Is TK2 p.Thr64Met (c.191C>T) pathogenic?

TK2 p.Thr64Met (c.191C>T) is classified Pathogenic/Likely pathogenic in TK2 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2025-11-24). AlphaMissense: likely pathogenic (0.7867); Very rare (popmax 0.00167%, amr); Associated with progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 3.

What condition is associated with TK2 p.Thr64Met (c.191C>T)?

TK2 p.Thr64Met (c.191C>T) is associated with progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 3, mitochondrial DNA depletion syndrome, myopathic form, mitochondrial DNA depletion syndrome (ClinVar).

How common is TK2 p.Thr64Met (c.191C>T) in the general population?

TK2 p.Thr64Met (c.191C>T) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about TK2 p.Thr64Met (c.191C>T)?

AlphaMissense predicts likely pathogenic (score 0.7867) — an in-silico prediction, not a clinical call.

TK2 p.Thr64Met

Q: How is Autosomal recessive progressive external ophthalmoplegia inherited?

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

c.191C>T · rs281865487 · VCV38979

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

likely pathogenic

0.7867 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 3

Computational evidence

Protein change
AlphaMissense	0.7867	likely pathogenic ✓ concordant with ClinVar
REVEL	0.907	moderately pathogenic-leaning
SaProt	LLR -14.18	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.8	GERP 1.9, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 38 kb · p 0.097 · regional, not allelic
Overall
CADD	33.0	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 0.00167% Admixed American · 1/60,004 alleles

Overall 0.000186% 3/1,614,044 alleles · very rare exomes 3/1,461,868 · genomes 0/152,176 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,004
Finnishnot grpmax-eligible	0.00156%	64,000
European (non-Finnish)	8.47e-05%	1,179,999

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: TK2
Protein: p.Thr64Met
Coding: c.191C>T
MANE Select: NM_004614
dbSNP: rs281865487
Type: single nucleotide variant
Location: chr16:66541919 (GRCh38)
Gene constraint: LOEUF 1.101 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.01
Residue 64: a UniProt-annotated variant site (in mtdps2); a binding site

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

Disease context

progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: mitochondrial DNA depletion syndrome, myopathic form mitochondrial DNA depletion syndrome mitochondrial disease

For Autosomal recessive progressive external ophthalmoplegia (Orphanet):

Inheritance: Autosomal recessive
Onset: All ages

Similar variants

TK2 p.Thr64= 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
TK2 p.Arg130Gln Pathogenic/Likely pathogenic ★★ ⚠ same condition
TK2 p.Arg130Trp 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-thr64met (accessed [today's date]).

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