Is EIF2B2 p.Ala224= (c.672C>T) pathogenic?

EIF2B2 p.Ala224= (c.672C>T) is classified Likely benign in EIF2B2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-04-22). Ultra-rare (popmax 0.0312%, eas); Associated with leukoencephalopathy with vanishing white matter.

What condition is associated with EIF2B2 p.Ala224= (c.672C>T)?

EIF2B2 p.Ala224= (c.672C>T) is associated with leukoencephalopathy with vanishing white matter (ClinVar).

How common is EIF2B2 p.Ala224= (c.672C>T) in the general population?

EIF2B2 p.Ala224= (c.672C>T) is ultra-rare (popmax 0.0312%, eas) (gnomAD).

How is CACH syndrome inherited?

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

EIF2B2 p.Ala224=

c.672C>T · rs528714025 · VCV1561773

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0312%, eas)

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 0.7	GERP -3.5, phastCons 1
Overall
CADD	13.37	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0312% East Asian · 14/44,832 alleles

Filtering AF 0.0188% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0151%

Overall 0.00229% 37/1,612,998 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0312%	3,202
South Asian	0.00439%	22,753
Remaining individualsnot grpmax-eligible	0.0016%	62,458
European (non-Finnish)	0.00153%	65,514

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.Ala224=
Coding: c.672C>T
MANE Select: NM_014239
dbSNP: rs528714025
Type: single nucleotide variant
Location: chr14:75005940 (GRCh38)
Gene constraint: LOEUF 1.25 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.82 · 38 PDB
Residue 224: 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.Lys273Arg Pathogenic/Likely pathogenic ★★ ⚠ same condition
EIF2B2 p.Pro291Ser Pathogenic ★★ ⚠ same condition
EIF2B2 p.Ser171Phe Pathogenic/Likely pathogenic ★★ same condition
EIF2B2 p.Val308Met 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-ala224 (accessed [today's date]).

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