Is TK2 p.Met1Leu (c.1A>T) pathogenic?

TK2 p.Met1Leu (c.1A>T) is classified Pathogenic in TK2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-03-26). Very rare (popmax 0.000171%, nfe); Associated with mitochondrial DNA depletion syndrome, myopathic form.

What condition is associated with TK2 p.Met1Leu (c.1A>T)?

TK2 p.Met1Leu (c.1A>T) is associated with mitochondrial DNA depletion syndrome, myopathic form, progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 3 (ClinVar).

How common is TK2 p.Met1Leu (c.1A>T) in the general population?

TK2 p.Met1Leu (c.1A>T) is very rare (popmax 0.000171%, nfe) (gnomAD).

TK2 p.Met1Leu

Q: How is Mitochondrial DNA depletion syndrome, myopathic form inherited?

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

c.1A>T · rs973152588 · VCV1496034

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

start-loss

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000171%, nfe)

Conditions

mitochondrial DNA depletion syndrome, myopathic form

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	start-loss	predicted loss-of-function
REVEL	0.477	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.7	GERP 1.4, phastCons 1
Overall
CADD	16.67	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 0.000171% European (non-Finnish) · 2/1,166,782 alleles

Filtering AF 2.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000126% 2/1,584,084 alleles · very rare exomes 2/1,431,812 · genomes 0/152,272 · joint denominator

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.Met1Leu
Coding: c.1A>T
MANE Select: NM_004614
dbSNP: rs973152588
Type: single nucleotide variant
Location: chr16:66550061 (GRCh38)
Gene constraint: LOEUF 1.101 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.01

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

Disease context

mitochondrial DNA depletion syndrome, myopathic form — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 3

For Mitochondrial DNA depletion syndrome, myopathic form (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

TK2 p.Met1Val Pathogenic ★ same residue
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.Arg130Trp Pathogenic/Likely pathogenic ★★ same condition
TK2 p.Arg183Trp Pathogenic ★★ ⚠ same condition
TK2 p.Arg192Lys Pathogenic ★★ same condition
TK2 p.Asn58Ser 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-met1leu (accessed [today's date]).

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