Is EIF2B2 p.Ile190fs (c.570del) pathogenic?

EIF2B2 p.Ile190fs (c.570del) is classified Pathogenic/Likely pathogenic in EIF2B2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-11-25). Very rare (popmax 0.0022%, nfe); Associated with leukoencephalopathy with vanishing white matter 2.

What condition is associated with EIF2B2 p.Ile190fs (c.570del)?

EIF2B2 p.Ile190fs (c.570del) is associated with leukoencephalopathy with vanishing white matter 2, leukoencephalopathy with vanishing white matter (ClinVar).

How common is EIF2B2 p.Ile190fs (c.570del) in the general population?

EIF2B2 p.Ile190fs (c.570del) is very rare (popmax 0.0022%, nfe) (gnomAD).

How is CACH syndrome inherited?

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

EIF2B2 p.Ile190fs

c.570del · rs755436800 · VCV632219

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.0022%, nfe)

Conditions

leukoencephalopathy with vanishing white matter 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 4 of 8
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 11	GERP 1.9, phastCons 1
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0022% European (non-Finnish) · 26/1,179,560 alleles

Filtering AF 0.00153% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0013%

Overall 0.00174% 28/1,612,774 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0032%	31,216
European (non-Finnish)grpmax	0.0022%	45,368

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ile190fs
Coding: c.570del
MANE Select: NM_014239
dbSNP: rs755436800
Type: Deletion
Location: chr14:75004872 (GRCh38)
Gene constraint: LOEUF 1.25 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.82 · 38 PDB
Residue 190: a β-strand

Full EIF2B2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

leukoencephalopathy with vanishing white matter 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: leukoencephalopathy with vanishing white matter

For CACH syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood

Similar variants

EIF2B2 p.Ile190Met Uncertain significance ★★ ⚠ same residue
EIF2B2 p.Ile15fs Pathogenic ★ same condition
EIF2B2 p.Ile190Thr Uncertain significance ★ ⚠ same residue
EIF2B2 p.Phe297fs Conflicting classifications of pathogenicity ★ same condition
EIF2B2 p.Pro311fs Conflicting classifications of pathogenicity ★ same condition
EIF2B2 p.Leu265fs Pathogenic same condition
EIF2B2 c.285-1G>A Likely pathogenic ★★ same condition
EIF2B2 c.832-2A>G 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-ile190fs (accessed [today's date]).

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