EIF2B4

Chr 2

eukaryotic translation initiation factor 2B subunit delta

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

NCBI Gene: 8890 ENSG00000115211 UniProt: Q9UI10

The protein functions as the delta subunit of eukaryotic initiation factor 2B (EIF2B), a GTP exchange factor essential for protein synthesis. Mutations cause leukoencephalopathy with vanishing white matter, sometimes accompanied by ovarian failure, through an autosomal recessive inheritance pattern. The high constraint scores (pLI 0.96, LOEUF 0.33) support that pathogenicity occurs predominantly through loss-of-function mechanisms affecting protein synthesis regulation.

GeneReviews ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

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]

GeneReviews ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.33

Clinical Summary— EIF2B4

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Gene-Disease Validity (ClinGen)

leukoencephalopathy with vanishing white matter 4 · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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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.

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ClinVar Variants

38 unique Pathogenic / Likely Pathogenic· 146 VUS of 513 total submissions

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GeneReview available — EIF2B4

Authoritative clinical overview · Recommended first read

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Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

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?

0.80Z-score

OE missense 0.87 (0.78–0.96)

257 obs / 295.6 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.14 (0.07–0.33)

0≤0.351.4

Missense OE?0.87 (0.78–0.96)

0≤0.61.4

Synonymous OE?1.16

0≤1.21.6

LoF obs/exp: 4 / 27.8Missense obs/exp: 257 / 295.6Syn Z: -1.35

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveEIF2B4-related leukoencephalopathy with vanishing white matterLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.4389th %ile

GOF

0.2895th %ile

LOF

0.66top 25%

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

513 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic20

Likely Pathogenic18

VUS146

Likely Benign274

Benign22

Conflicting15

Pathogenic

Likely Pathogenic

146

VUS

274

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	15	5	0	0	20
Likely Pathogenic	9	9	0	0	18
VUS	2	130	12	2	146
Likely Benign	1	10	113	150	274
Benign	0	2	17	3	22
Conflicting	—				15
Total	27	156	142	155	495

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

View in ClinVar →

15 pathogenic / likely-pathogenic (of 22) ClinVar copy-number / structural variants overlap EIF2B4 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →