TK2

Chr 16AR

thymidine kinase 2

Also known as: MTDPS2, MTTK, PEOB3, SCA31, TK2-EXT

NCBI Gene: 7084 ENSG00000166548 UniProt: O00142 OMIM: 188250

This gene encodes a mitochondrial deoxyribonucleoside kinase that phosphorylates thymidine, deoxycytidine, and deoxyuridine, which is essential for mitochondrial DNA synthesis. Mutations cause mitochondrial DNA depletion syndrome type 2 (myopathic type) and progressive external ophthalmoplegia with mitochondrial DNA deletions, both inherited in an autosomal recessive pattern. The pathogenic mechanism involves dominant-negative effects that disrupt mitochondrial DNA replication and maintenance.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene encodes a deoxyribonucleoside kinase that specifically phosphorylates thymidine, deoxycytidine, and deoxyuridine. The encoded enzyme localizes to the mitochondria and is required for mitochondrial DNA synthesis. Mutations in this gene are associated with a myopathic form of mitochondrial DNA depletion syndrome. Alternate splicing results in multiple transcript variants encoding distinct isoforms, some of which lack transit peptide, so are not localized to mitochondria. [provided by RefSeq, Dec 2012]

GeneReviews OMIM ResearchGenerating clinical summary…

MultiplemechanismARLOEUF 1.192 OMIM phenotypes

Clinical Summary— TK2

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Gene-Disease Validity (ClinGen)

mitochondrial disease · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

101 unique Pathogenic / Likely Pathogenic· 200 VUS of 641 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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GeneReview available — TK2

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.19LOEUF

pLI 0.000

Z-score 1.01

OE 0.73 (0.47–1.19)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.15Z-score

OE missense 0.96 (0.84–1.11)

139 obs / 144.2 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.73 (0.47–1.19)

0≤0.351.4

Missense OE?0.96 (0.84–1.11)

0≤0.61.4

Synonymous OE?1.15

0≤1.21.6

LoF obs/exp: 12 / 16.4Missense obs/exp: 139 / 144.2Syn Z: -0.89

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveTK2-related mitochondrial DNA depletion syndrome, myopathic formOTHERAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.75top 25%

GOF

0.6442th %ile

LOF

0.2774th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

641 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic52

Likely Pathogenic49

VUS200

Likely Benign257

Benign35

Conflicting35

Pathogenic

Likely Pathogenic

200

VUS

257

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	34	11	7	0	52
Likely Pathogenic	14	33	2	0	49
VUS	2	125	69	4	200
Likely Benign	1	6	146	104	257
Benign	0	1	33	1	35
Conflicting	—				35
Total	51	176	257	109	628

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

25 pathogenic / likely-pathogenic (of 36) ClinVar copy-number / structural variants overlap TK2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →