Is EIF2B5 p.Ser570Phe (c.1709C>T) pathogenic?

EIF2B5 p.Ser570Phe (c.1709C>T) is classified Uncertain significance in EIF2B5 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-15). AlphaMissense: ambiguous (0.464); Absent from gnomAD v4.1; Associated with leukoencephalopathy with vanishing white matter.

What condition is associated with EIF2B5 p.Ser570Phe (c.1709C>T)?

EIF2B5 p.Ser570Phe (c.1709C>T) is associated with leukoencephalopathy with vanishing white matter (ClinVar).

How common is EIF2B5 p.Ser570Phe (c.1709C>T) in the general population?

EIF2B5 p.Ser570Phe (c.1709C>T) is absent from gnomAD v4.1 (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.Ser570Phe (c.1709C>T)?

AlphaMissense predicts ambiguous (score 0.464) — an in-silico prediction, not a clinical call.

EIF2B5 p.Ser570Phe

c.1709C>T · rs770581569 · VCV902383

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.464 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

leukoencephalopathy with vanishing white matter

Computational evidence

Protein change
AlphaMissense	0.464	ambiguous
REVEL	0.655	pathogenic-leaning
SaProt	LLR -12.20	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.9, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 8,264 bp · p 4.1e-06 · regional, not allelic
Overall
CADD	28.2	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: EIF2B5
Protein: p.Ser570Phe
Coding: c.1709C>T
MANE Select: NM_003907
dbSNP: rs770581569
Type: single nucleotide variant
Location: chr3:184143106 (GRCh38)
Gene constraint: LOEUF 0.544 · pLI 0.16 (gnomAD)
Structure: AlphaFold pLDDT 79.35 · 37 PDB
Residue 570: the w2 domain

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.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
EIF2B5 p.Arg269Gln 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-ser570phe (accessed [today's date]).

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