Is EIF2B4 p.Arg9= (c.27C>T) pathogenic?

EIF2B4 p.Arg9= (c.27C>T) is classified Benign/Likely benign in EIF2B4 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-06-01). Low-frequency (popmax 1.49%, afr); Associated with leukoencephalopathy with vanishing white matter.

What condition is associated with EIF2B4 p.Arg9= (c.27C>T)?

EIF2B4 p.Arg9= (c.27C>T) is associated with leukoencephalopathy with vanishing white matter (ClinVar).

How common is EIF2B4 p.Arg9= (c.27C>T) in the general population?

EIF2B4 p.Arg9= (c.27C>T) is low-frequency (popmax 1.49%, afr) (gnomAD).

How is CACH syndrome inherited?

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

EIF2B4 p.Arg9=

c.27C>T · rs113310794 · VCV720908

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

low-frequency (popmax 1.49%, afr)

Conditions

leukoencephalopathy with vanishing white matter

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.17	GERP -3.4, phastCons 0.002
Overall
CADD	7.933	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.49% African / African-American · 1,093/73,484 alleles

Filtering AF 1.41% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.38%

Overall 0.0853% 1,321/1,548,040 alleles · low-frequency exomes 733/1,395,750 · genomes 588/152,290 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	1.49%	67
Middle Eastern	0.601%	166
Remaining individualsnot grpmax-eligible	0.174%	574
Admixed American	0.0876%	1,142
South Asian	0.00592%	16,890
European (non-Finnish)	0.00313%	31,923
Finnishnot grpmax-eligible	0.00192%	52,150

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: EIF2B4
Protein: p.Arg9=
Coding: c.27C>T
MANE Select: NM_001034116
dbSNP: rs113310794
Type: single nucleotide variant
Location: chr2:27370288 (GRCh38)
Gene constraint: LOEUF 0.687 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.37 · 38 PDB
Residue 9: the 'disordered' region

Full EIF2B4 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

EIF2B4 p.Arg9Cys Uncertain significance ★ same residue
EIF2B4 c.32-1G>T Likely pathogenic ★★ same condition
EIF2B4 p.Arg357Gln Likely pathogenic ★★ ⚠ same condition
EIF2B4 p.Pro243Leu Pathogenic/Likely pathogenic ★★ same condition
EIF2B4 p.Tyr489His Pathogenic/Likely pathogenic ★★ same condition
EIF2B4 p.Arg112Gln Uncertain significance ★★ ⚠ same condition
EIF2B4 p.Arg143His Uncertain significance ★★ ⚠ same condition
EIF2B4 p.Arg321Cys Uncertain significance ★★ ⚠ 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/eif2b4-p-arg9 (accessed [today's date]).

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