EGLN1
protein-codingegl-9 family hypoxia inducible factor 1, the group of Zinc fingers MYND-type
Gene summary
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]
- C1orf12
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~58.5 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0017366
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:1060184
Submitter: ClinGen
EGLN1 was first reported in relation to autosomal dominant EGLN1-related erythrocytosis and pheochromocytoma/paraganglioma predisposition in 2006 (Percy et al., PMID: 16407130). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found little evidence of difference in molecular mechanisms, inheritance patterns, or phenotypic variability, although there appears to be variable expressivity in pheochromocytoma/paraganglioma. Therefore, the following disease entities have been lumped into one disease entity: familial erythrocytosis 3 (OMIM:609820) and pheochromocytoma/paraganglioma (OMIM:171300). 23 variants (missense and nonsense) that have been reported in 31 probands in 7 publications (PMIDs: 16407130, 17579185, 19092153, 21933857, 37317877, 34309460, 25263965) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity appears to be loss of function. This gene-disease association is also supported by animal models that demonstrate how erythrocytosis can be induced by knocking out EGLN1 or by knocking in a variant that models the first reported human EGLN1 variant (PMIDs: 24121508, 20400342). Another animal model showed that inactivating EGLN1 in the adrenal medulla in mice resulted in a pattern of gene expression that resembles pseudohypoxic pheochromocytoma and paraganglioma (PMID: 34658364). In summary, EGLN1 is definitively associated with autosomal dominant EGLN1-related erythrocytosis and pheochromocytoma/paraganglioma predisposition. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Childhood, Adolescent, and Young Adult Cancer Predisposition GCEP on the meeting date September 9, 2025 (SOP Version 11).
Inheritance Pattern: AD
Disease ID:MONDO:0012353
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0012353
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0016599
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0044274
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0012353
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0012353
Submitter: Ambry Genetics
Clinical Genomic Database (CGD)
Manifestation: Hematologic; Oncologic
Intervention: Hematologic; Oncologic
Rationale: Phlebotomy can be used to maintain the hematocrit value in the desired range; Due to a reported increased risk of neoplasms, awareness may allow early detection and management, which may decrease associated morbidity and mortality
Comments: In some described individuals, it has been suggested that manifestations involved increased risk of neoplasms as well as hematologic manifestations
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to EGLN1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_022051.3. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 436 | 436 | ||||
| missense | 2 | 1 | 629 | 64 | 696 | |
| nonsense | 5 | 2 | 2 | 9 | ||
| start loss | 3 | 3 | ||||
| frameshift | 7 | 3 | 4 | 14 | ||
| splice donor/acceptor (+/-2bp) | 1 | 2 | 3 | |||
| Total | 14 | 7 | 640 | 500 | 0 | 1161 |
Highest pathogenic variant AF is 0.0000065684894
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_071334.1 | 5 | MANE Select | |
| Ensembl | ENSP00000355601.3 | 5 | MANE Select | |
| RefSeq | NP_001364189.1 | 4 | Standard | |
| RefSeq | NP_001364190.1 | 3 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Renal cell carcinoma - Homo sapiens (human)
- HIF-1 signaling pathway - Homo sapiens (human)
- Pathways in cancer - Homo sapiens (human)
- The oncogenic action of Succinate
- The oncogenic action of Fumarate
Biological Process
- response to hypoxia
- cellular iron ion homeostasis
- peptidyl-proline hydroxylation to 4-hydroxy-L-proline
- oxygen homeostasis
- negative regulation of DNA-binding transcription factor activity
Molecular Function
- protein binding
- ferrous iron binding
- 2-oxoglutarate-dependent dioxygenase activity
- enzyme binding
- L-ascorbic acid binding
Cellular Component
- nucleus
- cytoplasm
- cytosol
- postsynaptic density
- glutamatergic synapse
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000366641
- Coding exons
- 5
- Length
- 61294
- Individuals with no LoFs
- 125716
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 3
- Defined
- 125719
- p
- 0.0000119
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 2.15 | 119 | 206 | 0.578 | 0.0000107 | 2728 |
| Missense (PolyPhen) | 15 | 72.209 | 0.20773 | 844 | ||
| Synonymous | -2.09 | 109 | 84.6 | 1.29 | 0.00000463 | 850 |
| Loss of Function | 3.43 | 1 | 15.7 | 0.0639 | 8.39e-7 | 184 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0.000092 | 0.000092 | rare |
| European (Non-Finnish) | 0.0000088 | 0.0000088 | rare |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Cellular oxygen sensor that catalyzes, under normoxic conditions, the post-translational formation of 4-hydroxyproline in hypoxia-inducible factor (HIF) alpha proteins. Hydroxylates a specific proline found in each of the oxygen-dependent degradation (ODD) domains (N-terminal, NODD, and C-terminal, CODD) of HIF1A. Also hydroxylates HIF2A. Has a preference for the CODD site for both HIF1A and HIF1B. Hydroxylated HIFs are then targeted for proteasomal degradation via the von Hippel-Lindau ubiquitination complex. Under hypoxic conditions, the hydroxylation reaction is attenuated allowing HIFs to escape degradation resulting in their translocation to the nucleus, heterodimerization with HIF1B, and increased expression of hypoxy-inducible genes. EGLN1 is the most important isozyme under normoxia and, through regulating the stability of HIF1, involved in various hypoxia-influenced processes such as angiogenesis in retinal and cardiac functionality. Target proteins are preferentially recognized via a LXXLAP motif. {ECO:0000269|PubMed:11595184, ECO:0000269|PubMed:12181324, ECO:0000269|PubMed:12351678, ECO:0000269|PubMed:15897452, ECO:0000269|PubMed:19339211, ECO:0000269|PubMed:21792862, ECO:0000269|PubMed:25129147}.;
- Disease
- DISEASE: Erythrocytosis, familial, 3 (ECYT3) [MIM:609820]: An autosomal dominant disorder characterized by increased serum red blood cell mass, elevated serum hemoglobin and hematocrit, and normal serum erythropoietin levels. {ECO:0000269|PubMed:16407130, ECO:0000269|PubMed:17579185}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.0955
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- S
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.343
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |