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…

Primary Disease Associations & Inheritance

Leukoencephalopathy with vanishing white matter 5, with or without ovarian failureMIM #620315

Clinical highlights

Gene–disease validity (ClinGen · GenCC)

Definitive · leukoencephalopathy with vanishing white matter 5 · AR · ClinGen 2024
Definitive · leukoencephalopathy with vanishing white matter · AR · Myriad Women's Health
Strong · leukoencephalopathy with vanishing white matter 1 · AR · Labcorp Genetics (formerly Invitae)
Supportive · ovarioleukodystrophy · AR · Orphanet

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype) and the gene is intolerant of it in the population — truncating, frameshift and canonical splice variants carry more prior weight here than missense.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.44

LOEUF

LOF

Mechanism· G2P

📖

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

Background carrier burden — how many people carry a rare variant somewhere in EIF2B5?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 79

854 rare PASS variants

Rare truncating (LoF)

1 in 3,900

86 rare PASS variants

Rare synonymous (reference)

1 in 170

336 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for EIF2B5. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 84	1 in 3,300
South Asian	~43k	1 in 62	≈ 1 in 22,000
Remaining (unassigned)	~30k	1 in 80	≈ 1 in 10,000
European (Finnish)	~27k	1 in 440	≈ 1 in 13,000
Admixed American	~22k	1 in 62	1 in 4,400
African / African American	~21k	1 in 80	1 in 3,500
East Asian	~20k	1 in 93	≈ 1 in 6,600
Ashkenazi Jewish	~13k	1 in 220	≈ 1 in 13,000
Middle Eastern	~2,884	1 in 100	≈ 1 in 2,900

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 16 coding exons well covered in gnomAD exomes and genomes.? see exons ↓