Erythrocytosis, familial, 4

Summary

Erythrocytosis, familial, 4 (MONDO:0012729) is a disease caused by EPAS1 (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: EPAS1 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 157

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	erythrocytosis, familial, 4
Mondo ID	MONDO:0012729
MeSH	C567086
OMIM	611783
DOID	DOID:0080339
UMLS	C2673187
MedGen	435867
GARD	0018356
Is cancer (heuristic)	no

Also known as: ECYT4 · EPAS1 familial polycythemia · erythrocytosis, familial, 4 · erythrocytosis, familial, type 4 · familial polycythemia caused by mutation in EPAS1

Data availability: 157 ClinVar variants · 5 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 › erythrocytosis, familial, 4

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

157 retrieved; paginated sample, class counts are floors:

61 uncertain significance, 38 benign, 22 benign/likely benign, 21 conflicting classifications of pathogenicity, 8 likely benign, 4 pathogenic, 2 likely pathogenic, 1 drug response

ClinVar	Variant (HGVS)	Gene	Classification	Review
1699154	NM_001430.5(EPAS1):c.1604T>C (p.Met535Thr)	EPAS1	Pathogenic	criteria provided, multiple submitters, no conflicts
6468	NM_001430.5(EPAS1):c.1609G>T (p.Gly537Trp)	EPAS1	Pathogenic	no assertion criteria provided
6469	NM_001430.5(EPAS1):c.1609G>A (p.Gly537Arg)	EPAS1	Pathogenic	criteria provided, multiple submitters, no conflicts
6470	NM_001430.5(EPAS1):c.1603A>G (p.Met535Val)	EPAS1	Pathogenic	no assertion criteria provided
2920985	NM_001430.5(EPAS1):c.1601C>T (p.Pro534Leu)	EPAS1	Likely pathogenic	criteria provided, single submitter
3778704	NM_001430.5(EPAS1):c.1601C>G (p.Pro534Arg)	EPAS1	Likely pathogenic	criteria provided, single submitter
336258	NM_001430.5(EPAS1):c.1035-7C>G	EPAS1	drug response	reviewed by expert panel
1789887	NM_001430.5(EPAS1):c.2342C>T (p.Pro781Leu)	EPAS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2441242	NM_001430.5(EPAS1):c.2069G>A (p.Arg690Gln)	EPAS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2456394	NM_001430.5(EPAS1):c.587C>T (p.Thr196Met)	EPAS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
336235	NM_001430.5(EPAS1):c.146C>A (p.Ser49Tyr)	EPAS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
336260	NM_001430.5(EPAS1):c.1104G>A (p.Met368Ile)	EPAS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
336261	NM_001430.5(EPAS1):c.1121T>A (p.Phe374Tyr)	EPAS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
336263	NM_001430.5(EPAS1):c.1228G>A (p.Ala410Thr)	EPAS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
336264	NM_001430.5(EPAS1):c.1263C>T (p.Phe421=)	EPAS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
336267	NM_001430.5(EPAS1):c.1824C>G (p.Phe608Leu)	EPAS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
336277	NM_001430.5(EPAS1):c.2367C>T (p.Ile789=)	EPAS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
336278	NM_001430.5(EPAS1):c.2392A>G (p.Arg798Gly)	EPAS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
336279	NM_001430.5(EPAS1):c.2457G>A (p.Val819=)	EPAS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
435064	NM_001430.5(EPAS1):c.1281T>C (p.Tyr427=)	EPAS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
895867	NM_001430.5(EPAS1):c.591C>A (p.Gly197=)	EPAS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
895868	NM_001430.5(EPAS1):c.859G>A (p.Glu287Lys)	EPAS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
895930	NM_001430.5(EPAS1):c.2113A>G (p.Lys705Glu)	EPAS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
897664	NM_001430.5(EPAS1):c.41G>A (p.Arg14Lys)	EPAS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
897665	NM_001430.5(EPAS1):c.192G>T (p.Leu64=)	EPAS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
897741	NM_001430.5(EPAS1):c.1203C>A (p.Ala401=)	EPAS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
897742	NM_001430.5(EPAS1):c.1248C>T (p.Phe416=)	EPAS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
898828	NM_001430.5(EPAS1):c.238G>A (p.Glu80Lys)	EPAS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1767494	NM_001430.5(EPAS1):c.127C>G (p.Leu43Val)	EPAS1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1787754	NM_001430.5(EPAS1):c.220T>G (p.Cys74Gly)	EPAS1	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 3 · 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
EPAS1	Strong	Autosomal dominant	erythrocytosis, familial, 4	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
EPAS1	Orphanet:247511	Autosomal dominant secondary polycythemia
EPAS1	Orphanet:276621	Sporadic pheochromocytoma/secreting paraganglioma
EPAS1	Orphanet:324299	Multiple paragangliomas associated with polycythemia

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
EPAS1	HGNC:3374	ENSG00000116016	Q99814	Endothelial PAS domain-containing protein 1	gencc,clinvar
FBLN2	HGNC:3601	ENSG00000163520	P98095	Fibulin-2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
EPAS1	Endothelial PAS domain-containing protein 1	Transcription factor involved in the induction of oxygen regulated genes.
FBLN2	Fibulin-2	Its binding to fibronectin and some other ligands is calcium dependent.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 0 · 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
Complement	1	134.0×	0.015
Transcription factor	1	4.1×	0.228

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
EPAS1	Transcription factor	no		PAS, Nuc_translocat, PAC
FBLN2	Complement	yes		Anaphylatoxin/fibulin, EGF-type_Asp/Asn_hydroxyl_site, EGF

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
adult organism	1
lower lobe of lung	1
right lung	1
cardiac atrium	1
right atrium auricular region	1
right coronary artery	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
EPAS1	298	ubiquitous	marker	right lung, lower lobe of lung, adult organism
FBLN2	242	ubiquitous	marker	right atrium auricular region, cardiac atrium, right coronary artery

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
EPAS1	4,652
FBLN2	2,202

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
EPAS1	Q99814	43

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
FBLN2	P98095	67.85

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 9. Enrichment computed across 2 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
PTK6 Expression	1	951.7×	0.005	EPAS1
Regulation of gene expression by Hypoxia-inducible Factor	1	475.8×	0.005	EPAS1
Pexophagy	1	475.8×	0.005	EPAS1
Cellular response to hypoxia	1	439.2×	0.005	EPAS1
Transcriptional regulation of pluripotent stem cells	1	271.9×	0.007	EPAS1
Molecules associated with elastic fibres	1	154.3×	0.010	FBLN2
Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha	1	98.5×	0.013	EPAS1
Regulation of PD-L1(CD274) transcription	1	54.4×	0.021	EPAS1
Neddylation	1	23.7×	0.042	EPAS1

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
myoblast fate commitment	1	1685.2×	0.008	EPAS1
epithelial cell maturation	1	766.0×	0.008	EPAS1
intracellular oxygen homeostasis	1	766.0×	0.008	EPAS1
norepinephrine metabolic process	1	766.0×	0.008	EPAS1
regulation of protein neddylation	1	468.1×	0.009	EPAS1
surfactant homeostasis	1	401.2×	0.009	EPAS1
embryonic placenta development	1	383.0×	0.009	EPAS1
multicellular organismal-level iron ion homeostasis	1	290.6×	0.010	EPAS1
positive regulation of cell-substrate adhesion	1	247.8×	0.010	FBLN2
regulation of heart rate	1	234.1×	0.010	EPAS1
blood vessel remodeling	1	191.5×	0.011	EPAS1
mRNA transcription by RNA polymerase II	1	165.2×	0.012	EPAS1
erythrocyte differentiation	1	133.8×	0.014	EPAS1
lung development	1	99.1×	0.017	EPAS1
positive regulation of cold-induced thermogenesis	1	81.8×	0.019	EPAS1
mitochondrion organization	1	75.9×	0.020	EPAS1
response to oxidative stress	1	65.3×	0.022	EPAS1
cellular response to hypoxia	1	60.6×	0.022	EPAS1
response to hypoxia	1	47.9×	0.026	EPAS1
visual perception	1	39.8×	0.030	EPAS1
angiogenesis	1	31.2×	0.036	EPAS1
signal transduction	1	8.0×	0.132	EPAS1
positive regulation of transcription by RNA polymerase II	1	7.4×	0.136	EPAS1
regulation of transcription by RNA polymerase II	1	5.8×	0.164	EPAS1

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
EPAS1	BELZUTIFAN

Top cohort targets by molecule count

Symbol	Molecules	Max phase
EPAS1	7	4
FBLN2	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
BELZUTIFAN	4	EPAS1
EMETINE	4	EPAS1
DOXORUBICIN	4	EPAS1
TOPOTECAN	4	EPAS1
CYCLOHEXIMIDE	2	EPAS1
ALVESPIMYCIN	2	EPAS1
BAKUCHIOL	1	EPAS1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
EPAS1	241	Binding:233, Functional:8

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
EPAS1	241

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)
BELZUTIFAN	4	EPAS1
EMETINE	4	EPAS1
DOXORUBICIN	4	EPAS1
TOPOTECAN	4	EPAS1
CYCLOHEXIMIDE	2	EPAS1
ALVESPIMYCIN	2	EPAS1
BAKUCHIOL	1	EPAS1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	EPAS1
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	FBLN2
E	Difficult family or no structure, no drug	0

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)
FBLN2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.