Is TK2 p.Gln45Ter (c.133C>T) pathogenic?

TK2 p.Gln45Ter (c.133C>T) is classified Pathogenic in TK2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-21). Very rare (popmax 0.0017%, nfe); Associated with progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 3.

How common is TK2 p.Gln45Ter (c.133C>T) in the general population?

TK2 p.Gln45Ter (c.133C>T) is very rare (popmax 0.0017%, nfe) (gnomAD).

TK2 p.Gln45Ter

Q: What condition is associated with TK2 p.Gln45Ter (c.133C>T)?

TK2 p.Gln45Ter (c.133C>T) is associated with progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 3, mitochondrial DNA depletion syndrome, myopathic form, mitochondrial disease (ClinVar).

Q: How is Autosomal recessive progressive external ophthalmoplegia inherited?

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

c.133C>T · rs281865486 · VCV38974

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.0017%, nfe)

Conditions

progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 3

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 2 of 10
Splicing
SpliceAI	Δ0.23	acceptor loss · deltas
Pangolin	Δ0.34	loss · gain 0.01 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 4.1	GERP -0.64, phastCons 1
Overall
CADD	40.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0017% European (non-Finnish) · 20/1,179,658 alleles

Filtering AF 0.00111% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0009%

Overall 0.00136% 22/1,613,338 alleles · very rare exomes 20/1,461,388 · genomes 2/151,950 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0017%	58,983
Remaining individualsnot grpmax-eligible	0.0016%	62,434
South Asian	0.0011%	91,060

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.Gln45Ter
Coding: c.133C>T
MANE Select: NM_004614
dbSNP: rs281865486
Type: single nucleotide variant
Location: chr16:66549001 (GRCh38)
Gene constraint: LOEUF 1.101 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.01
Residue 45: the 'disordered' region

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 disease

For Autosomal recessive progressive external ophthalmoplegia (Orphanet):

Inheritance: Autosomal recessive
Onset: All ages

Similar variants

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
TK2 p.Arg183Gly 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-gln45ter (accessed [today's date]).

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