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: 54583 ENSG00000135766 UniProt: Q9GZT9 OMIM: 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.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene catalyzes the post-translational formation of 4-hydroxyproline in hypoxia-inducible factor (HIF) alpha proteins. HIF is a transcriptional complex that plays a central role in mammalian oxygen homeostasis. This protein functions as a cellular oxygen sensor, and under normal oxygen concentration, modification by prolyl hydroxylation is a key regulatory event that targets HIF subunits for proteasomal destruction via the von Hippel-Lindau ubiquitylation complex. Mutations in this gene are associated with erythrocytosis familial type 3 (ECYT3). [provided by RefSeq, Nov 2009]

GeneReviews OMIM ResearchGenerating clinical summary…

MultiplemechanismADLOEUF 0.302 OMIM phenotypes

Clinical Summary— EGLN1

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Gene-Disease Validity (ClinGen)

EGLN1-related erythrocytosis and pheochromocytoma/paraganglioma predisposition · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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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.

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ClinVar Variants

15 unique Pathogenic / Likely Pathogenic· 707 VUS of 1319 total submissions

Explore recent and relevant literature in Research Assistant →

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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 OE?0.06 (0.02–0.30)

0≤0.351.4

Missense OE?0.58 (0.50–0.67)

0≤0.61.4

Synonymous OE?1.29

0≤1.21.6

LoF obs/exp: 1 / 15.7Missense obs/exp: 119 / 205.8Syn Z: -2.09

This gene — mechanism propensity

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 · 87% of P/LP variants are LoF · LOEUF 0.30

GOF1 literature citation

Literature Evidence

GOFA genetic mechanism for Tibetan high-altitude adaptation1

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

References

1.PMID 25129147 ↗

ClinVar Variant Classifications

1319 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic13

Likely Pathogenic2

VUS707

Likely Benign481

Benign60

Conflicting47

Pathogenic

Likely Pathogenic

707

VUS

481

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	11	2	0	0	13
Likely Pathogenic	2	0	0	0	2
VUS	7	616	84	0	707
Likely Benign	0	28	38	415	481
Benign	0	1	58	1	60
Conflicting	—				47
Total	20	647	180	416	1,310

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

View in ClinVar →

36 pathogenic / likely-pathogenic (of 41) ClinVar copy-number / structural variants overlap EGLN1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →