Is TK2 p.Arg183Gln (c.548G>A) pathogenic?

TK2 p.Arg183Gln (c.548G>A) is classified Conflicting classifications of pathogenicity in TK2 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-01-11). AlphaMissense: likely benign (0.0774); Rare (popmax 0.145%, sas); Associated with Inborn genetic diseases.

What condition is associated with TK2 p.Arg183Gln (c.548G>A)?

TK2 p.Arg183Gln (c.548G>A) is associated with Inborn genetic diseases, mitochondrial disease (ClinVar).

How common is TK2 p.Arg183Gln (c.548G>A) in the general population?

TK2 p.Arg183Gln (c.548G>A) is rare (popmax 0.145%, sas) (gnomAD).

What do computational predictors say about TK2 p.Arg183Gln (c.548G>A)?

AlphaMissense predicts likely benign (score 0.0774) — an in-silico prediction, not a clinical call.

TK2 p.Arg183Gln

c.548G>A · rs780333412 · VCV1516956

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0774 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.145%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0774	likely benign
REVEL	0.462	indeterminate
SaProt	LLR -10.44	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	Δ0.57	acceptor gain · deltas
Pangolin	Δ0.26	loss · gain 0.21 · SpliceAI calls gain · independent
Constraint at this position
Conservation	phyloP 1.4	GERP -1.9, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 38 kb · p 0.097 · regional, not allelic
Overall
CADD	23.6	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 0.145% South Asian · 132/91,084 alleles

Filtering AF 0.125% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.117%

Overall 0.00917% 148/1,613,916 alleles · rare exomes 145/1,461,816 · genomes 3/152,100 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.145%	690
Remaining individualsnot grpmax-eligible	0.0064%	15,621
Admixed American	0.005%	19,994
European (non-Finnish)	0.000763%	131,107

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.Arg183Gln
Coding: c.548G>A
MANE Select: NM_004614
dbSNP: rs780333412
Type: single nucleotide variant
Location: chr16:66517206 (GRCh38)
Gene constraint: LOEUF 1.101 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.01
Residue 183: a UniProt-annotated variant site (in mtdps2 and peob3; reduction of activity; reduced affinity for atp)

Full TK2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: mitochondrial disease

Similar variants

TK2 p.Arg183Gly Pathogenic/Likely pathogenic ★★ same residue
TK2 p.Arg183Trp Pathogenic ★★ ⚠ same residue
TK2 p.Arg183= 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 p.Ala139Thr Pathogenic/Likely pathogenic ★★ same condition
TK2 p.Ala139Val Pathogenic/Likely pathogenic ★★ same condition
TK2 p.Arg104Cys 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-arg183gln (accessed [today's date]).

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