Is TK2 p.Arg130Gln (c.389G>A) pathogenic?

TK2 p.Arg130Gln (c.389G>A) is classified Pathogenic/Likely pathogenic in TK2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-11-24). AlphaMissense: likely benign (0.2185); Very rare (popmax 0.000678%, nfe); Associated with mitochondrial DNA depletion syndrome.

What condition is associated with TK2 p.Arg130Gln (c.389G>A)?

TK2 p.Arg130Gln (c.389G>A) is associated with mitochondrial DNA depletion syndrome, mitochondrial disease (ClinVar).

How common is TK2 p.Arg130Gln (c.389G>A) in the general population?

TK2 p.Arg130Gln (c.389G>A) is very rare (popmax 0.000678%, nfe) (gnomAD).

What do computational predictors say about TK2 p.Arg130Gln (c.389G>A)?

AlphaMissense predicts likely benign (score 0.2185) — an in-silico prediction, not a clinical call.

TK2 p.Arg130Gln

c.389G>A · rs281865492 · VCV38989

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.2185 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000678%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

mitochondrial DNA depletion syndrome

Computational evidence

Protein change
AlphaMissense	0.2185	likely benign ⚠ discordant with ClinVar
REVEL	0.654	pathogenic-leaning
SaProt	LLR -11.29	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.8, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 38 kb · p 0.097 · regional, not allelic
Overall
CADD	31.0	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 0.000678% European (non-Finnish) · 8/1,180,026 alleles

Filtering AF 0.000292% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000211%

Overall 0.000496% 8/1,614,042 alleles · very rare exomes 8/1,461,744 · genomes 0/152,298 · 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.Arg130Gln
Coding: c.389G>A
MANE Select: NM_004614
dbSNP: rs281865492
Type: single nucleotide variant
Location: chr16:66529054 (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 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: mitochondrial disease

Similar variants

TK2 p.Arg130Trp Pathogenic/Likely pathogenic ★★ 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.Arg183Gly Pathogenic/Likely pathogenic ★★ same condition
TK2 p.Arg183Trp 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-arg130gln (accessed [today's date]).

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