Is TK2 p.Arg104His (c.311G>A) pathogenic?

TK2 p.Arg104His (c.311G>A) is classified Conflicting classifications of pathogenicity in TK2 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-11-24). AlphaMissense: ambiguous (0.3654); Very rare (popmax 0.00223%, eas); Associated with mitochondrial disease.

What condition is associated with TK2 p.Arg104His (c.311G>A)?

TK2 p.Arg104His (c.311G>A) is associated with mitochondrial disease, mitochondrial DNA depletion syndrome (ClinVar).

How common is TK2 p.Arg104His (c.311G>A) in the general population?

TK2 p.Arg104His (c.311G>A) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about TK2 p.Arg104His (c.311G>A)?

AlphaMissense predicts ambiguous (score 0.3654) — an in-silico prediction, not a clinical call.

TK2 p.Arg104His

c.311G>A · rs770318536 · VCV1180625

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

ambiguous

0.3654 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Conditions

mitochondrial disease

Computational evidence

Protein change
AlphaMissense	0.3654	ambiguous
REVEL	0.52	indeterminate
SaProt	LLR -12.54	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.8	GERP -0.18, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 38 kb · p 0.097 · regional, not allelic
Overall
CADD	28.0	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 0.00223% East Asian · 1/44,890 alleles

Filtering AF 0.000688% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000539%

Overall 0.000929% 15/1,614,150 alleles · very rare exomes 15/1,461,872 · genomes 0/152,278 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,890
European (non-Finnish)	0.00119%	84,287

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.Arg104His
Coding: c.311G>A
MANE Select: NM_004614
dbSNP: rs770318536
Type: single nucleotide variant
Location: chr16:66531444 (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

Similar variants

TK2 p.Arg104Cys Pathogenic/Likely pathogenic ★★ 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-arg104his (accessed [today's date]).

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