Is EIF2B2 p.Glu293fs (c.877dup) pathogenic?

EIF2B2 p.Glu293fs (c.877dup) is classified Pathogenic in EIF2B2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-17). Very rare (popmax 8.48e-05%, nfe); Associated with leukoencephalopathy with vanishing white matter.

What condition is associated with EIF2B2 p.Glu293fs (c.877dup)?

EIF2B2 p.Glu293fs (c.877dup) is associated with leukoencephalopathy with vanishing white matter (ClinVar).

How common is EIF2B2 p.Glu293fs (c.877dup) in the general population?

EIF2B2 p.Glu293fs (c.877dup) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

How is CACH syndrome inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

EIF2B2 p.Glu293fs

c.877dup · VCV3768546

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Conditions

leukoencephalopathy with vanishing white matter

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	escapes	premature termination codon within the last 50 nt of the penultimate exon (7 of 8, 22 nt from its 3' end) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 3.5	GERP 0.43, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,936 alleles

Overall 6.84e-05% 1/1,461,660 alleles · very rare

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: EIF2B2
Protein: p.Glu293fs
Coding: c.877dup
MANE Select: NM_014239
Type: Duplication
Location: chr14:75007766 (GRCh38)
Gene constraint: LOEUF 1.25 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.82 · 38 PDB
Residue 293: an α-helix

Full EIF2B2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

leukoencephalopathy with vanishing white matter — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For CACH syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood

Similar variants

EIF2B2 c.285-1G>A Likely pathogenic ★★ same condition
EIF2B2 p.Glu213Gly Pathogenic ★★ ⚠ same condition
EIF2B2 p.Glu304Ter Pathogenic/Likely pathogenic ★★ same condition
EIF2B2 p.Gly200Val Pathogenic/Likely pathogenic ★★ same condition
EIF2B2 p.Ile190fs Pathogenic/Likely pathogenic ★★ same condition
EIF2B2 p.Lys273Arg Pathogenic/Likely pathogenic ★★ ⚠ same condition
EIF2B2 p.Pro291Ser Pathogenic ★★ ⚠ same condition
EIF2B2 p.Ser171Phe Pathogenic/Likely pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/eif2b2-p-glu293fs (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown