Is EEF2 p.Thr708Ile (c.2123C>T) pathogenic?

EEF2 p.Thr708Ile (c.2123C>T) is classified Uncertain significance in EEF2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-04). AlphaMissense: likely pathogenic (0.568); Very rare (popmax 0.00352%, amr); Associated with spinocerebellar ataxia type 26.

What condition is associated with EEF2 p.Thr708Ile (c.2123C>T)?

EEF2 p.Thr708Ile (c.2123C>T) is associated with spinocerebellar ataxia type 26 (ClinVar).

How common is EEF2 p.Thr708Ile (c.2123C>T) in the general population?

EEF2 p.Thr708Ile (c.2123C>T) is very rare (popmax 0.00352%, amr) (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.Thr708Ile (c.2123C>T)?

AlphaMissense predicts likely pathogenic (score 0.568) — an in-silico prediction, not a clinical call.

EEF2 p.Thr708Ile

c.2123C>T · VCV3901980

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.568 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00352%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

spinocerebellar ataxia type 26

Computational evidence

Protein change
AlphaMissense	0.568	likely pathogenic
REVEL	0.368	indeterminate
SaProt	LLR -11.66	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 9.9	GERP 2.2, phastCons 1
Regional constraint	o/e 0.71	unconstrained · MANE · 1,578 bp · p 7.1e-09 · regional, not allelic
Overall
CADD	25.1	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

Grpmax group 0.00352% Admixed American · 2/56,818 alleles

Filtering AF 0.000584% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000218%

Overall 0.00019% 3/1,581,154 alleles · very rare exomes 1/1,428,932 · genomes 2/152,222 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00352%	28,409
Finnishnot grpmax-eligible	0.00195%	51,298

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: EEF2
Protein: p.Thr708Ile
Coding: c.2123C>T
MANE Select: NM_001961
Type: single nucleotide variant
Location: chr19:3977555 (GRCh38)
Gene constraint: LOEUF 0.39 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 89.97 · 26 PDB
Residue 708: 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.Met453Ile Uncertain significance ★ ⚠ same condition
EEF2 p.Met494Leu 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-thr708ile (accessed [today's date]).

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