Is TK2 p.Glu133Asp (c.399G>T) pathogenic?

TK2 p.Glu133Asp (c.399G>T) is classified Likely pathogenic in TK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-24). AlphaMissense: likely pathogenic (0.926); Absent from gnomAD v4.1; Associated with mitochondrial disease.

What condition is associated with TK2 p.Glu133Asp (c.399G>T)?

TK2 p.Glu133Asp (c.399G>T) is associated with mitochondrial disease (ClinVar).

How common is TK2 p.Glu133Asp (c.399G>T) in the general population?

TK2 p.Glu133Asp (c.399G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TK2 p.Glu133Asp (c.399G>T)?

AlphaMissense predicts likely pathogenic (score 0.926) — an in-silico prediction, not a clinical call.

TK2 p.Glu133Asp

c.399G>T · VCV3778840

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.926 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

mitochondrial disease

Computational evidence

Protein change
AlphaMissense	0.926	likely pathogenic ✓ concordant with ClinVar · top 10% in TK2
REVEL	0.591	indeterminate
SaProt	LLR -11.42	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 1.1	GERP -0.35, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 38 kb · p 0.097 · regional, not allelic
Overall
CADD	24.9	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

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: TK2
Protein: p.Glu133Asp
Coding: c.399G>T
MANE Select: NM_004614
Type: single nucleotide variant
Location: chr16:66529044 (GRCh38)
Gene constraint: LOEUF 1.101 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.01
Residue 133: an active site

Full TK2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

mitochondrial disease — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TK2 p.Glu133Ala Likely pathogenic ★ same residue
TK2 p.Glu133Gln Likely pathogenic ★ same residue
TK2 p.Glu133= Likely benign ★ same residue
TK2 c.156+2T>C Pathogenic/Likely pathogenic ★★ same condition
TK2 c.157-2A>G Pathogenic/Likely pathogenic ★★ same condition
TK2 p.Ala139Thr Pathogenic/Likely pathogenic ★★ same condition
TK2 p.Ala139Val Pathogenic/Likely pathogenic ★★ same condition
TK2 p.Arg104Cys 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/tk2-p-glu133asp (accessed [today's date]).

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