Is TK2 p.Arg196Ser (c.588A>T) pathogenic?

TK2 p.Arg196Ser (c.588A>T) is classified Conflicting classifications of pathogenicity in TK2 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-11-24). AlphaMissense: likely pathogenic (0.9722); Very rare (popmax 0.00237%, nfe); Associated with mitochondrial DNA depletion syndrome, myopathic form.

What condition is associated with TK2 p.Arg196Ser (c.588A>T)?

TK2 p.Arg196Ser (c.588A>T) 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.Arg196Ser (c.588A>T) in the general population?

TK2 p.Arg196Ser (c.588A>T) is very rare (popmax 0.00237%, nfe) (gnomAD).

What do computational predictors say about TK2 p.Arg196Ser (c.588A>T)?

AlphaMissense predicts likely pathogenic (score 0.9722) — an in-silico prediction, not a clinical call.

TK2 p.Arg196Ser

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.588A>T · rs752949191 · VCV1217245

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.9722 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00237%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

mitochondrial DNA depletion syndrome, myopathic form

Computational evidence

Protein change
AlphaMissense	0.9722	likely pathogenic · top 4% in TK2
REVEL	0.902	moderately pathogenic-leaning
SaProt	LLR -13.32	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 0.022	GERP -3, phastCons 0.94
Regional constraint	o/e 0.91	unconstrained · MANE · 38 kb · p 0.097 · regional, not allelic
Overall
CADD	24.0	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 0.00237% European (non-Finnish) · 28/1,180,050 alleles

Filtering AF 0.00164% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00142%

Overall 0.0018% 29/1,614,078 alleles · very rare exomes 26/1,461,884 · genomes 3/152,194 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00237%	42,145
Remaining individualsnot grpmax-eligible	0.0016%	62,488

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.Arg196Ser
Coding: c.588A>T
MANE Select: NM_004614
dbSNP: rs752949191
Type: single nucleotide variant
Location: chr16:66517166 (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.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
TK2 p.Arg183Gly 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-arg196ser (accessed [today's date]).

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