Is TK2 p.Pro227fs (c.676_677dup) pathogenic?

TK2 p.Pro227fs (c.676677dup) is classified Likely pathogenic in TK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-24). Associated with mitochondrial disease.

What condition is associated with TK2 p.Pro227fs (c.676_677dup)?

TK2 p.Pro227fs (c.676_677dup) is associated with mitochondrial disease (ClinVar).

TK2 p.Pro227fs

c.676_677dup · VCV4686628

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

Conditions

mitochondrial disease

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	escapes	premature termination codon within the last 50 nt of the penultimate exon (9 of 10, 21 nt from its 3' end) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 1.9	GERP -0.52, phastCons 1

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

Variant & gene context

Gene: TK2
Protein: p.Pro227fs
Coding: c.676_677dup
MANE Select: NM_004614
Type: Duplication
Location: chr16:66513752 (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 disease — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TK2 p.Ser51fs Pathogenic ★★ same condition
TK2 p.Glu48fs Pathogenic ★ same condition
TK2 p.Trp4fs Pathogenic ★ same condition
TK2 p.Val113fs Pathogenic ★ same condition
TK2 p.Pro227Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
TK2 c.156+2T>C Pathogenic/Likely pathogenic ★★ same condition
TK2 c.157-2A>G Pathogenic/Likely pathogenic ★★ same condition
TK2 c.536_538+8del 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-pro227fs (accessed [today's date]).

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