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EGLN1 gene
Reviewed by Medicinsk Expert•Last updated: 2026-10-22•Gene

EGLN1 gene

The EGLN1 gene provides instructions for making an enzyme that regulates the body's response to oxygen levels and may act as a tumor suppressor.

Normal Function

The EGLN1 gene, often known as PHD2, provides instructions for making an enzyme called prolyl hydroxylase domain 2 (PHD2). The PHD2 enzyme interacts with a protein called hypoxia-inducible factor 2-alpha (HIF-2α). This protein is one part (subunit) of a larger HIF protein complex that plays a critical role in the body's ability to adapt to changing oxygen levels. HIF controls several important genes involved in cell division, the formation of new blood vessels, and the production of red blood cells. It is the major regulator of a hormone called erythropoietin, which controls red blood cell production.

The PHD2 enzyme's primary job is to target HIF-2α to be broken down (degraded) so it does not build up when it is not needed. When enough oxygen is available, the PHD2 enzyme is highly active to stimulate the breakdown of HIF-2α. However, when oxygen levels are lower than normal (hypoxia), the PHD2 enzyme becomes less active. As a result, HIF-2α is degraded more slowly, leaving more HIF available to stimulate the formation of new blood vessels and red blood cells. These activities help maximize the amount of oxygen that can be delivered to the body's organs and tissues.

Studies suggest that the EGLN1 gene is involved in the body's adaptation to high altitude. At higher altitudes, such as in mountainous regions, air pressure is lower and less oxygen enters the body through the lungs. Over time, the body compensates for the lower oxygen levels by changing breathing patterns and producing more red blood cells and blood vessels.

Researchers suspect that the EGLN1 gene may also act as a tumor suppressor gene because of its role in regulating cell division and other processes through its interaction with HIF. Tumor suppressors prevent cells from growing and dividing too fast or in an uncontrolled way, which could lead to the development of a tumor.

Health Conditions Related to Genetic Changes

Familial erythrocytosis

At least 10 mutations in the EGLN1 gene have been found to cause familial erythrocytosis, an inherited condition characterized by an increased number of red blood cells and an elevated risk of abnormal blood clots. When familial erythrocytosis results from EGLN1 gene mutations, it is often designated ECYT3.

  • Some EGLN1 gene mutations change single protein building blocks (amino acids) in the PHD2 enzyme, while others lead to the production of an abnormally short version of the enzyme.
  • Any of these genetic changes disrupt the enzyme's ability to interact with HIF-2α and target it for destruction. Consequently, HIF accumulates in cells even when adequate oxygen is available.
  • The presence of extra HIF leads to the production of red blood cells when no more are needed, resulting in an excess of these cells in the bloodstream.

At least one of the known EGLN1 gene mutations has been associated with both familial erythrocytosis and a tumor called a paraganglioma in the same individual. Paragangliomas are noncancerous (benign) tumors of the nervous system. The mutation, written as His374Arg or H374R, replaces the amino acid histidine with the amino acid arginine at position 374 in the PHD2 enzyme. This genetic change alters the interaction between the PHD2 enzyme and HIF-2α, which leads to the production of excess red blood cells. However, it is unclear how the mutation may be associated with the development of paragangliomas.

Frequently Asked Questions

Patients with reduced PHD2 activity may already have higher baseline hemoglobin, which can be protective against hypoxia but may also increase blood viscosity. In the peri‑operative setting, anesthesiologists typically monitor arterial oxygen saturation, hemoglobin, and blood pressure closely, regardless of genotype. If you know you carry a high‑altitude EGLN1 allele, inform the surgical team; they may adjust ventilatory settings or consider pre‑operative phlebotomy only if hematocrit is markedly elevated (>55%). Otherwise, standard oxygen supplementation and vigilant monitoring are sufficient.
EGLN1 (also called PHD2) encodes an enzyme that helps regulate the hypoxia‑inducible factor pathway. Certain common variants (e.g., rs1868092, rs12097901) reduce the enzyme’s activity, allowing more HIF‑2α to accumulate and stimulate red‑blood‑cell production. People who carry these “high‑altitude” alleles often have higher hemoglobin levels and better oxygen delivery. A clinical laboratory can perform targeted DNA testing for the known EGLN1 variants; the result is reported as “wild‑type,” “heterozygous,” or “homozygous” for the specific allele. The test is not diagnostic for any disease, but it can explain why you tolerate high altitude better than most people.
Research suggests that reduced PHD2 activity can alter the tumor micro‑environment by stabilizing HIF‑2α, which in some cancers promotes angiogenesis and growth. However, isolated EGLN1 variants have not been established as a high‑penetrance cancer predisposition in clinical practice. Current guidelines do not recommend routine cancer screening solely based on an EGLN1 finding. Continue age‑appropriate cancer screening (e.g., colonoscopy, mammography) and discuss any family history of early‑onset cancers with your physician.
loss‑of‑function mutation in EGLN1 can lead to chronic over‑activation of HIF‑2α, which raises erythropoietin and red‑cell mass. In rare families with pathogenic EGLN1 variants, this manifests as familial erythrocytosis (high hemoglobin/hematocrit). Elevated red‑cell mass thickens the blood and modestly increases the risk of thrombosis, especially if other risk factors (smoking, dehydration, sedentary lifestyle) are present. Regular monitoring of hemoglobin, hematocrit, and iron status, plus counseling on hydration and avoiding smoking, is recommended.
Source: MedlinePlus, National Library of Medicine

MedlinePlus brings together authoritative health information from the National Library of Medicine (NLM), the National Institutes of Health (NIH), and other government agencies and health-related organizations.

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