EIF2B3

Chr 1AR

eukaryotic translation initiation factor 2B subunit gamma

Also known as: EIF-2B, EIF2Bgamma, VWM3

NCBI Gene: 8891ENSG00000070785UniProt: Q9NR50

The protein encoded by this gene is one of the subunits of initiation factor eIF2B, which catalyzes the exchange of eukaryotic initiation factor 2-bound GDP for GTP. It has also been found to function as a cofactor of hepatitis C virus internal ribosome entry site-mediated translation. Mutations in this gene have been associated with leukodystrophy with vanishing white matter. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2009]

Primary Disease Associations & Inheritance

Leukoencephalopathy with vanishing white matter 3, with or without ovarian failureMIM #620313
AR
365
ClinVar variants
21
Pathogenic / LP
0.57
pLI score
0
Active trials
Clinical Summary— EIF2B3
🧬
Gene-Disease Validity (ClinGen)
leukoencephalopathy with vanishing white matter 3 · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Moderately constrained gene (pLI 0.57) — some intolerance to loss-of-function variants.
📋
ClinVar Variants
21 Pathogenic / Likely Pathogenic· 132 VUS of 365 total submissions

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.
0.43LOEUF
pLI 0.567
Z-score 3.63
OE 0.21 (0.11–0.43)
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.
1.04Z-score
OE missense 0.81 (0.72–0.91)
198 obs / 243.9 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.0.21 (0.11–0.43)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.81 (0.72–0.91)
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.0.80
0≤1.21.6
LoF obs/exp: 5 / 24.3Missense obs/exp: 198 / 243.9Syn Z: 1.41

ClinVar Variant Classifications

365 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic7
Likely Pathogenic14
VUS132
Likely Benign176
Benign25
Conflicting11
7
Pathogenic
14
Likely Pathogenic
132
VUS
176
Likely Benign
25
Benign
11
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
1
2
4
0
7
Likely Pathogenic
3
9
2
0
14
VUS
0
102
27
3
132
Likely Benign
1
6
73
96
176
Benign
0
1
23
1
25
Conflicting
—11
Total5120129100365

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

View in ClinVar →

Protein Context — Lollipop Plot

EIF2B3 · protein map & ClinVar variants

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Leukoencephalopathy with vanishing white matter 3, with or without ovarian failure

MIM #620313

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — EIF2B3
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Eif2b3 mutants recapitulate phenotypes of vanishing white matter disease and validate novel disease alleles in zebrafish.
Lee YR et al.·Hum Mol Genet
2021Functional
Diagnostic yield of clinical exome sequencing in adulthood in medical genetics clinics.
Mainali A et al.·Am J Med Genet A
2023Review
Adult-onset vanishing white matter in a patient with EIF2B3 variants misdiagnosed as multiple sclerosis.
Xu L et al.·Neurol Sci
2022
Identification of a Missense Variant in the EIF2B3 Gene Causing Vanishing White Matter Disease with Antenatal-Onset but Mild Symptoms and Long-Term Survival.
Khorrami M et al.·J Mol Neurosci
2021Case report
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
A rare case of adult-onset vanishing white matter leukoencephalopathy with movement disorder, expressing homozygous EIF2B3 and PRKN pathogenic variants.
Douden BKA et al.·BMC Neurol
2025Case report
Genotypic and phenotypic heterogeneity among Chinese pediatric genetic white matter disorders.
Dong L et al.·Ital J Pediatr
2023
Postmortem Whole Exome Sequencing Identifies Novel EIF2B3 Mutation With Prenatal Phenotype in 2 Siblings.
Song H et al.·J Child Neurol
2017Case report
Adult-onset leukodystrophy with vanishing white matter: a case series of 19 patients.
Benzoni C et al.·J Neurol
2023Cohort
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