Is EIF2B5 p.Ser614Ter (c.1841C>G) pathogenic?

EIF2B5 p.Ser614Ter (c.1841C>G) is classified Pathogenic in EIF2B5 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-06). Absent from gnomAD v4.1; Associated with leukoencephalopathy with vanishing white matter 5.

What condition is associated with EIF2B5 p.Ser614Ter (c.1841C>G)?

EIF2B5 p.Ser614Ter (c.1841C>G) is associated with leukoencephalopathy with vanishing white matter 5 (ClinVar).

How common is EIF2B5 p.Ser614Ter (c.1841C>G) in the general population?

EIF2B5 p.Ser614Ter (c.1841C>G) 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.

EIF2B5 p.Ser614Ter

c.1841C>G · rs754272609 · VCV3024560

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

leukoencephalopathy with vanishing white matter 5

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 13 of 16
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.25 · evaluated, not missing
Constraint at this position
Conservation	phyloP 6.1	GERP 0.58, phastCons 0.99
Overall
CADD	36.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

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.Ser614Ter
Coding: c.1841C>G
MANE Select: NM_003907
dbSNP: rs754272609
Type: single nucleotide variant
Location: chr3:184143537 (GRCh38)
Gene constraint: LOEUF 0.544 · pLI 0.16 (gnomAD)
Structure: AlphaFold pLDDT 79.35 · 37 PDB
Residue 614: an α-helix; the w2 domain

Full EIF2B5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

leukoencephalopathy with vanishing white matter 5 — 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.Arg113His Pathogenic ★★ ⚠ same condition
EIF2B5 p.Arg136Cys Pathogenic/Likely pathogenic ★★ same condition
EIF2B5 p.Arg195Cys Likely pathogenic ★★ ⚠ same condition
EIF2B5 p.Arg195His Pathogenic ★★ ⚠ same condition
EIF2B5 p.Arg269Gln Pathogenic/Likely pathogenic ★★ ⚠ same condition
EIF2B5 p.Arg315His Pathogenic/Likely pathogenic ★★ ⚠ same condition
EIF2B5 p.Arg339Trp 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-ser614ter (accessed [today's date]).

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