Is EIF2B5 p.Pro254Ser (c.760C>T) pathogenic?

EIF2B5 p.Pro254Ser (c.760C>T) is classified Uncertain significance in EIF2B5 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-27). AlphaMissense: ambiguous (0.4201); Very rare (popmax 0.000339%, nfe); Associated with Inborn genetic diseases.

What condition is associated with EIF2B5 p.Pro254Ser (c.760C>T)?

EIF2B5 p.Pro254Ser (c.760C>T) is associated with Inborn genetic diseases (ClinVar).

How common is EIF2B5 p.Pro254Ser (c.760C>T) in the general population?

EIF2B5 p.Pro254Ser (c.760C>T) is very rare (popmax 0.000339%, nfe) (gnomAD).

What do computational predictors say about EIF2B5 p.Pro254Ser (c.760C>T)?

AlphaMissense predicts ambiguous (score 0.4201) — an in-silico prediction, not a clinical call.

EIF2B5 p.Pro254Ser

c.760C>T · VCV3844093

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4201 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4201	ambiguous
REVEL	0.892	moderately pathogenic-leaning
SaProt	LLR -12.35	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 4.9	GERP 1.7, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 8,264 bp · p 4.1e-06 · regional, not allelic
Overall
CADD	26.1	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 0.000339% European (non-Finnish) · 4/1,180,028 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000274% 4/1,461,404 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.Pro254Ser
Coding: c.760C>T
MANE Select: NM_003907
Type: single nucleotide variant
Location: chr3:184138241 (GRCh38)
Gene constraint: LOEUF 0.544 · pLI 0.16 (gnomAD)
Structure: AlphaFold pLDDT 79.35 · 37 PDB
Residue 254: an α-helix

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

EIF2B5 p.Pro254= Likely benign ★ same residue
EIF2B5 p.Leu106Phe Pathogenic ★★ same condition
EIF2B5 p.Ala639Thr Uncertain significance ★★ ⚠ same condition
EIF2B5 p.Ala677Gly Uncertain significance ★★ ⚠ same condition
EIF2B5 p.Arg129Gln Uncertain significance ★★ ⚠ same condition
EIF2B5 p.Arg145Cys Uncertain significance ★★ ⚠ same condition
EIF2B5 p.Arg145His Uncertain significance ★★ ⚠ same condition
EIF2B5 p.Arg15Leu Uncertain significance ★★ ⚠ 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-pro254ser (accessed [today's date]).

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