Erythrocytosis, familial, 3

Summary

Erythrocytosis, familial, 3 (MONDO:0012353) is a disease caused by EGLN1 (GenCC Definitive), with 2 cohort genes.

At a glance

• Causal gene: EGLN1 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 561

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	erythrocytosis, familial, 3
Mondo ID	MONDO:0012353
MeSH	C565221
OMIM	609820
DOID	DOID:0080338
UMLS	C1853286
MedGen	377868
GARD	0018355
Is cancer (heuristic)	no

Also known as: ECYT3 · EGLN1 familial polycythemia · erythrocytosis, familial, 3 · erythrocytosis, familial, type 3 · familial polycythemia caused by mutation in EGLN1

Data availability: 561 ClinVar variants · 4 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, 3

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

561 retrieved; paginated sample, class counts are floors:

267 uncertain significance, 176 likely benign, 47 conflicting classifications of pathogenicity, 46 benign, 13 pathogenic, 10 benign/likely benign, 1 pathogenic/likely pathogenic, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1048777	NM_022051.3(EGLN1):c.1010dup (p.Val338fs)	EGLN1	Pathogenic	criteria provided, single submitter
2864415	NM_022051.3(EGLN1):c.494del (p.Pro165fs)	EGLN1	Pathogenic	criteria provided, single submitter
2901944	NM_022051.3(EGLN1):c.774G>A (p.Trp258Ter)	EGLN1	Pathogenic	criteria provided, single submitter
3608822	NM_022051.3(EGLN1):c.773G>A (p.Trp258Ter)	EGLN1	Pathogenic	criteria provided, single submitter
3656741	NM_022051.3(EGLN1):c.115_121del (p.Ser39fs)	EGLN1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3723092	NM_022051.3(EGLN1):c.373_403del (p.Ser125fs)	EGLN1	Pathogenic	criteria provided, single submitter
4356	NM_022051.3(EGLN1):c.1112G>A (p.Arg371His)	EGLN1	Pathogenic	no assertion criteria provided
4357	NM_022051.3(EGLN1):c.1121A>G (p.His374Arg)	EGLN1	Pathogenic	no assertion criteria provided
4723205	NM_022051.3(EGLN1):c.1133del (p.Pro378fs)	EGLN1	Pathogenic	criteria provided, single submitter
4724899	NM_022051.3(EGLN1):c.174C>A (p.Cys58Ter)	EGLN1	Pathogenic	criteria provided, single submitter
4732941	NM_022051.3(EGLN1):c.1137del (p.Tyr380fs)	EGLN1	Pathogenic	criteria provided, single submitter
4733674	NM_022051.3(EGLN1):c.1044_1045insATTTTCCAGAAAATTTCCAGAA (p.Gly349fs)	EGLN1	Pathogenic	criteria provided, single submitter
649669	NM_022051.3(EGLN1):c.461C>A (p.Ser154Ter)	EGLN1	Pathogenic	criteria provided, single submitter
4746929	NM_022051.3(EGLN1):c.840dup (p.Arg281fs)	LOC129932769	Pathogenic	criteria provided, single submitter
3777258	NM_001430.5(EPAS1):c.1573G>T (p.Asp525Tyr)	EPAS1	Likely pathogenic	criteria provided, single submitter
1023965	NM_022051.3(EGLN1):c.493C>G (p.Pro165Ala)	EGLN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1039916	NM_022051.3(EGLN1):c.325A>G (p.Lys109Glu)	EGLN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1059318	NM_022051.3(EGLN1):c.445C>A (p.Pro149Thr)	EGLN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1361243	NM_022051.3(EGLN1):c.256C>G (p.Pro86Ala)	EGLN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1372261	NM_022051.3(EGLN1):c.1264G>A (p.Gly422Ser)	EGLN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1375107	NM_022051.3(EGLN1):c.449C>T (p.Pro150Leu)	EGLN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1398683	NM_022051.3(EGLN1):c.763A>G (p.Lys255Glu)	EGLN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1404566	NM_022051.3(EGLN1):c.917A>G (p.Asn306Ser)	EGLN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1406280	NM_022051.3(EGLN1):c.546C>G (p.Asn182Lys)	EGLN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1429243	NM_022051.3(EGLN1):c.515C>T (p.Ala172Val)	EGLN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1732020	NM_022051.3(EGLN1):c.349C>T (p.Pro117Ser)	EGLN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1735598	NM_022051.3(EGLN1):c.385G>T (p.Ala129Ser)	EGLN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1745260	NM_022051.3(EGLN1):c.1192C>T (p.Arg398Ter)	EGLN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1764062	NM_022051.3(EGLN1):c.1265G>T (p.Gly422Val)	EGLN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1902316	NM_022051.3(EGLN1):c.738C>G (p.Asp246Glu)	EGLN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · Orphanet: 4 · 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
EGLN1	Definitive	Autosomal dominant	erythrocytosis, familial, 3	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
EGLN1	Orphanet:247511	Autosomal dominant secondary polycythemia
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
EGLN1	HGNC:1232	ENSG00000135766	Q9GZT9	Egl nine homolog 1	gencc,clinvar
EPAS1	HGNC:3374	ENSG00000116016	Q99814	Endothelial PAS domain-containing protein 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
EGLN1	Egl nine homolog 1	Cellular oxygen sensor that catalyzes, under normoxic conditions, the post-translational formation of 4-hydroxyproline in hypoxia-inducible factor (HIF) alpha proteins.
EPAS1	Endothelial PAS domain-containing protein 1	Transcription factor involved in the induction of oxygen regulated genes.

Protein-family classification

Druggable: 0 · Difficult: 2 · Unknown: 0 · Druggable fraction: 0.0

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
Transcription factor	2	8.3×	0.015

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
EGLN1	Transcription factor	no	1.14.11.2	Znf_MYND, Oxoglu/Fe-dep_dioxygenase_dom, Pro_4_hyd_alph
EPAS1	Transcription factor	no		PAS, Nuc_translocat, PAC

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
adrenal tissue	1
gastrocnemius	1
muscle of leg	1
adult organism	1
lower lobe of lung	1
right lung	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
EGLN1	214	ubiquitous	marker	gastrocnemius, muscle of leg, adrenal tissue
EPAS1	298	ubiquitous	marker	right lung, lower lobe of lung, adult organism

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
EPAS1	4,652
EGLN1	2,107

Intra-cohort edges

A	B	Sources
EGLN1	EPAS1	biogrid_interaction, intact, string_interaction

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
EGLN1	Q9GZT9	64
EPAS1	Q99814	43

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 8. 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
Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha	2	196.9×	2e-04	EGLN1, EPAS1
PTK6 Expression	1	951.7×	0.004	EPAS1
Regulation of gene expression by Hypoxia-inducible Factor	1	475.8×	0.004	EPAS1
Pexophagy	1	475.8×	0.004	EPAS1
Cellular response to hypoxia	1	439.2×	0.004	EPAS1
Transcriptional regulation of pluripotent stem cells	1	271.9×	0.005	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
intracellular oxygen homeostasis	2	1532.0×	1e-05	EGLN1, EPAS1
cellular response to hypoxia	2	121.2×	0.001	EGLN1, EPAS1
response to hypoxia	2	95.8×	0.001	EGLN1, EPAS1
negative regulation of hypoxia-inducible factor-1alpha signaling pathway	1	4213.0×	0.002	EGLN1
regulation protein catabolic process at postsynapse	1	2808.7×	0.002	EGLN1
myoblast fate commitment	1	1685.2×	0.003	EPAS1
response to nitric oxide	1	1685.2×	0.003	EGLN1
labyrinthine layer development	1	1053.2×	0.004	EGLN1
regulation of modification of postsynaptic structure	1	936.2×	0.004	EGLN1
epithelial cell maturation	1	766.0×	0.004	EPAS1
norepinephrine metabolic process	1	766.0×	0.004	EPAS1
cardiac muscle tissue morphogenesis	1	702.2×	0.004	EGLN1
heart trabecula formation	1	561.7×	0.005	EGLN1
regulation of protein neddylation	1	468.1×	0.005	EPAS1
surfactant homeostasis	1	401.2×	0.006	EPAS1
embryonic placenta development	1	383.0×	0.006	EPAS1
regulation of neuron apoptotic process	1	351.1×	0.006	EGLN1
multicellular organismal-level iron ion homeostasis	1	290.6×	0.006	EPAS1
regulation of heart rate	1	234.1×	0.007	EPAS1
ventricular septum morphogenesis	1	216.1×	0.007	EGLN1
regulation of angiogenesis	1	210.7×	0.007	EGLN1
positive regulation of transcription by RNA polymerase II	2	14.9×	0.007	EGLN1, EPAS1
blood vessel remodeling	1	191.5×	0.008	EPAS1
mRNA transcription by RNA polymerase II	1	165.2×	0.009	EPAS1
erythrocyte differentiation	1	133.8×	0.010	EPAS1
intracellular iron ion homeostasis	1	122.1×	0.011	EGLN1
lung development	1	99.1×	0.013	EPAS1
positive regulation of cold-induced thermogenesis	1	81.8×	0.015	EPAS1
mitochondrion organization	1	75.9×	0.015	EPAS1
response to oxidative stress	1	65.3×	0.017	EPAS1

Therapeutics

Drug target analysis

Approved (phase 4): 2 · Phase ≥3: 2 · Phased (≥1): 2 · Undrugged: 0

Druggability breadth: 2 of 2 evidence-associated genes (100%) 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
EGLN1	ROXADUSTAT
EPAS1	BELZUTIFAN

Top cohort targets by molecule count

Symbol	Molecules	Max phase
EGLN1	11	4
EPAS1	7	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
ROXADUSTAT	4	EGLN1
DAPRODUSTAT	4	EGLN1
VADADUSTAT	4	EGLN1
BELZUTIFAN	4	EPAS1
EMETINE	4	EPAS1
DOXORUBICIN	4	EPAS1
TOPOTECAN	4	EPAS1
ENARODUSTAT	3	EGLN1
DESIDUSTAT	3	EGLN1
FUMARIC ACID	3	EGLN1
SUCCINIC ACID	3	EGLN1
IZILENDUSTAT	2	EGLN1
MOLIDUSTAT	2	EGLN1
CYCLOHEXIMIDE	2	EPAS1
ALVESPIMYCIN	2	EPAS1
MOLIDUSTAT SODIUM	1	EGLN1
DDO-3055	1	EGLN1
BAKUCHIOL	1	EPAS1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
EPAS1	241	Binding:233, Functional:8
EGLN1	211	Binding:211

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
EGLN1	1.14.11.2, 1.14.11.29	procollagen-proline 4-dioxygenase, hypoxia-inducible factor-proline dioxygenase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
EGLN1	211
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

18 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)
ROXADUSTAT	4	EGLN1
DAPRODUSTAT	4	EGLN1
VADADUSTAT	4	EGLN1
BELZUTIFAN	4	EPAS1
EMETINE	4	EPAS1
DOXORUBICIN	4	EPAS1
TOPOTECAN	4	EPAS1
ENARODUSTAT	3	EGLN1
DESIDUSTAT	3	EGLN1
FUMARIC ACID	3	EGLN1
SUCCINIC ACID	3	EGLN1
IZILENDUSTAT	2	EGLN1
MOLIDUSTAT	2	EGLN1
CYCLOHEXIMIDE	2	EPAS1
ALVESPIMYCIN	2	EPAS1
MOLIDUSTAT SODIUM	1	EGLN1
DDO-3055	1	EGLN1
BAKUCHIOL	1	EPAS1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	EGLN1, EPAS1
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	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.