Is EIF2B2 p.Pro291Ser (c.871C>T) pathogenic?

EIF2B2 p.Pro291Ser (c.871C>T) is classified Pathogenic in EIF2B2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-12-04). AlphaMissense: ambiguous (0.5003); Very rare (popmax 0.000169%, nfe); Associated with leukoencephalopathy with vanishing white matter.

What condition is associated with EIF2B2 p.Pro291Ser (c.871C>T)?

EIF2B2 p.Pro291Ser (c.871C>T) is associated with leukoencephalopathy with vanishing white matter (ClinVar).

How common is EIF2B2 p.Pro291Ser (c.871C>T) in the general population?

EIF2B2 p.Pro291Ser (c.871C>T) is very rare (popmax 0.000169%, nfe) (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 EIF2B2 p.Pro291Ser (c.871C>T)?

AlphaMissense predicts ambiguous (score 0.5003) — an in-silico prediction, not a clinical call.

EIF2B2 p.Pro291Ser

c.871C>T · rs113994017 · VCV2691460

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.5003 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

leukoencephalopathy with vanishing white matter

Computational evidence

Protein change
AlphaMissense	0.5003	ambiguous
REVEL	0.832	moderately pathogenic-leaning
SaProt	LLR -8.90	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.6, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 6,194 bp · p 4.2e-05 · regional, not allelic
Overall
CADD	26.7	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

Grpmax group 0.000169% European (non-Finnish) · 2/1,179,964 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000137% 2/1,461,668 alleles · very rare

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.Pro291Ser
Coding: c.871C>T
MANE Select: NM_014239
dbSNP: rs113994017
Type: single nucleotide variant
Location: chr14:75007761 (GRCh38)
Gene constraint: LOEUF 1.25 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.82 · 38 PDB
Residue 291: an α-helix

Full EIF2B2 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

EIF2B2 c.285-1G>A Likely pathogenic ★★ same condition
EIF2B2 p.Glu213Gly Pathogenic ★★ ⚠ same condition
EIF2B2 p.Glu304Ter Pathogenic/Likely pathogenic ★★ same condition
EIF2B2 p.Gly200Val Pathogenic/Likely pathogenic ★★ same condition
EIF2B2 p.Lys273Arg Pathogenic/Likely pathogenic ★★ ⚠ same condition
EIF2B2 p.Ser171Phe Pathogenic/Likely pathogenic ★★ same condition
EIF2B2 p.Val308Met Pathogenic/Likely pathogenic ★★ ⚠ same condition
EIF2B2 p.Val316Asp 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-pro291ser (accessed [today's date]).

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