Is TK2 p.Arg104Cys (c.310C>T) pathogenic?

TK2 p.Arg104Cys (c.310C>T) is classified Pathogenic/Likely pathogenic in TK2 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-11-24). AlphaMissense: ambiguous (0.4566); Very rare (popmax 0.00267%, afr); Associated with mitochondrial disease.

What condition is associated with TK2 p.Arg104Cys (c.310C>T)?

TK2 p.Arg104Cys (c.310C>T) is associated with mitochondrial disease, mitochondrial DNA depletion syndrome, myopathic form, mitochondrial DNA depletion syndrome (ClinVar).

How common is TK2 p.Arg104Cys (c.310C>T) in the general population?

TK2 p.Arg104Cys (c.310C>T) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about TK2 p.Arg104Cys (c.310C>T)?

AlphaMissense predicts ambiguous (score 0.4566) — an in-silico prediction, not a clinical call.

TK2 p.Arg104Cys

c.310C>T · rs1194187379 · VCV694439

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

ambiguous

0.4566 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Conditions

mitochondrial disease

Computational evidence

Protein change
AlphaMissense	0.4566	ambiguous
REVEL	0.594	indeterminate
SaProt	LLR -13.37	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.3	GERP 1.9, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 38 kb · p 0.097 · regional, not allelic
Overall
CADD	29.5	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 0.00267% African / African-American · 2/75,042 alleles

Filtering AF 0.000442% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000312%

Overall 0.000867% 14/1,614,160 alleles · very rare exomes 12/1,461,876 · genomes 2/152,284 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,521
East Asian	0.00223%	44,886
South Asian	0.0011%	91,078
European (non-Finnish)	0.000847%	118,003

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.Arg104Cys
Coding: c.310C>T
MANE Select: NM_004614
dbSNP: rs1194187379
Type: single nucleotide variant
Location: chr16:66531445 (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: mitochondrial DNA depletion syndrome, myopathic form mitochondrial DNA depletion syndrome

Similar variants

TK2 p.Arg104His Conflicting classifications of pathogenicity ★ same residue
TK2 p.Arg104Leu 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.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-arg104cys (accessed [today's date]).

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