# NM_004614.5(TK2):c.760C>T (p.Arg254Ter)

https://sugi.bio/variant/tk2-p-arg254ter

## Summary

**TK2 p.Arg254Ter (c.760C>T)** is classified **Likely pathogenic** in TK2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-17). Very rare (popmax 0.000254%, nfe); Associated with mitochondrial disease.

**At a glance:** Likely pathogenic · review: Multiple submitters · rsID rs281865498 · 2 submitters · 1 linked condition · very rare (popmax 0.000254%, nfe)

## For patients & families {#patients}

This is a change in the TK2 gene that is considered likely disease-causing, submitted by 2 submitters, and is linked to mitochondrial disease.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Clinical trials | 104 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0027984/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [TK2](https://sugi.bio/atlas/gene/TK2/) |
| Protein change (HGVS p.) | p.Arg254Ter |
| Coding change (HGVS c.) | c.760C>T |
| MANE Select transcript | [NM_004614](https://www.ncbi.nlm.nih.gov/nuccore/NM_004614) |
| dbSNP | [rs281865498](https://www.ncbi.nlm.nih.gov/snp/rs281865498/) |
| Variant type | single nucleotide variant |
| Location | chr16:66512006-66512006 (GRCh38) |
| ClinVar | [VCV38997](https://www.ncbi.nlm.nih.gov/clinvar/variation/38997/) |

**All HGVS expressions:** `NC_000016.10:g.66512006G>A`, `NC_000016.9:g.66545909G>A`, `NG_016862.1:g.43407C>T`, `NM_001172643.1:c.667C>T`, `NM_001172644.2:c.685C>T`, `NM_001172645.2:c.706C>T`, `NM_001271934.2:c.613C>T`, `NM_001271935.1:c.*57C>T`, `NM_001272050.2:c.469C>T`, `NM_004614.5:c.760C>T`, `NR_073520.2:n.1749C>T`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 8.574, GERP 1.95, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **nonsense (stop-gain)** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.101, pLI 6.1251e-11. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in the last exon (10 of 10)** — predicted to **escape NMD**, so the truncated protein is likely expressed. An input to PVS1, not an applied code.
- CADD: **PHRED 37.0**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.000254%** (nfe) · FAF95 6.8e-05% · FAF99 1.9e-05% · 3/1,180,034 in the highest group · 3/1,614,134 alleles overall — very rare (popmax 0.000254%, nfe).

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**TK2** population constraint: LOEUF 1.101, pLI 6.1251e-11, missense-Z 0.5696. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **mitochondrial disease** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 85.01, 73% of residues very-high.

## What this gene does {#gene-function}

*Describes the biological roles of TK2 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** TK2's established molecular role includes deoxycytidine kinase activity.


### Pathways affected {#pathways}

TK2 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Pyrimidine salvage](https://reactome.org/content/detail/R-HSA-73614) | curated |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** deoxycytidine kinase activity, thymidine kinase activity.

## Clinical significance {#significance}

**Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-12-17.

**Submitter consensus:** unanimous (2/2 Likely pathogenic).

**Submission history:** 2 submissions (2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely pathogenic | criteria provided, single submitter | clinical testing | 2025-12-17 |
| Genomenon, Inc, Genomenon, Inc | Likely pathogenic | criteria provided, single submitter | curation | 2025-11-24 |

## Associated conditions {#conditions}

[mitochondrial disease](https://sugi.bio/atlas/disease/mitochondrial-disease/).

**Reported phenotype names (ClinVar):** Mitochondrial disease, not provided, none provided, Mitochondrial disorder, Mitochondrial disorders.

## Similar variants {#similar}

Related TK2 variant pages (same residue, condition, or type): [TK2 p.Arg254Leu](/variant/tk2-p-arg254leu), [TK2 c.156+2T>C](/variant/tk2-c-156-plus-2t-c), [TK2 c.157-2A>G](/variant/tk2-c-157-minus-2a-g), [TK2 p.Ala139Thr](/variant/tk2-p-ala139thr), [TK2 p.Ala139Val](/variant/tk2-p-ala139val), [TK2 p.Arg104Cys](/variant/tk2-p-arg104cys), [TK2 p.Arg130Gln](/variant/tk2-p-arg130gln), [TK2 p.Arg130Trp](/variant/tk2-p-arg130trp).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 38997). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*