Is TK2 p.Lys50fs (c.144_145del) pathogenic?

TK2 p.Lys50fs (c.144145del) is classified Pathogenic in TK2 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2025-11-24). Very rare (popmax 0.005%, amr); Associated with mitochondrial disease.

How common is TK2 p.Lys50fs (c.144_145del) in the general population?

TK2 p.Lys50fs (c.144_145del) is very rare (popmax 0.005%, amr) (gnomAD).

TK2 p.Lys50fs

Q: What condition is associated with TK2 p.Lys50fs (c.144_145del)?

TK2 p.Lys50fs (c.144_145del) is associated with mitochondrial disease, mitochondrial DNA depletion syndrome, myopathic form, progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 3 (ClinVar).

c.144_145del · rs1454450104 · VCV972912

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

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	predicted	premature termination codon in exon 2 of 10
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.52	GERP 1.6, phastCons 1
Overall
CADD	33.0	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 0.005% Admixed American · 3/60,002 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000971%

Overall 0.00192% 31/1,613,544 alleles · very rare exomes 28/1,461,312 · genomes 3/152,232 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.005%	20,001
African / African-American	0.00267%	37,460
East Asian	0.00223%	44,876
South Asian	0.0022%	45,538
European (non-Finnish)	0.00178%	56,171
Remaining individualsnot grpmax-eligible	0.0016%	62,456
Finnishnot grpmax-eligible	0.00156%	64,028

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.Lys50fs
Coding: c.144_145del
MANE Select: NM_004614
dbSNP: rs1454450104
Type: Microsatellite
Location: chr16:66548989 (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

Also linked: mitochondrial DNA depletion syndrome, myopathic form progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 3 mitochondrial DNA depletion syndrome

Similar variants

TK2 p.Thr74fs Pathogenic ★ same condition
TK2 c.699+6_699+9del Conflicting classifications of pathogenicity ★ same condition
TK2 p.Lys50Thr Uncertain significance ★ ⚠ 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
TK2 p.Ala139Thr Pathogenic/Likely pathogenic ★★ same condition
TK2 p.Ala139Val 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-lys50fs (accessed [today's date]).

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