Is EIF2B2 p.Thr77Ala (c.229A>G) pathogenic?

EIF2B2 p.Thr77Ala (c.229A>G) is classified Uncertain significance in EIF2B2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-06-01). AlphaMissense: likely benign (0.0858); Very rare (popmax 8.47e-05%, nfe); Associated with leukoencephalopathy with vanishing white matter.

What condition is associated with EIF2B2 p.Thr77Ala (c.229A>G)?

EIF2B2 p.Thr77Ala (c.229A>G) is associated with leukoencephalopathy with vanishing white matter (ClinVar).

How common is EIF2B2 p.Thr77Ala (c.229A>G) in the general population?

EIF2B2 p.Thr77Ala (c.229A>G) is very rare (popmax 8.47e-05%, 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.Thr77Ala (c.229A>G)?

AlphaMissense predicts likely benign (score 0.0858) — an in-silico prediction, not a clinical call.

EIF2B2 p.Thr77Ala

c.229A>G · rs1889569694 · VCV885153

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0858 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

leukoencephalopathy with vanishing white matter

Computational evidence

Protein change
AlphaMissense	0.0858	likely benign
REVEL	0.345	indeterminate
SaProt	LLR -6.16	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
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 0.81	unconstrained · MANE · 6,194 bp · p 4.2e-05 · regional, not allelic
Overall
CADD	22.5	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

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,000 alleles

Overall 0.000657% 1/152,098 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.Thr77Ala
Coding: c.229A>G
MANE Select: NM_014239
dbSNP: rs1889569694
Type: single nucleotide variant
Location: chr14:75003340 (GRCh38)
Gene constraint: LOEUF 1.25 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.82 · 38 PDB
Residue 77: 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 p.Thr77Pro Uncertain significance ★ ⚠ same residue
EIF2B2 p.Thr77= Likely benign ★ same residue
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.Pro291Ser 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-thr77ala (accessed [today's date]).

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