Is EIF2B5 p.Phe652= (c.1956C>T) pathogenic?

EIF2B5 p.Phe652= (c.1956C>T) is classified Conflicting classifications of pathogenicity in EIF2B5 (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2026-01-28). Rare (popmax 0.117%, nfe); Associated with leukoencephalopathy with vanishing white matter.

What condition is associated with EIF2B5 p.Phe652= (c.1956C>T)?

EIF2B5 p.Phe652= (c.1956C>T) is associated with leukoencephalopathy with vanishing white matter (ClinVar).

How common is EIF2B5 p.Phe652= (c.1956C>T) in the general population?

EIF2B5 p.Phe652= (c.1956C>T) is rare (popmax 0.117%, nfe) (gnomAD).

How is CACH syndrome inherited?

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

EIF2B5 p.Phe652=

c.1956C>T · rs149264256 · VCV779329

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

rare (popmax 0.117%, 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 4.9	GERP 0.81, phastCons 1
Overall
CADD	10.8	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.117% European (non-Finnish) · 1,385/1,180,054 alleles

Filtering AF 0.112% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.11%

Overall 0.0908% 1,466/1,614,240 alleles · rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.117%	852
Remaining individualsnot grpmax-eligible	0.106%	947
Admixed American	0.00833%	12,006
African / African-American	0.00799%	12,510
Ashkenazi Jewishnot grpmax-eligible	0.00675%	14,804
Finnishnot grpmax-eligible	0.00156%	64,038
South Asian	0.0011%	91,092

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.Phe652=
Coding: c.1956C>T
MANE Select: NM_003907
dbSNP: rs149264256
Type: single nucleotide variant
Location: chr3:184144185 (GRCh38)
Gene constraint: LOEUF 0.544 · pLI 0.16 (gnomAD)
Structure: AlphaFold pLDDT 79.35 · 37 PDB
Residue 652: 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-phe652 (accessed [today's date]).

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