Is EIF2B5 p.Phe57Ser (c.170T>C) pathogenic?

EIF2B5 p.Phe57Ser (c.170T>C) is classified Uncertain significance in EIF2B5 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-11-05). AlphaMissense: ambiguous (0.4688); Ultra-rare (popmax 0.0105%, amr); Associated with leukoencephalopathy with vanishing white matter.

What condition is associated with EIF2B5 p.Phe57Ser (c.170T>C)?

EIF2B5 p.Phe57Ser (c.170T>C) is associated with leukoencephalopathy with vanishing white matter (ClinVar).

How common is EIF2B5 p.Phe57Ser (c.170T>C) in the general population?

EIF2B5 p.Phe57Ser (c.170T>C) is ultra-rare (popmax 0.0105%, amr) (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.Phe57Ser (c.170T>C)?

AlphaMissense predicts ambiguous (score 0.4688) — an in-silico prediction, not a clinical call.

EIF2B5 p.Phe57Ser

c.170T>C · rs758129111 · VCV1372063

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.4688 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0105%, amr)

Conditions

leukoencephalopathy with vanishing white matter

Computational evidence

Protein change
AlphaMissense	0.4688	ambiguous
REVEL	0.628	indeterminate
SaProt	LLR -7.20	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.6, phastCons 1
Regional constraint	o/e 1.16	unconstrained · MANE · 1,237 bp · p 0.11 · regional, not allelic
Overall
CADD	24.4	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 0.0105% Admixed American · 6/57,340 alleles

Filtering AF 0.00455% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00306%

Overall 0.00163% 26/1,590,550 alleles · ultra-rare exomes 24/1,438,372 · genomes 2/152,178 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0105%	9,557
Remaining individualsnot grpmax-eligible	0.00326%	30,714
European (non-Finnish)	0.00154%	64,992

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.Phe57Ser
Coding: c.170T>C
MANE Select: NM_003907
dbSNP: rs758129111
Type: single nucleotide variant
Location: chr3:184135555 (GRCh38)
Gene constraint: LOEUF 0.544 · pLI 0.16 (gnomAD)
Structure: AlphaFold pLDDT 79.35 · 37 PDB
Residue 57: 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.Phe57= 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
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-phe57ser (accessed [today's date]).

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