Is TK2 p.Arg183Trp (c.547C>T) pathogenic?

TK2 p.Arg183Trp (c.547C>T) is classified Pathogenic in TK2 (ClinVar, Multiple submitters, 9 submitters; last evaluated 2025-11-24). AlphaMissense: likely benign (0.2929); Very rare (popmax 0.00801%, afr); Associated with TK2-related disorder.

How common is TK2 p.Arg183Trp (c.547C>T) in the general population?

TK2 p.Arg183Trp (c.547C>T) is very rare (popmax 0.00801%, afr) (gnomAD).

What do computational predictors say about TK2 p.Arg183Trp (c.547C>T)?

AlphaMissense predicts likely benign (score 0.2929) — an in-silico prediction, not a clinical call.

TK2 p.Arg183Trp

Q: What condition is associated with TK2 p.Arg183Trp (c.547C>T)?

TK2 p.Arg183Trp (c.547C>T) is associated with TK2-related disorder, mitochondrial DNA depletion syndrome, myopathic form, progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 3 (ClinVar).

c.547C>T · rs137886900 · VCV38992

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

AlphaMissense

likely benign

0.2929 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00801%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

TK2-related disorder

Computational evidence

Protein change
AlphaMissense	0.2929	likely benign ⚠ discordant with ClinVar
REVEL	0.92	moderately pathogenic-leaning
SaProt	LLR -14.36	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.45 · evaluated, not missing
Pangolin	Δ0.27	loss · gain 0.00 · SpliceAI below 0.2 · independent
Constraint at this position
Conservation	phyloP 9.9	GERP 1.5, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 38 kb · p 0.097 · regional, not allelic
Overall
CADD	34.0	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 0.00801% African / African-American · 6/74,914 alleles

Filtering AF 0.00394% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00361%

Overall 0.00781% 126/1,613,922 alleles · very rare exomes 112/1,461,794 · genomes 14/152,128 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0813%	1,231
Remaining individualsnot grpmax-eligible	0.0128%	7,811
African / African-Americangrpmax	0.00801%	12,486
European (non-Finnish)	0.005%	19,999
East Asian	0.00223%	44,894

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg183Trp
Coding: c.547C>T
MANE Select: NM_004614
dbSNP: rs137886900
Type: single nucleotide variant
Location: chr16:66517207 (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

TK2-related disorder

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

Similar variants

TK2 p.Arg183Gly Pathogenic/Likely pathogenic ★★ same residue
TK2 p.Arg183Gln Conflicting classifications of pathogenicity ★ ⚠ 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-arg183trp (accessed [today's date]).

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