Is EIF2B2 p.Phe297fs (c.890del) pathogenic?

EIF2B2 p.Phe297fs (c.890del) is classified Conflicting classifications of pathogenicity in EIF2B2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-09-08). Ultra-rare (popmax 0.0183%, amr); Associated with leukoencephalopathy with vanishing white matter 2.

What condition is associated with EIF2B2 p.Phe297fs (c.890del)?

EIF2B2 p.Phe297fs (c.890del) is associated with leukoencephalopathy with vanishing white matter 2 (ClinVar).

How common is EIF2B2 p.Phe297fs (c.890del) in the general population?

EIF2B2 p.Phe297fs (c.890del) is ultra-rare (popmax 0.0183%, amr) (gnomAD).

How is CACH syndrome inherited?

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

EIF2B2 p.Phe297fs

c.890del · rs773041356 · VCV632220

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0183%, amr)

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	escapes	premature termination codon within the last 50 nt of the penultimate exon (7 of 8, 9 nt from its 3' end) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.5	GERP -3.1, phastCons 1
Overall
CADD	33.0	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 0.0183% Admixed American · 11/59,998 alleles

Filtering AF 0.0102% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00785%

Overall 0.00136% 22/1,613,814 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0183%	5,454
Ashkenazi Jewishnot grpmax-eligible	0.0135%	7,401
Remaining individualsnot grpmax-eligible	0.0032%	31,241
European (non-Finnish)	0.000424%	235,986

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.Phe297fs
Coding: c.890del
MANE Select: NM_014239
dbSNP: rs773041356
Type: Deletion
Location: chr14:75007779 (GRCh38)
Gene constraint: LOEUF 1.25 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.82 · 38 PDB
Residue 297: an α-helix

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

For CACH syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood

Similar variants

EIF2B2 p.Ile190fs Pathogenic/Likely pathogenic ★★ 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
EIF2B2 p.Arg183Ter Pathogenic/Likely pathogenic ★★ same condition
EIF2B2 p.Glu213Gly Pathogenic ★★ ⚠ same condition
EIF2B2 p.Gly200Val Pathogenic/Likely pathogenic ★★ same condition
EIF2B2 p.Lys273Arg 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/eif2b2-p-phe297fs (accessed [today's date]).

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