Polycythemia

Summary

Polycythemia (MONDO:0005571) is a disease (an umbrella term covering 5 Mondo subtypes) with 2 cohort genes (13 GWAS associations across 5 studies) and 10 clinical trials. Top therapeutic interventions include lisinopril anhydrous, oxygen, and tak-901.

At a glance

• Umbrella term: 5 Mondo subtypes
• Cohort genes: 2
• GWAS associations: 13
• ClinVar variants: 2
• Clinical trials: 10

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	polycythemia
Mondo ID	MONDO:0005571
EFO	EFO:0005804
MeSH	D011086
Orphanet	98427
DOID	DOID:8432
NCIT	C26863
UMLS	C0032461
MedGen	18552
MedDRA	10036051
Is cancer (heuristic)	no

Also known as: polycythemia · polycythemia (disease)

Data availability: 2 ClinVar variants · 13 GWAS associations (5 studies) · 1 HPO phenotype.

Disease family

An umbrella term covering 5 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › immune system disorder › bone marrow disorder › polycythemia

Related subtypes (6): bone marrow failure syndrome, osteomyelitis, bone marrow neoplasm, Fanconi anemia, Drachtman Weinblatt Sitarz syndrome, premature ovarian failure 15

Subtypes (5): familial polycythemia, polycythemia neonatorum, acquired polycythemia, physiological polycythemia, secondary polycythemia

Genetics & variants

GWAS landscape

13 GWAS associations across 5 studies. Top hits map to 7 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs77375493	2e-117	JAK2	G	3.14
rs17476364	1e-20	HK1	T	0.33
rs1800562	1e-17	HFE, H2BC4	G	0.34
rs855791	2e-15	TMPRSS6	A	0.17
chr2:46347023	4e-13		G	0.21
rs3768751	1e-12	PRKCE	T	0.19
rs1037585879	1e-11	CNTROB	A	2.94
rs56261104	3e-11	EPO - ZAN	C	0.16

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST90475822	Verma A	2024	4,086	444,229	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90476490	Verma A	2024	452	121,102	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90479992	Verma A	2024	452	121,102	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90481673	Verma A	2024	431	59,170	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90435833	Zhou W	2018	295	400,749	Efficiently controlling for case-control imbalance and sample relatedness in large-scale genetic association studies.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

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

MAF distribution

Bucket	Variants
common (>=0.05)	6
low_freq (0.01-0.05)	0
rare (<0.01)	2
unknown	0

Functional consequences

Consequence	Count
missense_variant	3
intron_variant	3
unknown	1
regulatory_region_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	2e-117	Tier 1: coding
rs17476364	10	69334748	T>C	0.097	intron_variant	HK1	1e-20	Tier 4: intronic/intergenic
rs1800562	6	26092913	G>A,T	0.051	missense_variant	HFE, H2BC4	1e-17	Tier 1: coding
rs855791	22	37066896	A>C,G,T	0.384	missense_variant	TMPRSS6	2e-15	Tier 1: coding
chr2:46347023				0.26			4e-13	Tier 4: intronic/intergenic
rs3768751	2	46119577	T>A,C	0.32	intron_variant	PRKCE	1e-12	Tier 4: intronic/intergenic
rs1037585879	17	7935355	A>C	0.001	intron_variant	CNTROB	1e-11	Tier 4: intronic/intergenic
rs56261104	7	100727213	C>A,G	0.29	regulatory_region_variant	EPO - ZAN	3e-11	Tier 3: regulatory

ClinVar germline variants

2 retrieved; paginated sample, class counts are floors:

1 pathogenic/likely pathogenic, 1 uncertain significance

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
161400	NM_000551.4(VHL):c.235C>T (p.Arg79Cys)	VHL	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 4 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
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

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
VHL	HGNC:12687	ENSG00000134086	P40337	von Hippel-Lindau disease tumor suppressor	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)
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.

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
Enzyme (other)	1	6.0×	0.320
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
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

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
cortical plate	1
monocyte	1
mononuclear cell	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
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

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
VHL	3,522
INSL6	509

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
VHL	P40337	142

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
INSL6	Q9Y581	54.46

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 7. 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
Replication of the SARS-CoV-1 genome	1	2855.0×	0.001	VHL
Replication of the SARS-CoV-2 genome	1	2855.0×	0.001	VHL
RHOBTB3 ATPase cycle	1	1142.0×	0.002	VHL
SUMOylation of ubiquitinylation proteins	1	292.8×	0.006	VHL
Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha	1	196.9×	0.007	VHL
Neddylation	1	47.4×	0.025	VHL
Antigen processing: Ubiquitination & Proteasome degradation	1	37.2×	0.027	VHL

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
regulation of cellular response to hypoxia	1	2808.7×	0.007	VHL
negative regulation of receptor signaling pathway via JAK-STAT	1	887.0×	0.009	VHL
negative regulation of transcription elongation by RNA polymerase II	1	766.0×	0.009	VHL
amyloid fibril formation	1	601.9×	0.009	VHL
negative regulation of signal transduction	1	374.5×	0.010	VHL
negative regulation of TORC1 signaling	1	324.1×	0.010	VHL
positive regulation of cell differentiation	1	267.5×	0.010	VHL
negative regulation of autophagy	1	259.3×	0.010	VHL
cell morphogenesis	1	157.5×	0.015	VHL
cellular response to hypoxia	1	121.2×	0.017	VHL
regulation of gene expression	1	83.4×	0.023	VHL
negative regulation of gene expression	1	69.1×	0.024	VHL
protein stabilization	1	66.9×	0.024	VHL
proteasome-mediated ubiquitin-dependent protein catabolic process	1	52.2×	0.029	VHL
negative regulation of cell population proliferation	1	42.1×	0.032	VHL
protein ubiquitination	1	41.4×	0.032	VHL
negative regulation of apoptotic process	1	34.8×	0.034	VHL
proteolysis	1	34.2×	0.034	VHL
regulation of DNA-templated transcription	1	31.6×	0.035	VHL
positive regulation of DNA-templated transcription	1	27.9×	0.038	VHL
negative regulation of transcription by RNA polymerase II	1	17.7×	0.056	VHL

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
VHL	OSIMERTINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
VHL	7	4
INSL6	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
OSIMERTINIB	4	VHL
BRIGATINIB	4	VHL
CRIZOTINIB	4	VHL
ADAGRASIB	4	VHL
ZIMLOVISERTIB	2	VHL
FORETINIB	2	VHL
DT-2216	1	VHL

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
VHL	3,575	Binding:3482, Functional:54, ADMET:39

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
VHL	2.3.2.B13

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
VHL	3,575

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

7 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)
OSIMERTINIB	4	VHL
BRIGATINIB	4	VHL
CRIZOTINIB	4	VHL
ADAGRASIB	4	VHL
ZIMLOVISERTIB	2	VHL
FORETINIB	2	VHL
DT-2216	1	VHL

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	VHL
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: 10.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	6
PHASE4	2
PHASE2	1
PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT06089603	PHASE4	RECRUITING	CPAP Effect on the Polycythemia in Patients With Obstructive Sleep Apnea
NCT07594535	PHASE4	NOT_YET_RECRUITING	The Effect Of Lisinopril On Polycythemia
NCT06038630	PHASE2	RECRUITING	129Xe MRI Cardiopulmonary
NCT00807677	PHASE1	COMPLETED	A Phase 1 Dose Escalation Study of TAK-901 in Subjects With Advanced Hematologic Malignancies
NCT00722527	Not specified	RECRUITING	Molecular Biology of Polycythemia and Thrombocytosis
NCT05396170	Not specified	RECRUITING	Effect of Phlebotomy on Heartrate in Polycythemia Patients
NCT06785870	Not specified	NOT_YET_RECRUITING	EVAluation of Erythrocytosis PRospEctive Cohort STudy
NCT07341048	Not specified	NOT_YET_RECRUITING	Potential Biological and Physiological Determinants for Exercice in Patients With Polycythemia Vera
NCT03008642	Not specified	COMPLETED	CO-Rebreathing in Comparison to Isotopic Red Cell Volume Determination in the Diagnosis of Primitive and Secondary Polycythemia
NCT05510518	Not specified	UNKNOWN	Late Gestational Diabetes Mellitus Diagnosis in Obese Women

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
LISINOPRIL ANHYDROUS	4	2
OXYGEN	4	1
TAK-901	1	1