Is EIF2B5 p.Arg339Pro (c.1016G>C) pathogenic?

EIF2B5 p.Arg339Pro (c.1016G>C) is classified Pathogenic/Likely pathogenic in EIF2B5 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-11-13). AlphaMissense: likely pathogenic (0.8501); Very rare (popmax 0.000678%, nfe); Associated with leukoencephalopathy with vanishing white matter.

What condition is associated with EIF2B5 p.Arg339Pro (c.1016G>C)?

EIF2B5 p.Arg339Pro (c.1016G>C) is associated with leukoencephalopathy with vanishing white matter (ClinVar).

How common is EIF2B5 p.Arg339Pro (c.1016G>C) in the general population?

EIF2B5 p.Arg339Pro (c.1016G>C) is very rare (popmax 0.000678%, 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 EIF2B5 p.Arg339Pro (c.1016G>C)?

AlphaMissense predicts likely pathogenic (score 0.8501) — an in-silico prediction, not a clinical call.

EIF2B5 p.Arg339Pro

c.1016G>C · rs113994069 · VCV692119

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely pathogenic

0.8501 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000678%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

leukoencephalopathy with vanishing white matter

Computational evidence

Protein change
AlphaMissense	0.8501	likely pathogenic ✓ concordant with ClinVar
REVEL	0.869	moderately pathogenic-leaning
SaProt	LLR -9.15	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.7, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 8,264 bp · p 4.1e-06 · regional, not allelic
Overall
CADD	29.9	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 0.000678% European (non-Finnish) · 8/1,180,040 alleles

Filtering AF 0.000292% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000211%

Overall 0.000547% 8/1,461,894 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: EIF2B5
Protein: p.Arg339Pro
Coding: c.1016G>C
MANE Select: NM_003907
dbSNP: rs113994069
Type: single nucleotide variant
Location: chr3:184140590 (GRCh38)
Gene constraint: LOEUF 0.544 · pLI 0.16 (gnomAD)
Structure: AlphaFold pLDDT 79.35 · 37 PDB
Residue 339: a UniProt-annotated variant site (in vwm5); a turn

Full EIF2B5 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

EIF2B5 p.Arg339Gln Pathogenic/Likely pathogenic ★★ ⚠ same residue
EIF2B5 p.Arg339Trp Pathogenic/Likely pathogenic ★★ same residue
EIF2B5 p.Arg339= Likely benign ★ same residue
EIF2B5 p.Ala403Val Pathogenic/Likely pathogenic ★★ ⚠ same condition
EIF2B5 p.Arg113Cys Pathogenic/Likely pathogenic ★★ ⚠ same condition
EIF2B5 p.Arg113His Pathogenic ★★ ⚠ same condition
EIF2B5 p.Arg121Ter Pathogenic/Likely pathogenic ★★ same condition
EIF2B5 p.Arg136His 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/eif2b5-p-arg339pro (accessed [today's date]).

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