EIF2B5

Chr 3AR

eukaryotic translation initiation factor 2B subunit epsilon

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

NCBI Gene: 8893 ENSG00000145191 UniProt: Q13144 OMIM: 603945

The protein is the epsilon subunit of eukaryotic translation initiation factor 2B (EIF2B), a GTP exchange factor that regulates protein synthesis by activating eukaryotic initiation factor 2. Mutations cause leukoencephalopathy with vanishing white matter, an autosomal recessive leukodystrophy that may be associated with ovarian failure in females. The pathogenic mechanism involves loss of function of the EIF2B complex, disrupting cellular protein synthesis regulation.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

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]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 0.441 OMIM phenotype

Clinical Summary— EIF2B5

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Gene-Disease Validity (ClinGen)

leukoencephalopathy with vanishing white matter 5 · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.26) despite low pLI — interpret in context.

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ClinVar Variants

120 unique Pathogenic / Likely Pathogenic· 239 VUS of 863 total submissions

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Clinical Trials

2 active or recruiting trials — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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GeneReview available — EIF2B5

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

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?

0.78Z-score

OE missense 0.89 (0.81–0.97)

346 obs / 389.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.26 (0.16–0.44)

0≤0.351.4

Missense OE?0.89 (0.81–0.97)

0≤0.61.4

Synonymous OE?0.95

0≤1.21.6

LoF obs/exp: 10 / 38.5Missense obs/exp: 346 / 389.1Syn Z: 0.44

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveEIF2B5-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.

0.6356th %ile

GOF

0.5366th %ile

LOF

0.3357th %ile

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

863 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic48

Likely Pathogenic72

VUS239

Likely Benign443

Benign15

Conflicting29

Pathogenic

Likely Pathogenic

239

VUS

443

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	33	12	3	0	48
Likely Pathogenic	29	42	1	0	72
VUS	2	214	18	5	239
Likely Benign	0	6	163	274	443
Benign	0	1	14	0	15
Conflicting	—				29
Total	64	275	199	279	846

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

View in ClinVar →

40 pathogenic / likely-pathogenic (of 47) ClinVar copy-number / structural variants overlap EIF2B5 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →