Chuvash polycythemia

Summary

Chuvash polycythemia (MONDO:0009892) is a disease caused by VHL (GenCC Strong), with 6 cohort genes and 2 clinical trials. Molecularly, VHL R200W (c.598C>T) confers sensitivity to Ruxolitinib in Chuvash Polycythemia (CIViC Level C). Top therapeutic interventions include ruxolitinib.

At a glance

• Prevalence: Unknown (Worldwide)
• Causal gene: VHL (GenCC Strong)
• Cohort genes: 6
• ClinVar variants: 1,557
• Clinical trials: 2
• Precision-medicine evidence (CIViC): 1 subtype–drug association

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Chuvash polycythemia
Mondo ID	MONDO:0009892
MeSH	C563918
OMIM	263400
Orphanet	238557
DOID	DOID:0060474
UMLS	C1837915
MedGen	332974
GARD	0017176
Is cancer (heuristic)	no

Also known as: Chuvash polycythemia · ECYT2 · erythrocytosis, familial, 2 · erythrocytosis, familial, type 2 · familial polycythemia caused by mutation in VHL · VHL familial polycythemia · Von Hippel-Lindau-dependent polycythemia

Data availability: 1,557 ClinVar variants · 3 GenCC gene-disease records.

Disease family

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

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

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

600 retrieved; paginated sample, class counts are floors:

302 uncertain significance, 108 likely benign, 63 conflicting classifications of pathogenicity, 52 pathogenic, 42 benign/likely benign, 15 pathogenic/likely pathogenic, 10 likely pathogenic, 8 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1068736	NC_000003.11:g.10094065-?_10191654+?del	FANCD2	Pathogenic	criteria provided, single submitter
1070024	NC_000003.11:g.10106407-?_10191654+?del	FANCD2	Pathogenic	criteria provided, single submitter
1069709	NM_000551.4(VHL):c.400G>T (p.Glu134Ter)	LOC107303340	Pathogenic	criteria provided, multiple submitters, no conflicts
1070973	NM_000551.4(VHL):c.504_519del (p.Ser168fs)	LOC107303340	Pathogenic	criteria provided, single submitter
1208816	NM_000551.4(VHL):c.383T>C (p.Leu128Pro)	LOC107303340	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
127829	NM_000551.4(VHL):c.445G>T (p.Ala149Ser)	LOC107303340	Pathogenic	criteria provided, multiple submitters, no conflicts
1451803	NM_000551.4(VHL):c.475A>T (p.Lys159Ter)	LOC107303340	Pathogenic	criteria provided, multiple submitters, no conflicts
1457709	NM_000551.4(VHL):c.463+1G>T	LOC107303340	Pathogenic	criteria provided, multiple submitters, no conflicts
1457988	NM_000551.4(VHL):c.341-11T>A	LOC107303340	Pathogenic	criteria provided, single submitter
1737544	NM_000551.4(VHL):c.406T>G (p.Phe136Val)	LOC107303340	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
182959	NM_000551.4(VHL):c.477del (p.Glu160fs)	LOC107303340	Pathogenic	reviewed by expert panel
182974	NM_000551.4(VHL):c.525C>G (p.Tyr175Ter)	LOC107303340	Pathogenic	criteria provided, multiple submitters, no conflicts
182980	NM_000551.4(VHL):c.473T>C (p.Leu158Pro)	LOC107303340	Pathogenic	criteria provided, multiple submitters, no conflicts
182983	NM_000551.4(VHL):c.482G>A (p.Arg161Gln)	LOC107303340	Pathogenic	criteria provided, multiple submitters, no conflicts
195093	NM_000551.4(VHL):c.449del (p.Asn150fs)	LOC107303340	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
196284	NM_000551.4(VHL):c.586A>T (p.Lys196Ter)	LOC107303340	Pathogenic	reviewed by expert panel
2034796	NM_000551.4(VHL):c.341-2A>T	LOC107303340	Pathogenic	criteria provided, multiple submitters, no conflicts
2087924	NM_000551.4(VHL):c.349T>C (p.Trp117Arg)	LOC107303340	Pathogenic	criteria provided, single submitter
2119727	NM_000551.4(VHL):c.524dup (p.Tyr175Ter)	LOC107303340	Pathogenic	criteria provided, multiple submitters, no conflicts
2203306	NM_000551.4(VHL):c.361G>A (p.Asp121Asn)	LOC107303340	Pathogenic	criteria provided, single submitter
2215	NM_000551.4(VHL):c.548C>A (p.Ser183Ter)	LOC107303340	Pathogenic	criteria provided, multiple submitters, no conflicts
2216	NM_000551.4(VHL):c.500G>A (p.Arg167Gln)	LOC107303340	Pathogenic	reviewed by expert panel
2217	NM_000551.4(VHL):c.481C>T (p.Arg161Ter)	LOC107303340	Pathogenic	criteria provided, multiple submitters, no conflicts
2218	NM_000551.4(VHL):c.499C>T (p.Arg167Trp)	LOC107303340	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2219	NM_000551.4(VHL):c.499C>G (p.Arg167Gly)	LOC107303340	Pathogenic	criteria provided, multiple submitters, no conflicts
2224	NM_000551.4(VHL):c.496G>T (p.Val166Phe)	LOC107303340	Pathogenic	criteria provided, multiple submitters, no conflicts
2229	NM_000551.4(VHL):c.388G>C (p.Val130Leu)	LOC107303340	Pathogenic	criteria provided, multiple submitters, no conflicts
1070179	NM_000551.4(VHL):c.239G>A (p.Ser80Asn)	VHL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1071196	NM_000551.4(VHL):c.244_259dup (p.Val87fs)	VHL	Pathogenic	criteria provided, single submitter
1072069	NM_000551.4(VHL):c.241_244dup (p.Arg82fs)	VHL	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 12 · 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
VHL	Strong	Autosomal recessive	autosomal recessive secondary polycythemia not associated with VHL gene	12

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
CEP120	Orphanet:220493	Joubert syndrome with ocular defect
CEP120	Orphanet:474	Jeune syndrome
CEP120	Orphanet:475	Isolated Joubert syndrome
FANCD2	Orphanet:84	Fanconi anemia

Cohort genes → proteins

6 cohort genes, 6 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	6

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
VHL	HGNC:12687	ENSG00000134086	P40337	von Hippel-Lindau disease tumor suppressor	gencc,clinvar,civic_evidence
BRK1	HGNC:23057	ENSG00000254999	Q8WUW1	Protein BRICK1	clinvar
CEP120	HGNC:26690	ENSG00000168944	Q8N960	Centrosomal protein of 120 kDa	clinvar
FANCD2OS	HGNC:28623	ENSG00000163705	Q96PS1	FANCD2 opposite strand protein	clinvar
FANCD2	HGNC:3585	ENSG00000144554	Q9BXW9	Fanconi anemia group D2 protein	clinvar
IRAK2	HGNC:6113	ENSG00000134070	O43187	Interleukin-1 receptor-associated kinase-like 2	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.
BRK1	Protein BRICK1	Involved in regulation of actin and microtubule organization.
CEP120	Centrosomal protein of 120 kDa	Plays a role in the microtubule-dependent coupling of the nucleus and the centrosome.
FANCD2OS	FANCD2 opposite strand protein	Reduces testosterone levels by inhibiting steroidogenic enzymes and by promoting apoptosis in Leydig cells.
FANCD2	Fanconi anemia group D2 protein	Required for maintenance of chromosomal stability.
IRAK2	Interleukin-1 receptor-associated kinase-like 2	Binds to the IL-1 type I receptor following IL-1 engagement, triggering intracellular signaling cascades leading to transcriptional up-regulation and mRNA stabilization.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 4 · 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
Kinase	1	4.6×	0.458
Enzyme (other)	1	2.0×	0.458
Other/Unknown	4	1.2×	0.458

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
BRK1	Other/Unknown	no		BRICK1
CEP120	Other/Unknown	no		C2_dom, DUF3668, C2_domain_sf
FANCD2OS	Other/Unknown	no		FANCD2OS
FANCD2	Other/Unknown	no		FANCD2
IRAK2	Kinase	yes	2.7.10.2	Death_dom, Prot_kinase_dom, Kinase-like_dom_sf

Expression context

Cohort genes with no expression data: 0.

5 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)	6
unknown	0

Top tissues across cohort

Tissue	Cohort genes
epithelial cell of pancreas	2
secondary oocyte	2
cortical plate	1
monocyte	1
mononuclear cell	1
adult organism	1
sperm	1
upper arm skin	1
calcaneal tendon	1
mucosa of paranasal sinus	1
left testis	1
right testis	1
testis	1
male germ line stem cell (sensu Vertebrata) in testis	1
ventricular zone	1
cartilage tissue	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
VHL	186	ubiquitous	marker	cortical plate, monocyte, mononuclear cell
BRK1	256	ubiquitous	marker	sperm, upper arm skin, adult organism
CEP120	254	ubiquitous	yes	calcaneal tendon, epithelial cell of pancreas, mucosa of paranasal sinus
FANCD2OS	120	tissue_specific	marker	left testis, right testis, testis
FANCD2	200	ubiquitous	marker	male germ line stem cell (sensu Vertebrata) in testis, ventricular zone, secondary oocyte
IRAK2	213	ubiquitous	marker	cartilage tissue, epithelial cell of pancreas, secondary oocyte

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
FANCD2	3,820
VHL	3,522
IRAK2	2,033
CEP120	1,928
BRK1	1,680
FANCD2OS	349

Structural data

PDB: 5 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
VHL	P40337	142
FANCD2	Q9BXW9	13
BRK1	Q8WUW1	5
CEP120	Q8N960	4
IRAK2	O43187	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
FANCD2OS	Q96PS1	61.31

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 70. Enrichment computed across 6 evidence-associated genes (4 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 4 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	713.8×	0.039	VHL
Replication of the SARS-CoV-2 genome	1	713.8×	0.039	VHL
IRAK2 mediated activation of TAK1 complex	1	285.5×	0.039	IRAK2
RHOBTB3 ATPase cycle	1	285.5×	0.039	VHL
IRAK2 mediated activation of TAK1 complex upon TLR7/8 or 9 stimulation	1	190.3×	0.039	IRAK2
TRAF6-mediated induction of TAK1 complex within TLR4 complex	1	178.4×	0.039	IRAK2
JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1	1	129.8×	0.039	IRAK2
activated TAK1 mediates p38 MAPK activation	1	124.1×	0.039	IRAK2
Nucleotide-binding domain, leucine rich repeat containing receptor (NLR) signaling pathways	1	89.2×	0.039	IRAK2
Parasite infection	1	86.5×	0.039	BRK1
Leishmania phagocytosis	1	86.5×	0.039	BRK1
NOD1/2 Signaling Pathway	1	79.3×	0.039	IRAK2
RHO GTPases Activate WASPs and WAVEs	1	79.3×	0.039	BRK1
MAP kinase activation	1	77.2×	0.039	IRAK2
TAK1-dependent IKK and NF-kappa-B activation	1	75.1×	0.039	IRAK2
SUMOylation of ubiquitinylation proteins	1	73.2×	0.039	VHL
Fcgamma receptor (FCGR) dependent phagocytosis	1	69.6×	0.039	BRK1
Fanconi Anemia Pathway	1	69.6×	0.039	FANCD2
Interleukin-1 family signaling	1	68.0×	0.039	IRAK2
SARS-CoV-1 activates/modulates innate immune responses	1	68.0×	0.039	IRAK2
Interleukin-17 signaling	1	63.4×	0.039	IRAK2
Signaling by VEGF	1	54.9×	0.039	BRK1
Toll Like Receptor 10 (TLR10) Cascade	1	53.9×	0.039	IRAK2
Toll Like Receptor 5 (TLR5) Cascade	1	53.9×	0.039	IRAK2
MyD88 cascade initiated on plasma membrane	1	51.0×	0.039	IRAK2
Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha	1	49.2×	0.039	VHL
Toll Like Receptor 3 (TLR3) Cascade	1	48.4×	0.039	IRAK2
TRIF (TICAM1)-mediated TLR4 signaling	1	47.6×	0.039	IRAK2
TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activation	1	47.6×	0.039	IRAK2
MyD88 dependent cascade initiated on endosome	1	47.6×	0.039	IRAK2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 6 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 cytokine-mediated signaling pathway	1	936.2×	0.016	IRAK2
negative regulation of testosterone biosynthetic process	1	702.2×	0.016	FANCD2OS
regulation of CD40 signaling pathway	1	702.2×	0.016	FANCD2
positive regulation of centrosome duplication	1	561.7×	0.016	CEP120
interkinetic nuclear migration	1	561.7×	0.016	CEP120
regulation of actin polymerization or depolymerization	1	468.1×	0.016	BRK1
regulation of cellular response to hypoxia	1	468.1×	0.016	VHL
positive regulation of establishment of protein localization	1	468.1×	0.016	CEP120
Toll signaling pathway	1	401.2×	0.016	IRAK2
positive regulation of centriole elongation	1	401.2×	0.016	CEP120
positive regulation of Arp2/3 complex-mediated actin nucleation	1	351.1×	0.017	BRK1
regulation of regulatory T cell differentiation	1	312.1×	0.018	FANCD2
astral microtubule organization	1	216.1×	0.022	CEP120
double-strand break repair involved in meiotic recombination	1	216.1×	0.022	FANCD2
MyD88-dependent toll-like receptor signaling pathway	1	156.0×	0.024	IRAK2
mitotic intra-S DNA damage checkpoint signaling	1	156.0×	0.024	FANCD2
gamete generation	1	147.8×	0.024	FANCD2
negative regulation of receptor signaling pathway via JAK-STAT	1	147.8×	0.024	VHL
interleukin-1-mediated signaling pathway	1	133.8×	0.024	IRAK2
negative regulation of transcription elongation by RNA polymerase II	1	127.7×	0.024	VHL
positive regulation of cilium assembly	1	127.7×	0.024	CEP120
brain morphogenesis	1	122.1×	0.024	FANCD2
neuronal stem cell population maintenance	1	112.3×	0.025	FANCD2
homologous chromosome pairing at meiosis	1	100.3×	0.025	FANCD2
positive regulation of lamellipodium assembly	1	100.3×	0.025	BRK1
amyloid fibril formation	1	100.3×	0.025	VHL
response to gamma radiation	1	96.8×	0.025	FANCD2
Rac protein signal transduction	1	93.6×	0.025	BRK1
lipopolysaccharide-mediated signaling pathway	1	87.8×	0.025	IRAK2
toll-like receptor 4 signaling pathway	1	87.8×	0.025	IRAK2

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 5

Druggability breadth: 4 of 6 evidence-associated genes (67%) 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
BRK1	0	0
CEP120	0	0
FANCD2OS	0	0
FANCD2	0	0
IRAK2	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): 2.

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

Symbol	Assays	Type breakdown
VHL	3,575	Binding:3482, Functional:54, ADMET:39
FANCD2	2	Binding:2
IRAK2	2	Binding:2
BRK1	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
VHL	2.3.2.B13
IRAK2	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
VHL	3,575

Pharmacogenomics

Cohort genes with a PharmGKB record: 6; 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	1	IRAK2
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	4	BRK1, CEP120, FANCD2OS, FANCD2

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
BRK1	1	—
CEP120	0	—
FANCD2OS	0	—
FANCD2	2	—
IRAK2	2	—

Clinical trials & evidence

Clinical trials

Clinical trials: 2.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00495638	Not specified	COMPLETED	Pulmonary Hypertension, Hypoxia and Sickle Cell Disease
NCT01730755	Not specified	NO_LONGER_AVAILABLE	Ruxolitinib for Chuvash Polycythemia

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
RUXOLITINIB	4	1

Precision-medicine subtype map (CIViC)

Drug × molecular subtype: 1 predictive associations from 1 curated evidence items; also 6 predisposing.

Molecular subtype	Therapy	Effect	Level	CIViC
VHL R200W (c.598C>T)	Ruxolitinib	Sensitivity/Response	CIViC C	EID1608