Is EIF2B4 p.Arg170Ter (c.508C>T) pathogenic?

EIF2B4 p.Arg170Ter (c.508C>T) is classified Pathogenic in EIF2B4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-14). Very rare (popmax 0.00017%, nfe).

How common is EIF2B4 p.Arg170Ter (c.508C>T) in the general population?

EIF2B4 p.Arg170Ter (c.508C>T) is very rare (popmax 0.00017%, nfe) (gnomAD).

EIF2B4 p.Arg170Ter

c.508C>T · rs1572607363 · VCV2785772

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

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 6 of 13
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.22 · evaluated, not missing
Constraint at this position
Conservation	phyloP 8.6	GERP 1.7, phastCons 1
Overall
CADD	37.0	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 0.00017% European (non-Finnish) · 2/1,179,804 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000137% 2/1,461,614 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: EIF2B4
Protein: p.Arg170Ter
Coding: c.508C>T
MANE Select: NM_001034116
dbSNP: rs1572607363
Type: single nucleotide variant
Location: chr2:27368454 (GRCh38)
Gene constraint: LOEUF 0.687 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.37 · 38 PDB
Residue 170: an α-helix; the 'may bind the chemical integrated stress response (isr) inhibitor isrib' region

Full EIF2B4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EIF2B4 c.32-1G>T Likely pathogenic ★★ same type
EIF2B4 p.Arg357Gln Likely pathogenic ★★ ⚠ same type
EIF2B4 p.Pro243Leu Pathogenic/Likely pathogenic ★★ same type
EIF2B4 p.Thr502Met Likely pathogenic ★★ same type
EIF2B4 p.Tyr489His Pathogenic/Likely pathogenic ★★ same type
EIF2B4 p.Ala228Thr Uncertain significance ★★ ⚠ same type
EIF2B4 p.Ala349Thr Uncertain significance ★★ ⚠ same type
EIF2B4 p.Ala66Thr Uncertain significance ★★ ⚠ same type

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/eif2b4-p-arg170ter (accessed [today's date]).

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