Is EIF2B1 p.Phe239Val (c.715T>G) pathogenic?

EIF2B1 p.Phe239Val (c.715T>G) is classified Pathogenic in EIF2B1 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2015-11-01). AlphaMissense: likely pathogenic (0.9677); Absent from gnomAD v4.1; Associated with leukoencephalopathy with vanishing white matter.

What condition is associated with EIF2B1 p.Phe239Val (c.715T>G)?

EIF2B1 p.Phe239Val (c.715T>G) is associated with leukoencephalopathy with vanishing white matter (ClinVar).

How common is EIF2B1 p.Phe239Val (c.715T>G) in the general population?

EIF2B1 p.Phe239Val (c.715T>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 EIF2B1 p.Phe239Val (c.715T>G)?

AlphaMissense predicts likely pathogenic (score 0.9677) — an in-silico prediction, not a clinical call.

EIF2B1 p.Phe239Val

c.715T>G · rs863225052 · VCV217282

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9677 · 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

Computational evidence

Protein change
AlphaMissense	0.9677	likely pathogenic ✓ concordant with ClinVar
REVEL	0.703	pathogenic-leaning
SaProt	LLR -13.80	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 11	GERP 1.9, phastCons 1
Regional constraint	o/e 0.72	unconstrained · MANE · 12 kb · p 8.2e-08 · 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: EIF2B1
Protein: p.Phe239Val
Coding: c.715T>G
MANE Select: NM_001414
dbSNP: rs863225052
Type: single nucleotide variant
Location: chr12:123622674 (GRCh38)
Gene constraint: LOEUF 1.06 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 91.67 · 38 PDB

Full EIF2B1 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

EIF2B1 p.Phe239= Likely benign ★ same residue
EIF2B1 p.Arg147Ter Pathogenic/Likely pathogenic ★★ same condition
EIF2B1 p.Tyr275Cys Pathogenic/Likely pathogenic ★★ same condition
EIF2B1 c.-183C>G Uncertain significance ★★ same condition
EIF2B1 c.*506C>T Uncertain significance ★★ same condition
EIF2B1 p.Val175Asp Uncertain significance ★★ ⚠ same condition
EIF2B1 c.-144G>C Benign ★★ same condition
EIF2B1 c.-164G>A Likely benign ★★ 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/eif2b1-p-phe239val (accessed [today's date]).

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