Is EIF2B4 p.Val4Leu (c.10G>C) pathogenic?

EIF2B4 p.Val4Leu (c.10G>C) is classified Uncertain significance in EIF2B4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-05-20). AlphaMissense: likely benign (0.2293); Absent from gnomAD v4.1; Associated with leukoencephalopathy with vanishing white matter.

What condition is associated with EIF2B4 p.Val4Leu (c.10G>C)?

EIF2B4 p.Val4Leu (c.10G>C) is associated with leukoencephalopathy with vanishing white matter (ClinVar).

How common is EIF2B4 p.Val4Leu (c.10G>C) in the general population?

EIF2B4 p.Val4Leu (c.10G>C) 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 EIF2B4 p.Val4Leu (c.10G>C)?

AlphaMissense predicts likely benign (score 0.2293) — an in-silico prediction, not a clinical call.

EIF2B4 p.Val4Leu

c.10G>C · rs371924054 · VCV2582342

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2293 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

leukoencephalopathy with vanishing white matter

Computational evidence

Protein change
AlphaMissense	0.2293	likely benign
REVEL	0.275	benign-leaning
SaProt	LLR -7.63	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.2	GERP 0.6, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 5,450 bp · p 0.8 · regional, not allelic
Overall
CADD	21.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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: EIF2B4
Protein: p.Val4Leu
Coding: c.10G>C
MANE Select: NM_001034116
dbSNP: rs371924054
Type: single nucleotide variant
Location: chr2:27370305 (GRCh38)
Gene constraint: LOEUF 0.687 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.37 · 38 PDB
Residue 4: the 'disordered' region

Full EIF2B4 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

EIF2B4 p.Val4Met Uncertain significance ★ same residue
EIF2B4 c.32-1G>T Likely pathogenic ★★ same condition
EIF2B4 p.Arg357Gln Likely pathogenic ★★ ⚠ same condition
EIF2B4 p.Pro243Leu Pathogenic/Likely pathogenic ★★ ⚠ same condition
EIF2B4 p.Tyr489His Pathogenic/Likely pathogenic ★★ same condition
EIF2B4 p.Arg112Gln Uncertain significance ★★ ⚠ same condition
EIF2B4 p.Arg143His Uncertain significance ★★ ⚠ same condition
EIF2B4 p.Arg321Cys Uncertain significance ★★ ⚠ 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/eif2b4-p-val4leu (accessed [today's date]).

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