Is EIF2B5 p.Ala640= (c.1920C>T) pathogenic?

EIF2B5 p.Ala640= (c.1920C>T) is classified Likely benign in EIF2B5 (ClinVar, Single submitter, 2 submitters; last evaluated 2026-01-31). Ultra-rare (popmax 0.0426%, afr); Associated with leukoencephalopathy with vanishing white matter.

What condition is associated with EIF2B5 p.Ala640= (c.1920C>T)?

EIF2B5 p.Ala640= (c.1920C>T) is associated with leukoencephalopathy with vanishing white matter (ClinVar).

How common is EIF2B5 p.Ala640= (c.1920C>T) in the general population?

EIF2B5 p.Ala640= (c.1920C>T) is ultra-rare (popmax 0.0426%, afr) (gnomAD).

How is CACH syndrome inherited?

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

EIF2B5 p.Ala640=

c.1920C>T · rs149329097 · VCV765778

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0426%, afr)

Conditions

leukoencephalopathy with vanishing white matter

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -3.3	GERP -3.7
Overall
CADD	1.879	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0426% African / African-American · 32/75,042 alleles

Filtering AF 0.031% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0271%

Overall 0.00297% 48/1,614,198 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0426%	2,345
Middle Eastern	0.0165%	6,060
Admixed American	0.00833%	12,004
Remaining individualsnot grpmax-eligible	0.0032%	31,252
East Asian	0.00223%	44,878
South Asian	0.0022%	45,544
European (non-Finnish)	0.000424%	236,010

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.Ala640=
Coding: c.1920C>T
MANE Select: NM_003907
dbSNP: rs149329097
Type: single nucleotide variant
Location: chr3:184144149 (GRCh38)
Gene constraint: LOEUF 0.544 · pLI 0.16 (gnomAD)
Structure: AlphaFold pLDDT 79.35 · 37 PDB
Residue 640: an α-helix; the w2 domain

Full EIF2B5 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

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.Arg136His Pathogenic ★★ same condition
EIF2B5 p.Arg195His Pathogenic ★★ ⚠ same condition
EIF2B5 p.Arg241Ter Pathogenic/Likely pathogenic ★★ same condition
EIF2B5 p.Arg269Gln 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/eif2b5-p-ala640 (accessed [today's date]).

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