EGLN1

Chr 1AD

egl-9 family hypoxia inducible factor 1

Also known as: C1orf12, ECYT3, HALAH, HIF-PH2, HIFPH2, HPH-2, HPH2, PHD2

NCBI Gene: 54583ENSG00000135766UniProt: Q9GZT9OMIM: 606425

The protein functions as a cellular oxygen sensor that catalyzes the hydroxylation of hypoxia-inducible factor (HIF) alpha proteins under normal oxygen conditions, targeting them for degradation and thereby regulating cellular responses to hypoxia. Mutations cause familial erythrocytosis type 3, characterized by elevated red blood cell production. This gene shows autosomal dominant inheritance and is highly constrained against loss-of-function variants.

GeneReviewsOMIMResearchSummary from RefSeq, OMIM, UniProt
MultiplemechanismADLOEUF 0.302 OMIM phenotypes
Clinical Summary— EGLN1
🧬
Gene-Disease Validity (ClinGen)
EGLN1-related erythrocytosis and pheochromocytoma/paraganglioma predisposition · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.97). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
7 unique Pathogenic / Likely Pathogenic· 118 VUS of 200 total submissions
Explore recent and relevant literature in Research Assistant →
📖
GeneReview available — EGLN1
Authoritative clinical overview · Recommended first read
Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
LoF Constraint
0.30LOEUF
pLI 0.974
Z-score 3.43
OE 0.06 (0.02–0.30)
Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint
2.15Z-score
OE missense 0.58 (0.50–0.67)
119 obs / 205.8 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios
LoF OE0.06 (0.02–0.30)
0≤0.351.4
Missense OE0.58 (0.50–0.67)
0≤0.61.4
Synonymous OE1.29
0≤1.21.6
LoF obs/exp: 1 / 15.7Missense obs/exp: 119 / 205.8Syn Z: -2.09
DN
0.3296th %ile
GOF
0.4481th %ile
LOF
0.67top 25%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFprediction above median · 86% of P/LP variants are LoF · LOEUF 0.30
GOF1 literature citation

Literature Evidence

GOFA genetic mechanism for Tibetan high-altitude adaptationPMID:25129147

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

200 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic6
Likely Pathogenic1
VUS118
Likely Benign66
6
Pathogenic
1
Likely Pathogenic
118
VUS
66
Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
5
0
1
0
6
Likely Pathogenic
1
0
0
0
1
VUS
4
107
7
0
118
Likely Benign
0
8
3
55
66
Benign
0
0
0
0
0
Total101151155191

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

EGLN1 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

3D Protein StructureAlphaFold

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →
Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
HCMV infection depends on EGLN1-mediated mitochondrial activation to increase dNTP pools for viral DNA replication.
Simpson LA et al.·Cell Rep
2026
Epigenetic dichotomy in florid vs. gliotic proliferative diabetic retinopathy: hypomethylation of EGLN1 and MMP9 drives divergent pathogenic pathways in angiogenesis and fibrosis.
Ren X et al.·Front Endocrinol (Lausanne)
2026Open Access
Downregulation of EPAS1 and EGLN1 mRNA Expression Associated With High-Altitude Adaptive Genetic Variants in Sherpa Highlanders.
Droma Y et al.·Ann Hum Genet
2026Open Access
High-impact Genetic Variants in EGLN1, EPAS1, and Other Genes Identified in Mountaineers by Exome Sequencing.
Maksiutenko EM et al.·Front Biosci (Schol Ed)
2026
EGLN1 (PHD2) role in tumor microenvironment: insights for therapeutic targeting.
Verna G et al.·Exp Mol Med
2025Open Access
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients