Is EIF2B5 p.Arg121Ter (c.361C>T) pathogenic?

EIF2B5 p.Arg121Ter (c.361C>T) is classified Pathogenic/Likely pathogenic in EIF2B5 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-12-27). Very rare (popmax 0.000254%, nfe); Associated with EIF2B5-related disorders.

What condition is associated with EIF2B5 p.Arg121Ter (c.361C>T)?

EIF2B5 p.Arg121Ter (c.361C>T) is associated with EIF2B5-related disorders, leukoencephalopathy with vanishing white matter (ClinVar).

How common is EIF2B5 p.Arg121Ter (c.361C>T) in the general population?

EIF2B5 p.Arg121Ter (c.361C>T) is very rare (popmax 0.000254%, nfe) (gnomAD).

EIF2B5 p.Arg121Ter

c.361C>T · rs1030566286 · VCV1070707

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Conditions

EIF2B5-related disorders

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 3 of 16
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.9	GERP 1.7, phastCons 1
Overall
CADD	38.0	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

Grpmax group 0.000254% European (non-Finnish) · 3/1,180,036 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000205% 3/1,461,888 alleles · very rare

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.Arg121Ter
Coding: c.361C>T
MANE Select: NM_003907
dbSNP: rs1030566286
Type: single nucleotide variant
Location: chr3:184137660 (GRCh38)
Gene constraint: LOEUF 0.544 · pLI 0.16 (gnomAD)
Structure: AlphaFold pLDDT 79.35 · 37 PDB
Residue 121: a β-strand

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

Disease context

EIF2B5-related disorders

Also linked: leukoencephalopathy with vanishing white matter

Similar variants

EIF2B5 p.Arg121Gln Uncertain significance ★★ ⚠ 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.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-arg121ter (accessed [today's date]).

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