Is EEF2 p.Met453Ile (c.1359G>A) pathogenic?

EEF2 p.Met453Ile (c.1359G>A) is classified Uncertain significance in EEF2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-03-31). AlphaMissense: likely pathogenic (0.9924); Absent from gnomAD v4.1; Associated with spinocerebellar ataxia type 26.

What condition is associated with EEF2 p.Met453Ile (c.1359G>A)?

EEF2 p.Met453Ile (c.1359G>A) is associated with spinocerebellar ataxia type 26 (ClinVar).

How common is EEF2 p.Met453Ile (c.1359G>A) in the general population?

EEF2 p.Met453Ile (c.1359G>A) is absent from gnomAD v4.1 (gnomAD).

How is Spinocerebellar ataxia type 26 inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about EEF2 p.Met453Ile (c.1359G>A)?

AlphaMissense predicts likely pathogenic (score 0.9924) — an in-silico prediction, not a clinical call.

EEF2 p.Met453Ile

c.1359G>A · rs2145360047 · VCV1699353

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9924 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

spinocerebellar ataxia type 26

Computational evidence

Protein change
AlphaMissense	0.9924	likely pathogenic
REVEL	0.617	indeterminate
SaProt	LLR -11.08	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.2, phastCons 1
Regional constraint	o/e 0.21	constrained · MANE · 63 bp · p 5.4e-06 · regional, not allelic
Overall
CADD	31.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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: EEF2
Protein: p.Met453Ile
Coding: c.1359G>A
MANE Select: NM_001961
dbSNP: rs2145360047
Type: single nucleotide variant
Location: chr19:3980054 (GRCh38)
Gene constraint: LOEUF 0.39 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 89.97 · 26 PDB
Residue 453: a β-strand

Full EEF2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

spinocerebellar ataxia type 26 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Spinocerebellar ataxia type 26 (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult

Similar variants

EEF2 c.1150+15T>C Benign ★★ same condition
EEF2 p.His544= Benign ★★ same condition
EEF2 p.Pro596His Pathogenic ★ same condition
EEF2 p.Asn600Lys Uncertain significance ★ ⚠ same condition
EEF2 p.Asn660Ser Uncertain significance ★ ⚠ same condition
EEF2 p.Leu155Met Uncertain significance ★ ⚠ same condition
EEF2 p.Met494Leu Uncertain significance ★ ⚠ same condition
EEF2 p.Pro377Leu 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/eef2-p-met453ile (accessed [today's date]).

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