Is EIF2B5 p.Ser447= (c.1341G>A) pathogenic?

EIF2B5 p.Ser447= (c.1341G>A) is classified Benign/Likely benign in EIF2B5 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-06-01). Rare (popmax 0.812%, nfe); Associated with leukoencephalopathy with vanishing white matter.

What condition is associated with EIF2B5 p.Ser447= (c.1341G>A)?

EIF2B5 p.Ser447= (c.1341G>A) is associated with leukoencephalopathy with vanishing white matter (ClinVar).

How common is EIF2B5 p.Ser447= (c.1341G>A) in the general population?

EIF2B5 p.Ser447= (c.1341G>A) is rare (popmax 0.812%, nfe) (gnomAD).

How is CACH syndrome inherited?

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

EIF2B5 p.Ser447=

c.1341G>A · rs138857267 · VCV344335

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

rare (popmax 0.812%, nfe)

Conditions

leukoencephalopathy with vanishing white matter

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.30	acceptor gain · deltas
Constraint at this position
Conservation	phyloP -3.9	GERP -3.1
Overall
CADD	12.92	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.812% European (non-Finnish) · 9,587/1,180,020 alleles

Filtering AF 0.799% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.793%

Overall 0.755% 12,182/1,614,030 alleles · rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	2.67%	37
European (non-Finnish)grpmax	0.812%	123
Remaining individualsnot grpmax-eligible	0.704%	142
Middle Eastern	0.297%	337
South Asian	0.242%	414
Ashkenazi Jewishnot grpmax-eligible	0.216%	463
Admixed American	0.118%	845
African / African-American	0.0947%	1,056

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ser447=
Coding: c.1341G>A
MANE Select: NM_003907
dbSNP: rs138857267
Type: single nucleotide variant
Location: chr3:184142275 (GRCh38)
Gene constraint: LOEUF 0.544 · pLI 0.16 (gnomAD)
Structure: AlphaFold pLDDT 79.35 · 37 PDB
Residue 447: the 'disordered' region; a UniProt-annotated variant site (in vwm5)

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.Ser447Leu Pathogenic/Likely pathogenic ★★ ⚠ 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
EIF2B5 p.Arg195His Pathogenic ★★ ⚠ same condition
EIF2B5 p.Arg241Ter 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/eif2b5-p-ser447 (accessed [today's date]).

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