythemia due to EPO receptor mutation, Chuvash polycythemia, erythrocytosis, familial, 3, erythrocytosis, familial, 4, erythrocytosis, familial, 5, erythrocytosis, familial, 6, erythrocytosis, familial, 7

Genetics & variants

GWAS landscape

8 GWAS associations across 6 studies. Top hits map to 4 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs77375493	1e-323	JAK2	G	5.33
rs75202656	1e-12	EIF3LP1 - Metazoa_SRP	G	3.02
rs147001633	3e-12	DNMT3A	C	2.23
rs80215559	1e-11	SLC17A2	T	0.39
rs117085177	1e-11	DPP8	G	1.45
rs144861591	2e-11	H1-2 - H2BC4	C	0.38

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST90475609	Verma A	2024	2,102	447,939	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90435641	Zhou W	2018	390	401,145	Efficiently controlling for case-control imbalance and sample relatedness in large-scale genetic association studies.
GCST90041883	Jiang L	2021	334	456,014	A generalized linear mixed model association tool for biobank-scale data.
GCST90476478	Verma A	2024	242	121,546	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90479825	Verma A	2024	242	121,546	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90043939	Jiang L	2021	151	456,197	A generalized linear mixed model association tool for biobank-scale data.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	2
Tier 2: splice/UTR	0
Tier 3: regulatory	0
Tier 4: intronic/intergenic	4

MAF distribution

Bucket	Variants
common (>=0.05)	2
low_freq (0.01-0.05)	0
rare (<0.01)	4
unknown	0

Functional consequences

Consequence	Count
intron_variant	3
missense_variant	2
intergenic_variant	1

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs77375493	9	5073770	G>A,C,T	0	missense_variant	JAK2	1e-323	Tier 1: coding
rs75202656	14	82421073	G>A	0	intron_variant	EIF3LP1 - Metazoa_SRP	1e-12	Tier 4: intronic/intergenic
rs147001633	2	25234373	C>A,G,T	0	missense_variant	DNMT3A	3e-12	Tier 1: coding
rs80215559	6	25917997	T>C	0.064	intron_variant	SLC17A2	1e-11	Tier 4: intronic/intergenic
rs117085177	15	65466580	G>A	0.002	intron_variant	DPP8	1e-11	Tier 4: intronic/intergenic
rs144861591	6	26072764	C>T	0.053	intergenic_variant	H1-2 - H2BC4	2e-11	Tier 4: intronic/intergenic

ClinVar germline variants

16 retrieved; paginated sample, class counts are floors:

5 conflicting classifications of pathogenicity, 5 uncertain significance, 2 benign/likely benign, 1 pathogenic, 1 pathogenic/likely pathogenic, 1 likely pathogenic, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1174013	Single allele	ATM	Pathogenic	no assertion criteria provided
14662	NM_004972.4(JAK2):c.1849G>T (p.Val617Phe)	INSL6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3391058	NM_004972.4(JAK2):c.3284C>T (p.Pro1095Leu)	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
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
1251934	NM_004972.4(JAK2):c.1694G>C (p.Arg565Thr)	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
3064508	NM_004972.4(JAK2):c.1619_1627del (p.Ile540_Glu543delinsLys)	INSL6	Uncertain significance	criteria provided, single submitter
3597474	NM_004972.4(JAK2):c.2768G>T (p.Arg923Leu)	INSL6	Uncertain significance	criteria provided, single submitter
3776101	NM_004972.4(JAK2):c.2861T>G (p.Leu954Arg)	INSL6	Uncertain significance	criteria provided, single submitter
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: 0 · Orphanet: 18 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

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
VHL	Orphanet:238557	Chuvash erythrocytosis
VHL	Orphanet:276621	Sporadic pheochromocytoma/secreting paraganglioma
VHL	Orphanet:29072	Hereditary pheochromocytoma-paraganglioma
VHL	Orphanet:892	Von Hippel-Lindau disease
ATM	Orphanet:100	Ataxia-telangiectasia
ATM	Orphanet:1331	Familial prostate cancer
ATM	Orphanet:145	Hereditary breast and/or ovarian cancer syndrome
ATM	Orphanet:227535	Hereditary breast cancer
ATM	Orphanet:370109	Ataxia-telangiectasia variant
ATM	Orphanet:440437	Familial colorectal cancer Type X
ATM	Orphanet:52416	Mantle cell lymphoma
ATM	Orphanet:67038	B-cell chronic lymphocytic leukemia

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
civic_only	1
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
JAK2	HGNC:6192	ENSG00000096968	O60674	Tyrosine-protein kinase JAK2	clinvar,civic_evidence
VHL	HGNC:12687	ENSG00000134086	P40337	von Hippel-Lindau disease tumor suppressor	civic_evidence
INSL6	HGNC:6089	ENSG00000120210	Q9Y581	Insulin-like peptide INSL6	clinvar
ATM	HGNC:795	ENSG00000149311	Q13315	Serine-protein kinase ATM	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.
VHL	von Hippel-Lindau disease tumor suppressor	Involved in the ubiquitination and subsequent proteasomal degradation via the von Hippel-Lindau ubiquitination complex.
INSL6	Insulin-like peptide INSL6	May have a role in sperm development and fertilization.
ATM	Serine-protein kinase ATM	Serine/threonine protein kinase which activates checkpoint signaling upon double strand breaks (DSBs), apoptosis and genotoxic stresses such as ionizing ultraviolet A light (UVA), thereby acting as a DNA damage sensor.

Protein-family classification

Druggable: 3 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.75

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	2	13.9×	0.022
Enzyme (other)	1	3.0×	0.441
Other/Unknown	1	0.5×	0.962

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
JAK2	Kinase	yes	2.7.10.2	FERM_domain, Prot_kinase_dom, SH2
VHL	Enzyme (other)	yes	2.3.2.B13	VHL_tumour_suppress_b/a_dom, VHL_alpha_dom, VHL_beta_dom
INSL6	Other/Unknown	no		Insulin-like, Insulin-like_pep_6, Insulin_CS
ATM	Kinase	yes	2.7.11.1	PI3/4_kinase_cat_dom, PIK-rel_kinase_FAT, FATC_dom

Expression context

Cohort genes with no expression data: 0.

4 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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
calcaneal tendon	2
monocyte	2
blood vessel layer	1
cortical plate	1
mononuclear cell	1
left testis	1
male germ line stem cell (sensu Vertebrata) in testis	1
right testis	1
colonic epithelium	1
corpus callosum	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
VHL	186	ubiquitous	marker	cortical plate, monocyte, mononuclear cell
INSL6	152	tissue_specific	marker	male germ line stem cell (sensu Vertebrata) in testis, left testis, right testis
ATM	286	ubiquitous	marker	calcaneal tendon, colonic epithelium, corpus callosum

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ATM	7,383
JAK2	6,197
VHL	3,522
INSL6	509

Structural data

PDB: 3 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
JAK2	O60674	164
VHL	P40337	142
ATM	Q13315	14

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
INSL6	Q9Y581	54.46

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 132. Enrichment computed across 4 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Replication of the SARS-CoV-1 genome	1	951.7×	0.018	VHL
Replication of the SARS-CoV-2 genome	1	951.7×	0.018	VHL
Sensing of DNA Double Strand Breaks	1	634.4×	0.018	ATM
Erythropoietin activates Phospholipase C gamma (PLCG)	1	543.8×	0.018	JAK2
Erythropoietin activates STAT5	1	543.8×	0.018	JAK2
Interleukin-6 family signaling	1	475.8×	0.018	JAK2
IFNG signaling activates MAPKs	1	475.8×	0.018	JAK2
Interleukin-23 signaling	1	423.0×	0.018	JAK2
MAPK1 (ERK2) activation	1	380.7×	0.018	JAK2
Signaling by KIT in disease	1	380.7×	0.018	JAK2
RHOBTB3 ATPase cycle	1	380.7×	0.018	VHL
MAPK3 (ERK1) activation	1	346.1×	0.018	JAK2
Signaling by Leptin	1	346.1×	0.018	JAK2
Signaling by Erythropoietin	1	346.1×	0.018	JAK2
Interleukin-27 signaling	1	346.1×	0.018	JAK2
Interleukin-6 signaling	1	317.2×	0.018	JAK2
TP53 Regulates Transcription of Caspase Activators and Caspases	1	317.2×	0.018	ATM
Interleukin-35 Signalling	1	317.2×	0.018	JAK2
Erythropoietin activates Phosphoinositide-3-kinase (PI3K)	1	317.2×	0.018	JAK2
Pexophagy	1	317.2×	0.018	ATM
Defective homologous recombination repair (HRR) due to PALB2 loss of function	1	317.2×	0.018	ATM
Regulation of IFNG signaling	1	271.9×	0.018	JAK2
Diseases of DNA Double-Strand Break Repair	1	271.9×	0.018	ATM
Defective homologous recombination repair (HRR) due to BRCA2 loss of function	1	271.9×	0.018	ATM
Prolactin receptor signaling	1	253.8×	0.018	JAK2
Stabilization of p53	1	253.8×	0.018	ATM
Erythropoietin activates RAS	1	253.8×	0.018	JAK2
p53-Dependent G1 DNA Damage Response	1	237.9×	0.018	ATM
p53-Dependent G1/S DNA damage checkpoint	1	237.9×	0.018	ATM
G1/S DNA Damage Checkpoints	1	223.9×	0.018	ATM

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
negative regulation of TORC1 signaling	2	216.1×	0.004	VHL, ATM
positive regulation of cell differentiation	2	178.3×	0.004	JAK2, VHL
nuclear receptor-mediated mineralocorticoid signaling pathway	1	5617.3×	0.005	JAK2
symbiont-induced defense-related programmed cell death	1	5617.3×	0.005	JAK2
interleukin-35-mediated signaling pathway	1	5617.3×	0.005	JAK2
response to interleukin-12	1	2808.7×	0.005	JAK2
establishment of RNA localization to telomere	1	2808.7×	0.005	ATM
establishment of protein-containing complex localization to telomere	1	2808.7×	0.005	ATM
positive regulation of growth factor dependent skeletal muscle satellite cell proliferation	1	2808.7×	0.005	JAK2
positive regulation of telomerase catalytic core complex assembly	1	2808.7×	0.005	ATM
regulation of postsynapse to nucleus signaling pathway	1	2808.7×	0.005	JAK2
protein autophosphorylation	2	96.8×	0.005	JAK2, ATM
pre-B cell allelic exclusion	1	1872.4×	0.006	ATM
positive regulation of growth hormone receptor signaling pathway	1	1872.4×	0.006	JAK2
cellular response to nitrosative stress	1	1872.4×	0.006	ATM
collagen-activated signaling pathway	1	1404.3×	0.006	JAK2
granulocyte-macrophage colony-stimulating factor signaling pathway	1	1404.3×	0.006	JAK2
activation of Janus kinase activity	1	1404.3×	0.006	JAK2
peptidyl-serine autophosphorylation	1	1123.5×	0.006	ATM
negative regulation of telomere capping	1	1123.5×	0.006	ATM
regulation of telomere maintenance via telomerase	1	936.2×	0.006	ATM
post-embryonic hemopoiesis	1	936.2×	0.006	JAK2
cellular response to interleukin-3	1	936.2×	0.006	JAK2
interleukin-5-mediated signaling pathway	1	936.2×	0.006	JAK2
interleukin-23-mediated signaling pathway	1	936.2×	0.006	JAK2
erythropoietin-mediated signaling pathway	1	936.2×	0.006	JAK2
positive regulation of NK T cell proliferation	1	936.2×	0.006	JAK2
positive regulation of leukocyte proliferation	1	936.2×	0.006	JAK2
regulation of cellular response to hypoxia	1	936.2×	0.006	VHL
positive regulation of telomere maintenance via telomere lengthening	1	936.2×	0.006	ATM

Therapeutics

Drugs indicated for this disease

1 approved, 9 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
ROPEGINTERFERON ALFA-2B	Approved (phase 4)
Anagrelide	Phase 3 (in late-stage trials)
Aspirin	Phase 3 (in late-stage trials)
Hydroxyurea	Phase 3 (in late-stage trials)
Interferon Alfa	Phase 3 (in late-stage trials)
PEGINTERFERON ALFA-2A	Phase 3 (in late-stage trials)
PEGINTERFERON ALFA-2B	Phase 3 (in late-stage trials)
Pipobroman	Phase 3 (in late-stage trials)
Rusfertide	Phase 3 (in late-stage trials)
Ruxolitinib	Phase 3 (in late-stage trials)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Bomedemstat, Clopidogrel, Dasatinib Anhydrous, Erlotinib, Fludarabine Phosphate, Idasanutlin, Imetelstat, Lenalidomide, Lestaurtinib, Melphalan, Methotrexate, Momelotinib, Mycophenolate Mofetil, Navtemadlin, Pomalidomide, Prednisone, Tacrolimus Anhydrous, Tipifarnib, Vorinostat, Zinpentraxin Alfa.

Drug target analysis

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

Druggability breadth: 3 of 4 evidence-associated genes (75%) 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
VHL	OSIMERTINIB
ATM	AMIODARONE HYDROCHLORIDE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
JAK2	100	4
ATM	35	4
VHL	7	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, VHL
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): 3.

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

Symbol	Assays	Type breakdown
VHL	3,575	Binding:3482, Functional:54, ADMET:39
JAK2	2,018	Binding:1911, Functional:51, ADMET:48, Unclassified:4, Toxicity:4
ATM	240	Binding:233, Functional:5, ADMET:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
JAK2	2.7.10.2	non-specific protein-tyrosine kinase
VHL	2.3.2.B13
ATM	2.7.11.1	non-specific serine/threonine protein 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
VHL	3,575
ATM	240

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

26 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)
TOFACITINIB	4	JAK2
UPADACITINIB	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
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, VHL
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)	3	JAK2, VHL, ATM
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: 157.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE2	50
Not specified	50
PHASE1	21
PHASE3	19
PHASE1/PHASE2	12
PHASE4	3
EARLY_PHASE1	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT02386800	PHASE4	ACTIVE_NOT_RECRUITING	CINC424A2X01B Rollover Protocol
NCT06290765	PHASE4	NOT_YET_RECRUITING	Efficacy and Safety of Ropeginterferon Alfa 2b (P1101) for Patients With Polycythemia Vera
NCT05853458	PHASE4	TERMINATED	Evaluation of HU-resistance in Adult Patients With Polycythemia Vera Who Meet PV-AIM Predictors
NCT04116502	PHASE3	RECRUITING	MITHRIDATE: Ruxolitinib Versus Hydroxycarbamide or Interferon as First Line Therapy in High Risk Polycythemia Vera
NCT04655092	PHASE3	RECRUITING	Extension Study of P1101 After Completion of Phase 2 Study in PV Patients or Phase 3 Study in ET Patients
NCT05198960	PHASE3	RECRUITING	AVAJAK: Apixaban/Rivaroxaban Versus Aspirin for Primary Prevention of Thrombo-embolic Complications in JAK2V617F-positive Myeloproliferative Neoplasms
NCT05210790	PHASE3	ACTIVE_NOT_RECRUITING	A Phase 3 Study of Rusfertide in Patients With Polycythemia Vera
NCT05481151	PHASE3	ACTIVE_NOT_RECRUITING	A Study to Assess Efficacy, Safety, and Tolerability of P1101 in Adult Patients With PV
NCT06033586	PHASE3	ACTIVE_NOT_RECRUITING	Study to Evaluate the Long-term Safety of Rusfertide (PTG-300) in Subjects With Polycythemia Vera
NCT06093672	PHASE3	RECRUITING	Study on Efficacy and Safety of Givinostat Versus Hydroxyurea in Patients With Polycythemia Vera
NCT06351631	PHASE3	RECRUITING	A Study to Evaluate Safety and Efficacy of Bomedemstat (MK-3543-017)
NCT07429266	PHASE3	RECRUITING	A Study of Sapablursen Evaluating the Safety and Efficacy in Participants With Polycythemia Vera (PV)
NCT01243944	PHASE3	COMPLETED	Study of Efficacy and Safety in Polycythemia Vera Subjects Who Are Resistant to or Intolerant of Hydroxyurea: JAK Inhibitor INC424 (INCB018424) Tablets Versus Best Available Care: (The RESPONSE Trial)
NCT01387763	PHASE3	COMPLETED	A Study of Low Dose Interferon Alpha Versus Hydroxyurea in Treatment of Chronic Myeloid Neoplasms
NCT01632904	PHASE3	COMPLETED	Randomized Switch Study From Hydroxyurea to Ruxolitinib for RELIEF of Polycythemia Vera Symptoms: The Relief Study
NCT01645124	PHASE3	TERMINATED	Large-scale Trial Testing the Intensity of CYTOreductive Therapy in Polycythemia Vera (PV)
NCT01949805	PHASE3	COMPLETED	Pegylated Interferon Alpha-2b Versus Hydroxyurea in Polycythemia Vera
NCT02038036	PHASE3	COMPLETED	Ruxolitinib Efficacy and Safety in Patients With HU Resistant or Intolerant Polycythemia Vera vs Best Available Therapy.
NCT02218047	PHASE3	COMPLETED	AOP2014 vs. BAT in Patients With Polycythemia Vera Who Previously Participated in the PROUD-PV Study.
NCT02292446	PHASE3	COMPLETED	Expanded Treatment Protocol (ETP) of Ruxolitinib in Patients With Polycythemia Vera Who Were Hydroxyurea Resistant or Intolerant and for Whom no Treatment Alternatives Was Available.
NCT02523638	PHASE3	COMPLETED	Study to Assess the Self-administration of AOP2014 Using a Pen, Developed for the Treatment of Polycythemia Vera Patients
NCT06002490	PHASE3	COMPLETED	A Study to Evaluate P1101 in Japanese PV Patients
NCT02577926	PHASE2	ACTIVE_NOT_RECRUITING	The Ruxo-BEAT Trial in Patients With High-risk Polycythemia Vera or High-risk Essential Thrombocythemia
NCT03289910	PHASE2	ACTIVE_NOT_RECRUITING	Topotecan Hydrochloride and Carboplatin With or Without Veliparib in Treating Advanced Myeloproliferative Disorders and Acute Myeloid Leukemia or Chronic Myelomonocytic Leukemia
NCT03862157	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Azacitidine, Venetoclax, and Pevonedistat in Treating Patients With Newly Diagnosed Acute Myeloid Leukemia
NCT04262141	PHASE2	ACTIVE_NOT_RECRUITING	IMG-7289 in Patients With Essential Thrombocythemia (ET) or Polycythemia Vera (PV)
NCT04282187	PHASE2	RECRUITING	Decitabine With Ruxolitinib, Fedratinib or Pacritinib for the Treatment of Accelerated/Blast Phase Myeloproliferative Neoplasms
NCT04644211	PHASE2	RECRUITING	Ruxolitinib in Thrombocythemia and Polycythemia Vera
NCT05031897	PHASE2	RECRUITING	Two Step Haplo With Radiation Conditioning
NCT05123365	PHASE1/PHASE2	RECRUITING	An Optimal Dose Finding Study of N-Acetylcysteine in Patients With Myeloproliferative Neoplasms
NCT05485948	PHASE2	ACTIVE_NOT_RECRUITING	A Study to Access Efficacy and Safety of P1101 in Chinese PV Patients Who Are Intolerant or Resistance to HU
NCT05499013	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Study to Assess SLN124 in Patients With Polycythemia Vera
NCT05870475	PHASE2	RECRUITING	Pegylated Interferon α-2b in Combination With Ruxolitinib for Treating Hydroxyurea-resistant/Intolerant PV
NCT06063486	PHASE2	RECRUITING	Curcumin to Improve Inflammation and Symptoms in Patients With Clonal Cytopenia of Undetermined Significance, Low Risk Myelodysplastic Syndrome, and Myeloproliferative Neoplasms
NCT06541249	PHASE2	RECRUITING	MethoTRExATE in MyelOpRolifErative Neoplasms (TREATMORE) Trial
NCT06985147	PHASE2	RECRUITING	A Phase 2, Open-Label Study of DISC-3405 in Participants With Polycythemia Vera (PV)
NCT07232290	PHASE2	RECRUITING	Phase IIa Study on Flonoltinib Maleate Tablets in the Treatment of Patients With Polycythemia Vera
NCT00039416	PHASE2	COMPLETED	Imatinib Mesylate in Treating Patients With Myelofibrosis
NCT00047190	PHASE2	COMPLETED	Tipifarnib in Treating Patients With Myelofibrosis and Myeloid Metaplasia
NCT00052520	PHASE1/PHASE2	COMPLETED	Biological Therapy in Treating Patients With Advanced Myelodysplastic Syndrome, Acute or Chronic Myeloid Leukemia, or Acute Lymphoblastic Leukemia Who Are Undergoing Stem Cell Transplantation

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
RUXOLITINIB	4	23
HYDROXYUREA	4	7
ROPEGINTERFERON ALFA-2B	4	6
DASATINIB ANHYDROUS	4	4
FOSCARNET	4	4
PACRITINIB	4	3
GIVINOSTAT	4	2
MOMELOTINIB	4	2
SONIDEGIB	4	2
CEDAZURIDINE	4	1
FEDRATINIB	4	1
GANCICLOVIR	4	1
IMATINIB MESYLATE	4	1
MIRABEGRON	4	1
PANOBINOSTAT	4	1
PEGINTERFERON ALFA-2A	4	1
PEGINTERFERON ALFA-2B	4	1
POMALIDOMIDE	4	1
SILTUXIMAB	4	1
TOPOTECAN HYDROCHLORIDE	4	1
UMBRALISIB TOSYLATE	4	1
VALGANCICLOVIR	4	1
RUSFERTIDE	3	4
VELIPARIB	3	4
BOMEDEMSTAT	3	3
IDASANUTLIN	3	2
LESTAURTINIB	3	2
CURCUMIN	3	1
IMETELSTAT	3	1
ITACITINIB	3	1

Precision-medicine subtype map (CIViC)

Drug × molecular subtype: 2 predictive associations from 2 curated evidence items; also 3 predisposing.

Molecular subtype	Therapy	Effect	Level	CIViC
JAK2 V617F	Peginterferon Alfa-2b	Sensitivity/Response	CIViC B	EID19
JAK2 V617F	Fedratinib	Sensitivity/Response	CIViC D	EID20