Is TK2 p.Tyr148fs (c.441del) pathogenic?

TK2 p.Tyr148fs (c.441del) is classified Pathogenic/Likely pathogenic in TK2 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2025-11-24). Ultra-rare (popmax 0.0362%, sas); Associated with mitochondrial DNA depletion syndrome, myopathic form.

What condition is associated with TK2 p.Tyr148fs (c.441del)?

TK2 p.Tyr148fs (c.441del) is associated with mitochondrial DNA depletion syndrome, myopathic form, progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 3, mitochondrial disease (ClinVar).

How common is TK2 p.Tyr148fs (c.441del) in the general population?

TK2 p.Tyr148fs (c.441del) is ultra-rare (popmax 0.0362%, sas) (gnomAD).

TK2 p.Tyr148fs

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.441del · rs768548319 · VCV1323691

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0362%, sas)

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	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 6 of 10
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 8	GERP 1.8, phastCons 1
Overall
CADD	22.1	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 0.0362% South Asian · 33/91,084 alleles

Filtering AF 0.0265% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0231%

Overall 0.00204% 33/1,613,924 alleles · ultra-rare exomes 31/1,461,710 · genomes 2/152,214 · 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.Tyr148fs
Coding: c.441del
MANE Select: NM_004614
dbSNP: rs768548319
Type: Deletion
Location: chr16:66529002 (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 mitochondrial disease

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

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

TK2 c.536_538+8del Pathogenic/Likely pathogenic ★★ same condition
TK2 p.Leu182fs Pathogenic/Likely pathogenic ★★ same condition
TK2 p.Lys202del Pathogenic/Likely pathogenic ★★ same condition
TK2 p.Lys43fs Pathogenic ★★ same condition
TK2 p.Tyr148= Likely benign ★★ same residue
TK2 p.Ile168fs Pathogenic ★ same condition
TK2 p.Asp42_Lys43delinsGlu Conflicting classifications of pathogenicity ★ same condition
TK2 c.156+2T>C 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-tyr148fs (accessed [today's date]).

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