Is TK2 p.Leu220Pro (c.659T>C) pathogenic?

TK2 p.Leu220Pro (c.659T>C) is classified Conflicting classifications of pathogenicity in TK2 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2025-11-24). AlphaMissense: likely pathogenic (0.9743); Very rare (popmax 0.00223%, eas); Associated with mitochondrial disease.

What condition is associated with TK2 p.Leu220Pro (c.659T>C)?

TK2 p.Leu220Pro (c.659T>C) is associated with mitochondrial disease, inborn mitochondrial myopathy, mitochondrial DNA depletion syndrome, myopathic form (ClinVar).

How common is TK2 p.Leu220Pro (c.659T>C) in the general population?

TK2 p.Leu220Pro (c.659T>C) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about TK2 p.Leu220Pro (c.659T>C)?

AlphaMissense predicts likely pathogenic (score 0.9743) — an in-silico prediction, not a clinical call.

TK2 p.Leu220Pro

c.659T>C · rs1168827071 · VCV972913

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely pathogenic

0.9743 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

mitochondrial disease

Computational evidence

Protein change
AlphaMissense	0.9743	likely pathogenic · top 3% in TK2
REVEL	0.956	strongly pathogenic-leaning
SaProt	LLR -17.31	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.5, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 38 kb · p 0.097 · regional, not allelic
Overall
CADD	28.1	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,872 alleles

Overall 6.2e-05% 1/1,614,036 alleles · very rare exomes 1/1,461,826 · genomes 0/152,210 · 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.Leu220Pro
Coding: c.659T>C
MANE Select: NM_004614
dbSNP: rs1168827071
Type: single nucleotide variant
Location: chr16:66513771 (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: inborn mitochondrial myopathy mitochondrial DNA depletion syndrome, myopathic form progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 3

Similar variants

TK2 p.Leu220= Likely benign ★ same residue
TK2 c.156+2T>C Pathogenic/Likely pathogenic ★★ same condition
TK2 c.157-2A>G Pathogenic/Likely pathogenic ★★ same condition
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.Arg130Gln Pathogenic/Likely pathogenic ★★ ⚠ same condition
TK2 p.Arg130Trp 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-leu220pro (accessed [today's date]).

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