Is EIF2B4 p.Pro243= (c.729G>A) pathogenic?

EIF2B4 p.Pro243= (c.729G>A) is classified Benign/Likely benign in EIF2B4 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-02-04). Low-frequency (popmax 2.6%, nfe); Associated with leukoencephalopathy with vanishing white matter.

What condition is associated with EIF2B4 p.Pro243= (c.729G>A)?

EIF2B4 p.Pro243= (c.729G>A) is associated with leukoencephalopathy with vanishing white matter (ClinVar).

How common is EIF2B4 p.Pro243= (c.729G>A) in the general population?

EIF2B4 p.Pro243= (c.729G>A) is low-frequency (popmax 2.6%, nfe) (gnomAD).

How is CACH syndrome inherited?

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

EIF2B4 p.Pro243=

c.729G>A · rs41288829 · VCV128989

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

gnomAD v4.1

Rare

low-frequency (popmax 2.6%, nfe)

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 -0.035	GERP -3.5, phastCons 0.038
Overall
CADD	7.121	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 2.6% European (non-Finnish) · 30,726/1,179,528 alleles

Filtering AF 2.58% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.57%

Overall 2.21% 35,701/1,613,502 alleles · low-frequency

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	2.6%	38
Amishnot grpmax-eligible	2.53%	40
Middle Eastern	2.36%	42
Remaining individualsnot grpmax-eligible	2.13%	47
Finnishnot grpmax-eligible	1.99%	50
Ashkenazi Jewishnot grpmax-eligible	1.86%	54
Admixed American	1.3%	77
South Asian	0.583%	172
African / African-American	0.451%	222
East Asian	0.00223%	44,866

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.Pro243=
Coding: c.729G>A
MANE Select: NM_001034116
dbSNP: rs41288829
Type: single nucleotide variant
Location: chr2:27367799 (GRCh38)
Gene constraint: LOEUF 0.687 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.37 · 38 PDB

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.Pro243Leu Pathogenic/Likely pathogenic ★★ same residue
EIF2B4 c.32-1G>T Likely pathogenic ★★ same condition
EIF2B4 p.Arg357Gln 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
EIF2B4 p.Cys437Phe 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-pro243 (accessed [today's date]).

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