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EIF2B5

eukaryotic translation initiation factor 2B subunit epsilon

The EIF2B5 gene provides instructions for a subunit of the eIF2B protein, which is essential for regulating protein production within cells. The EIF2B5 gene codes for the epsilon subunit of the eukaryotic translation initiation factor 2B (eIF2B) protein.

Chromosome 3q27.1 Various HGNC:3261 Tier C
EIF2B5 3q27.1 p arm q arm 3

EIF2B5 is located on the long (q) arm of chromosome 3, at band 3q27.1. Arm ratio per GRCh38 - banding schematic.

Explore chromosome 3 in the library →

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Clinical tests that include this

Carrier Screening panel
EIF2B5 is 1 of 1,008 genes on this panel
Expanded carrier screening for recessive and X-linked conditions

Overview

The EIF2B5 gene (eukaryotic translation initiation factor 2B subunit epsilon) is crucial for normal cellular function, specifically in managing protein synthesis. It produces a component of the eIF2B protein, which acts as a key regulator in the cell's machinery for manufacturing proteins. Proper regulation of protein synthesis is vital for cells to adapt to changing conditions, such as growth or stress.

Variations in the EIF2B5 gene are linked to inherited neurological disorders, highlighting its importance in brain health and development.

What the gene does

The EIF2B5 gene encodes the epsilon subunit, an integral part of the eIF2B protein complex. This complex acts as a guanine nucleotide exchange factor (GEF) for the eukaryotic translation initiation factor 2 (eIF2), playing a central role in initiating protein synthesis. The eIF2B protein helps regulate the cell's protein production by facilitating the recycling of GTP molecules, which are essential for the eIF2 protein to begin protein synthesis.

Under certain cellular conditions, eIF2B can enhance protein synthesis by promoting GTP recycling. Conversely, under other conditions, it can tightly bind to eIF2, rendering eIF2B inactive and consequently slowing down protein synthesis. This intricate regulatory mechanism ensures that protein levels are correctly maintained, allowing cells to cope with diverse physiological demands, such as rapid proliferation or periods of rest.

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Chromosome location

The EIF2B5 gene is located on chromosome 3 at position 3q27.1. This specific chromosomal band indicates its precise address within the human genome.

Protein structure

The EIF2B5 protein consists of 721 amino acids and features several distinct regions. It contains three disordered regions: one spanning amino acids 1-40, another from amino acids 444-483, and a third from amino acids 523-547. A notable functional segment is the W2 domain, located from amino acids 543-720.

Domain map · 721 amino acids
W2 (543-720)W2543-7201~361721
Domain - independent functional unit
🧬 Explore 3D structure on AlphaFold
UniProt:Q13144Length:721 aaStructure:AlphaFold

Key variants

Genetic variants within the EIF2B5 gene can alter the function of the eIF2B protein, leading to disrupted protein synthesis regulation. These alterations can range from single nucleotide changes to larger deletions or insertions within the gene sequence. The impact of these variants varies, with some leading to severe clinical outcomes while others may have milder effects.

The table below shows the top 10 pathogenic or likely-pathogenic variants currently classified in ClinVar for EIF2B5.
View all on ClinVar →

Sample of pathogenic variants

10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.

Variant (HGVS) Protein change Classification Evidence Associated condition
c.1289T>C
single nucleotide variant
 p.Val430Ala Pathogenic/Likely pathogenic ★★☆☆ Vanishing white matter disease
c.1694delinsTTTCTTGTGCATCTCCACTACAGAGGAGCGGGGCATCTCCACTAC
Indel
 p.Lys565fs Pathogenic ★★☆☆ Vanishing white matter disease
c.1813del
Deletion
 p.Leu605fs Pathogenic ★★☆☆ Vanishing white matter disease
c.1960del
Deletion
 p.Phe653_Leu654insTer Pathogenic/Likely pathogenic ★★☆☆ Leukoencephalopathy with vanishing white matter 5
c.203T>C
single nucleotide variant
 p.Leu68Ser Pathogenic/Likely pathogenic ★★☆☆ EIF2B5-related disorder
c.406C>T
single nucleotide variant
 p.Arg136Cys Pathogenic/Likely pathogenic ★★☆☆ Leukoencephalopathy with vanishing white matter 5
c.439_442del
Deletion
 p.Asp147fs Pathogenic/Likely pathogenic ★★☆☆ Vanishing white matter disease
c.721C>T
single nucleotide variant
 p.Arg241Ter Pathogenic/Likely pathogenic ★★☆☆ Vanishing white matter disease
c.799C>T
single nucleotide variant
 p.Gln267Ter Pathogenic ★★☆☆ Vanishing white matter disease
c.805C>T
single nucleotide variant
 p.Arg269Ter Pathogenic ★★☆☆ Vanishing white matter disease

Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.

Associated conditions

Pathogenic variants in the EIF2B5 gene are primarily associated with leukoencephalopathy with vanishing white matter (VWM). This neurodegenerative condition affects the brain's white matter, leading to progressive neurological deterioration. The severity and presentation can vary, with some forms appearing in early childhood and others later in life.

No disease links recorded for this gene in our reference set.

UK clinical status

The EIF2B5 gene is included in several NHS England Genomic Medicine Service approved panels, indicating its clinical relevance in the UK. It is assessed under panels such as "Ataxia and cerebellar anomalies - childhood onset," "Hereditary ataxia," "Inherited white matter disorders," and "Leukodystrophy, adult onset." This inclusion highlights its importance for genetic testing in individuals presenting with these conditions.

Green-listed
High evidence · clinically actionable in NHS testing
Included in NHS GMS signed-off panels
Leukodystrophy, adult onset · R62 NHS GMS → Ataxia and cerebellar anomalies - childhood onset NHS GMS → DDG2P NHS GMS → Early onset or syndromic epilepsy NHS GMS → Hereditary ataxia, adult onset NHS GMS → Neurodegenerative disorders, adult onset NHS GMS → White matter disorders and cerebral calcification - childhood onset NHS GMS →
NHS Genomic Medicine Service Jeen carrier screening

Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory

Frequently asked questions

What is the primary function of the EIF2B5 gene?

The EIF2B5 gene codes for a subunit of the eIF2B protein, which is vital for regulating protein synthesis within cells. It helps control how efficiently cells make proteins by recycling molecules involved in the initiation of protein production.

What medical condition is most commonly associated with EIF2B5 gene variants?

The EIF2B5 gene is primarily associated with leukoencephalopathy with vanishing white matter (VWM). This is a progressive neurological disorder that affects the brain's white matter.

Is the EIF2B5 gene tested in the UK healthcare system?

Yes, the EIF2B5 gene is part of several NHS England Genomic Medicine Service approved panels. It is considered for individuals with conditions such as ataxia, hereditary ataxia, and inherited white matter disorders.

References

  1. Fogli A, Boespflug-Tanguy O. The large spectrum of eIF2B-related diseases. Biochemical Society transactions. 2006. PMID: 16246171
  2. Scheper GC, Proud CG, van der Knaap MS. Defective translation initiation causes vanishing of cerebral white matter. Trends in molecular medicine. 2006. PMID: 16545608
  3. Pronk JC, van Kollenburg B, Scheper GC. Vanishing white matter disease: a review with focus on its genetics. Mental retardation and developmental disabilities research reviews. 2006. PMID: 16807905
  4. van Kollenburg B, van Dijk J, Garbern J. Glia-specific activation of all pathways of the unfolded protein response in vanishing white matter disease. Journal of neuropathology and experimental neurology. 2006. PMID: 16825957
  5. Scali O, Di Perri C, Federico A. The spectrum of mutations for the diagnosis of vanishing white matter disease. Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology. 2006. PMID: 16998732
  6. Dietrich J, Lacagnina M, Gass D. EIF2B5 mutations compromise GFAP+ astrocyte generation in vanishing white matter leukodystrophy. Nature medicine. 2005. PMID: 15723074
  7. van der Voorn JP, van Kollenburg B, Bertrand G. The unfolded protein response in vanishing white matter disease. Journal of neuropathology and experimental neurology. 2005. PMID: 16141786
  8. Pavitt GD. eIF2B, a mediator of general and gene-specific translational control. Biochemical Society transactions. 2005. PMID: 16246152
  9. Fogli A, Schiffmann R, Hugendubler L. Decreased guanine nucleotide exchange factor activity in eIF2B-mutated patients. European journal of human genetics : EJHG. 2004. PMID: 15054402
  10. Li W, Wang X, Van Der Knaap MS. Mutations linked to leukoencephalopathy with vanishing white matter impair the function of the eukaryotic initiation factor 2B complex in diverse ways. Molecular and cellular biology. 2004. PMID: 15060152
Educational content. This page is not medical or genetic advice, is not individually reviewed by a clinician for each reader, and should not replace a consultation with a qualified healthcare professional or genetic counsellor. If you are considering genetic testing or acting on a test result, book a consultation.
Data sources Last updated 4 October 2026. Content compiled from HGNC · MedlinePlus Genetics · ClinGen · Genomics England PanelApp · NHS National Genomic Test Directory · ClinVar · UniProt · AlphaFold .