EIF2B5

Chr 3AR

eukaryotic translation initiation factor 2B subunit epsilon

Also known as: CACH, CLE, EIF-2B, EIF2Bepsilon, LVWM, VWM5

NCBI Gene: 8893ENSG00000145191UniProt: Q13144

This gene encodes one of five subunits of eukaryotic translation initiation factor 2B (EIF2B), a GTP exchange factor for eukaryotic initiation factor 2 and an essential regulator for protein synthesis. Mutations in this gene and the genes encoding other EIF2B subunits have been associated with leukoencephalopathy with vanishing white matter. [provided by RefSeq, Nov 2009]

Primary Disease Associations & Inheritance

Leukoencephalopathy with vanishing white matter 5, with or without ovarian failureMIM #620315
AR
580
ClinVar variants
110
Pathogenic / LP
0.06
pLI score
2
Active trials
Clinical Summary— EIF2B5
🧬
Gene-Disease Validity (ClinGen)
leukoencephalopathy with vanishing white matter 5 · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.26) despite low pLI — interpret in context.
📋
ClinVar Variants
110 Pathogenic / Likely Pathogenic· 208 VUS of 580 total submissions
💊
Clinical Trials
2 active or recruiting trials — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.44LOEUF
pLI 0.064
Z-score 4.25
OE 0.26 (0.16–0.44)
Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
0.78Z-score
OE missense 0.89 (0.81–0.97)
346 obs / 389.1 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.26 (0.16–0.44)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.89 (0.81–0.97)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.95
0≤1.21.6
LoF obs/exp: 10 / 38.5Missense obs/exp: 346 / 389.1Syn Z: 0.44

ClinVar Variant Classifications

580 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic66
Likely Pathogenic44
VUS208
Likely Benign225
Benign12
Conflicting25
66
Pathogenic
44
Likely Pathogenic
208
VUS
225
Likely Benign
12
Benign
25
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
12
14
40
0
66
Likely Pathogenic
4
30
10
0
44
VUS
1
182
20
5
208
Likely Benign
0
2
71
152
225
Benign
0
1
11
0
12
Conflicting
—25
Total17229152157580

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

View in ClinVar →

Protein Context — Lollipop Plot

EIF2B5 · protein map & ClinVar variants

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

Gene2Phenotype Curations

EIF2B5-related leukoencephalopathy with vanishing white matter

definitive
ARLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Leukoencephalopathy with vanishing white matter 5, with or without ovarian failure

MIM #620315

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — EIF2B5
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Multiple Sclerosis and EIF2B5: A Paradox or a Missing Link.
Zahoor I et al.·Adv Exp Med Biol
2017Review
Diagnosis of Genetic White Matter Disorders by Singleton Whole-Exome and Genome Sequencing Using Interactome-Driven Prioritization.
Schlüter A et al.·Neurology
2022
A novel missense variant in EIF2B5 identified in a consanguineous Iranian family with vanishing white matter disease and a brief review of the literature.
Nourmohammadi P et al.·J Genet
2023Review
The ovarioleukodystrophy.
Mathis S et al.·Clin Neurol Neurosurg
2008Case report
Genetic variants in diminished ovarian reserve and premature ovarian insufficiency: implications for assisted reproductive outcomes.
Xu Q et al.·J Assist Reprod Genet
2025
Low EIF2B5 expression predicts poor prognosis in ovarian cancer.
Hou L et al.·Medicine (Baltimore)
2020
A novel hypomorphic splice variant in EIF2B5 gene is associated with mild ovarioleukodystrophy.
Rodríguez-Palmero A et al.·Ann Clin Transl Neurol
2020Case report
Clinical and genetic characterization of leukoencephalopathies in adults.
Lynch DS et al.·Brain
2017
In vivo base editing of a pathogenic Eif2b5 variant improves vanishing white matter phenotypes in mice.
Böck D et al.·Mol Ther
2024
Genotypic and phenotypic heterogeneity among Chinese pediatric genetic white matter disorders.
Dong L et al.·Ital J Pediatr
2023
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Infantile-Onset Vanishing White Matter Disease in an Azerbaijani Infant With a Homozygous EIF2B5 p.(Arg195His) Variant.
Isayev C et al.·Cureus
2026🔓 Open Access
Adult-onset vanishing white matter disease caused by the EIF2B5 c.185A>T (p.Asp62Val) variant.
Zhou J et al.·Front Genet
2026🔓 Open Access
Cell-specific Eif2b5 mutant mice: novel insights into roles of macroglia in vanishing white matter.
Triñanes-Ramos J et al.·Brain
2025🔓 Open Access
"Case report": Whole-exome sequencing reveals compound heterozygous variants in the EIF2B5 gene in a familial case of vanishing white matter.
Savy S et al.·Front Genet
2025🔓 Open AccessCase report
EIF2B5 promotes malignant progression of hepatocellular carcinoma by activating the PI3K/AKT signaling pathway through targeting RPL6.
Xi Y et al.·Cell Signal
2025
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Cree Leukoencephalopathy

Single Patient Investigational Treatment for Cree Leukoencephalopathy

ACTIVE NOT RECRUITING
NCT07300397Phase NAMcGill University Health Centre/Research Institute of the McGill University Health CentreStarted 2025-12-03
Fosigotifator
Cree LeukoencephalopathyVanishing White Matter

Research Study for Single-Patient Treatment of Cree Leukoencephalopathy/Vanishing White Matter Disease

ACTIVE NOT RECRUITING
NCT07272525Phase EARLY_PHASE1McGill University Health Centre/Research Institute of the McGill University Health CentreStarted 2024-11-14
Fosigotifator (FGT/ABBV-CLS-7262)

External Resources

Links to major genomics databases and tools