Is EIF2B5 p.Val389= (c.1167G>A) pathogenic?

EIF2B5 p.Val389= (c.1167G>A) is classified Conflicting classifications of pathogenicity in EIF2B5 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-01-26). Rare (popmax 0.208%, afr); Associated with leukoencephalopathy with vanishing white matter 5.

What condition is associated with EIF2B5 p.Val389= (c.1167G>A)?

EIF2B5 p.Val389= (c.1167G>A) is associated with leukoencephalopathy with vanishing white matter 5, leukoencephalopathy with vanishing white matter (ClinVar).

How common is EIF2B5 p.Val389= (c.1167G>A) in the general population?

EIF2B5 p.Val389= (c.1167G>A) is rare (popmax 0.208%, afr) (gnomAD).

How is CACH syndrome inherited?

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

EIF2B5 p.Val389=

c.1167G>A · rs112278360 · VCV735947

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

rare (popmax 0.208%, afr)

Conditions

leukoencephalopathy with vanishing white matter 5

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.41	acceptor loss, 10 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 5	GERP -0.72, phastCons 1
Overall
CADD	4.34	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.208% African / African-American · 156/75,014 alleles

Filtering AF 0.181% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.171%

Overall 0.0107% 173/1,614,066 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.208%	481
Middle Eastern	0.0165%	6,062
Remaining individualsnot grpmax-eligible	0.016%	6,251
Admixed American	0.00667%	14,995
South Asian	0.0011%	91,076
European (non-Finnish)	8.47e-05%	1,180,020

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: EIF2B5
Protein: p.Val389=
Coding: c.1167G>A
MANE Select: NM_003907
dbSNP: rs112278360
Type: single nucleotide variant
Location: chr3:184141935 (GRCh38)
Gene constraint: LOEUF 0.544 · pLI 0.16 (gnomAD)
Structure: AlphaFold pLDDT 79.35 · 37 PDB

Full EIF2B5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

leukoencephalopathy with vanishing white matter 5 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: leukoencephalopathy with vanishing white matter

For CACH syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood

Similar variants

EIF2B5 p.Val389Met Likely pathogenic ★★ same residue
EIF2B5 p.Ala403Val Pathogenic/Likely pathogenic ★★ ⚠ same condition
EIF2B5 p.Arg113Cys Pathogenic/Likely pathogenic ★★ ⚠ same condition
EIF2B5 p.Arg113His Pathogenic ★★ ⚠ same condition
EIF2B5 p.Arg121Ter Pathogenic/Likely pathogenic ★★ same condition
EIF2B5 p.Arg136Cys Pathogenic/Likely pathogenic ★★ same condition
EIF2B5 p.Arg136His Pathogenic ★★ same condition
EIF2B5 p.Arg195Cys 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/eif2b5-p-val389 (accessed [today's date]).

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