EIF2B4

Chr 2AR

eukaryotic translation initiation factor 2B subunit delta

Also known as: EIF-2B, EIF2B, EIF2Bdelta, VWM4

NCBI Gene: 8890ENSG00000115211UniProt: Q9UI10

Eukaryotic initiation factor 2B (EIF2B), which is necessary for protein synthesis, is a GTP exchange factor composed of five different subunits. The protein encoded by this gene is the fourth, or delta, subunit. Defects in this gene are a cause of leukoencephalopathy with vanishing white matter (VWM) and ovarioleukodystrophy. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

Leukoencephalopathy with vanishing white matter 4, with or without ovarian failureMIM #620314
AR
512
ClinVar variants
52
Pathogenic / LP
0.96
pLI score· haploinsufficient
0
Active trials
Clinical Summary— EIF2B4
🧬
Gene-Disease Validity (ClinGen)
leukoencephalopathy with vanishing white matter 4 · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.96). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
52 Pathogenic / Likely Pathogenic· 147 VUS of 512 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
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.
0.33LOEUF
pLI 0.961
Z-score 4.18
OE 0.14 (0.07–0.33)
Highly constrained

Highly LoF-intolerant (top ~10% 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.
0.80Z-score
OE missense 0.87 (0.78–0.96)
257 obs / 295.6 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.0.14 (0.07–0.33)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.87 (0.78–0.96)
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.1.16
0≤1.21.6
LoF obs/exp: 4 / 27.8Missense obs/exp: 257 / 295.6Syn Z: -1.35

ClinVar Variant Classifications

512 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic34
Likely Pathogenic18
VUS147
Likely Benign275
Benign23
Conflicting15
34
Pathogenic
18
Likely Pathogenic
147
VUS
275
Likely Benign
23
Benign
15
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
10
5
19
0
34
Likely Pathogenic
8
9
1
0
18
VUS
1
123
21
2
147
Likely Benign
1
10
114
150
275
Benign
0
2
18
3
23
Conflicting
—15
Total20149173155512

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

View in ClinVar →

Protein Context — Lollipop Plot

EIF2B4 · protein map & ClinVar variants

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

Gene2Phenotype Curations

EIF2B4-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 4, with or without ovarian failure

MIM #620314

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — EIF2B4
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Screening of premature ovarian insufficiency associated genes in Hungarian patients with next generation sequencing.
Illés A et al.·BMC Med Genomics
2024Cohort
EIF2B4 promotes hepatocellular carcinoma progression and immune evasion by driving STAT3 translation via a GEF-dependent mechanism.
He Y et al.·Cell Oncol (Dordr)
2025Functional
Genotypic and phenotypic heterogeneity among Chinese pediatric genetic white matter disorders.
Dong L et al.·Ital J Pediatr
2023
The spectrum of mutations for the diagnosis of vanishing white matter disease.
Scali O et al.·Neurol Sci
2006Review
Vanishing white matter disease with different faces.
Güngör G et al.·Childs Nerv Syst
2020
Identification of ten novel mutations in patients with eIF2B-related disorders.
Ohlenbusch A et al.·Hum Mutat
2005Cohort
Leukoencephalopathy with vanishing white matter: from magnetic resonance imaging pattern to five genes.
Leegwater PA et al.·J Child Neurol
2003Review
Efficient detection of frequent eIF2B mutations for the rapid molecular diagnosis of CACH/VWM syndrome.
Ferreira MC et al.·Clin Biochem
2015
Eif2b3 mutants recapitulate phenotypes of vanishing white matter disease and validate novel disease alleles in zebrafish.
Lee YR et al.·Hum Mol Genet
2021Functional
Mendelian adult-onset leukodystrophy genes in Alzheimer's disease: critical influence of CSF1R and NOTCH3.
Sassi C et al.·Neurobiol Aging
2018
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools