Is EIF2B2 p.Pro333= (c.999T>A) pathogenic?

EIF2B2 p.Pro333= (c.999T>A) is classified Conflicting classifications of pathogenicity in EIF2B2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-08-11). Ultra-rare (popmax 0.0186%, nfe); Associated with leukoencephalopathy with vanishing white matter.

What condition is associated with EIF2B2 p.Pro333= (c.999T>A)?

EIF2B2 p.Pro333= (c.999T>A) is associated with leukoencephalopathy with vanishing white matter (ClinVar).

How common is EIF2B2 p.Pro333= (c.999T>A) in the general population?

EIF2B2 p.Pro333= (c.999T>A) is ultra-rare (popmax 0.0186%, nfe) (gnomAD).

How is CACH syndrome inherited?

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

EIF2B2 p.Pro333=

c.999T>A · rs147596765 · VCV756133

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0186%, nfe)

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 -1.8	GERP -3.5
Overall
CADD	3.665	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0186% European (non-Finnish) · 219/1,180,016 alleles

Filtering AF 0.0165% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0157%

Overall 0.0141% 227/1,614,028 alleles · ultra-rare exomes 213/1,461,862 · genomes 14/152,166 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0186%	5,388
Admixed American	0.00833%	12,001
Remaining individualsnot grpmax-eligible	0.0032%	31,244
African / African-American	0.00134%	74,906

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.Pro333=
Coding: c.999T>A
MANE Select: NM_014239
dbSNP: rs147596765
Type: single nucleotide variant
Location: chr14:75009131 (GRCh38)
Gene constraint: LOEUF 1.25 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.82 · 38 PDB
Residue 333: 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-pro333 (accessed [today's date]).

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