EIF2B1

Chr 12AR

eukaryotic translation initiation factor 2B subunit alpha

Also known as: EIF2B, EIF2BA, EIF2Balpha, VWM1

NCBI Gene: 1967 ENSG00000111361 UniProt: Q14232 OMIM: 606686

The protein is a subunit of eukaryotic translation initiation factor 2B, which functions as a GTP exchange factor for eukaryotic initiation factor 2 and regulates protein synthesis. Mutations cause leukoencephalopathy with vanishing white matter, inherited in an autosomal recessive pattern, with some patients also developing ovarian failure. Disease mutations can cause pathogenicity through dominant-negative effects that disrupt the essential regulatory function of the EIF2B complex.

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, Oct 2009]

GeneReviews OMIM ResearchGenerating clinical summary…

DNmechanismARLOEUF 0.981 OMIM phenotype

Clinical Summary— EIF2B1

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Gene-Disease Validity (ClinGen)

leukoencephalopathy with vanishing white matter 1 · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

43 unique Pathogenic / Likely Pathogenic· 99 VUS of 331 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — EIF2B1

Authoritative clinical overview · Recommended first read

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.98LOEUF

pLI 0.000

Z-score 1.64

OE 0.56 (0.34–0.98)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.38Z-score

OE missense 0.70 (0.60–0.81)

114 obs / 163.7 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.56 (0.34–0.98)

0≤0.351.4

Missense OE?0.70 (0.60–0.81)

0≤0.61.4

Synonymous OE?1.10

0≤1.21.6

LoF obs/exp: 9 / 16.1Missense obs/exp: 114 / 163.7Syn Z: -0.61

This gene — mechanism propensity

0.7035th %ile

GOF

0.4579th %ile

LOF

0.3162th %ile

The highest-scoring mechanism for this gene is dominant-negative.

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

331 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic31

Likely Pathogenic12

VUS99

Likely Benign154

Benign19

Conflicting8

Pathogenic

Likely Pathogenic

VUS

154

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	20	5	6	0	31
Likely Pathogenic	10	2	0	0	12
VUS	1	68	27	3	99
Likely Benign	0	2	67	85	154
Benign	0	0	18	1	19
Conflicting	—				8
Total	31	77	118	89	323

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

View in ClinVar →

23 pathogenic / likely-pathogenic (of 35) ClinVar copy-number / structural variants overlap EIF2B1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →