Is EIF2B5 p.Phe56Cys (c.167T>G) pathogenic?

EIF2B5 p.Phe56Cys (c.167T>G) is classified Pathogenic in EIF2B5 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2007-07-24). AlphaMissense: likely pathogenic (0.9137); Absent from gnomAD v4.1; Associated with leukoencephalopathy with vanishing white matter 5.

What condition is associated with EIF2B5 p.Phe56Cys (c.167T>G)?

EIF2B5 p.Phe56Cys (c.167T>G) is associated with leukoencephalopathy with vanishing white matter 5 (ClinVar).

How common is EIF2B5 p.Phe56Cys (c.167T>G) in the general population?

EIF2B5 p.Phe56Cys (c.167T>G) is absent from gnomAD v4.1 (gnomAD).

How is CACH syndrome inherited?

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

What do computational predictors say about EIF2B5 p.Phe56Cys (c.167T>G)?

AlphaMissense predicts likely pathogenic (score 0.9137) — an in-silico prediction, not a clinical call.

EIF2B5 p.Phe56Cys

c.167T>G · rs121908541 · VCV5952

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9137 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

leukoencephalopathy with vanishing white matter 5

Computational evidence

Protein change
AlphaMissense	0.9137	likely pathogenic ✓ concordant with ClinVar
REVEL	0.966	strongly pathogenic-leaning
SaProt	LLR -13.01	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.6, phastCons 1
Regional constraint	o/e 1.16	unconstrained · MANE · 1,237 bp · p 0.11 · regional, not allelic
Overall
CADD	29.9	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: EIF2B5
Protein: p.Phe56Cys
Coding: c.167T>G
MANE Select: NM_003907
dbSNP: rs121908541
Type: single nucleotide variant
Location: chr3:184135552 (GRCh38)
Gene constraint: LOEUF 0.544 · pLI 0.16 (gnomAD)
Structure: AlphaFold pLDDT 79.35 · 37 PDB
Residue 56: a turn

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

For CACH syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood

Similar variants

EIF2B5 p.Phe56Tyr Uncertain significance ★ ⚠ same residue
EIF2B5 p.Phe56Val Conflicting classifications of pathogenicity ★ ⚠ same residue
EIF2B5 p.Phe56Leu Uncertain significance ★ ⚠ same residue
EIF2B5 p.Ala403Val Pathogenic/Likely pathogenic ★★ ⚠ same condition
EIF2B5 p.Arg113His Pathogenic ★★ ⚠ same condition
EIF2B5 p.Arg136Cys Pathogenic/Likely pathogenic ★★ same condition
EIF2B5 p.Arg195Cys Likely pathogenic ★★ ⚠ same condition
EIF2B5 p.Arg195His 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-phe56cys (accessed [today's date]).

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