# NM_004614.5(TK2):c.125A>C (p.Asp42Ala)

https://sugi.bio/variant/tk2-p-asp42ala

## Summary

**TK2 p.Asp42Ala (c.125A>C)** is classified **Uncertain significance** in TK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-13). AlphaMissense: likely benign (0.0745); Absent from gnomAD v4.1; Associated with mitochondrial DNA depletion syndrome, myopathic form.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs763416136 · 1 submitter · 1 linked condition · AlphaMissense likely benign · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the TK2 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to mitochondrial DNA depletion syndrome, myopathic form.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal recessive |
| Age of onset (of this condition) | Infancy, Neonatal |
| Clinical trials | 5 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | TK2 is a diagnostic-grade gene on 12 Genomics England panels |

**Commonly reported features of Mitochondrial DNA depletion syndrome, myopathic form** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Myopathy — Obligate (100%)
- Generalized hypotonia — Very frequent (99-80%)
- Muscle weakness — Very frequent (99-80%)
- Respiratory insufficiency — Very frequent (99-80%)
- Motor deterioration — Very frequent (99-80%)
- Hypotonia — Frequent (79-30%)
- Hyporeflexia — Frequent (79-30%)
- Motor delay — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0017228/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.Asp42Ala |
| Coding change (HGVS c.) | c.125A>C |
| MANE Select transcript | [NM_004614](https://www.ncbi.nlm.nih.gov/nuccore/NM_004614) |
| dbSNP | [rs763416136](https://www.ncbi.nlm.nih.gov/snp/rs763416136/) |
| Variant type | single nucleotide variant |
| Location | chr16:66549009-66549009 (GRCh38) |
| ClinVar | [VCV887674](https://www.ncbi.nlm.nih.gov/clinvar/variation/887674/) |

**All HGVS expressions:** `NC_000016.10:g.66549009T>G`, `NC_000016.9:g.66582912T>G`, `NG_016862.1:g.6404A>C`, `NM_001172643.1:c.32A>C`, `NM_001172644.2:c.125A>C`, `NM_001172645.2:c.125A>C`, `NM_001271934.2:c.-118A>C`, `NM_001271935.1:c.32A>C`, `NM_001272050.2:c.-167A>C`, `NM_004614.5:c.125A>C`, `NR_073520.2:n.1114A>C`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.0745)
- REVEL 0.328 (indeterminate)
- SaProt LLR -5.039 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate
- Conservation: phyloP 1.612, GERP -0.599, phastCons 1 — weakly conserved position
- CADD: **PHRED 15.94**. 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.*
- Regional missense constraint: **o/e 0.91** across the covering region of the MANE Select transcript (66,511,971–66,550,061), spanning 38,090 bp. Chi-square p 0.097. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (T>A, Δ0.20 acceptor loss), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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}

Residue **42** lies in the 'disordered' region.

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. p.Asp42Ala falls in the disordered region.


### 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}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2018-01-13.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Illumina Laboratory Services, Illumina | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-01-13 |

## Associated conditions {#conditions}

[mitochondrial DNA depletion syndrome, myopathic form](https://sugi.bio/atlas/disease/mitochondrial-dna-depletion-syndrome-myopathic-form/).

**Reported phenotype names (ClinVar):** Mitochondrial DNA depletion syndrome, myopathic form, MITOCHONDRIAL DNA DEPLETION MYOPATHY, TK2-RELATED, TK2-Related Mitochondrial DNA Maintenance Defect, Myopathic Form, MITOCHONDRIAL DNA DEPLETION SYNDROME 2 (MYOPATHIC TYPE).

## Same-residue context {#hotspot}

Residue **42** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [TK2 p.Asp42Asn](/variant/tk2-p-asp42asn). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related TK2 variant pages (same residue, condition, or type): [TK2 p.Asp42Asn](/variant/tk2-p-asp42asn), [TK2 p.Ala139Thr](/variant/tk2-p-ala139thr), [TK2 p.Ala139Val](/variant/tk2-p-ala139val), [TK2 p.Arg104Cys](/variant/tk2-p-arg104cys), [TK2 p.Arg130Trp](/variant/tk2-p-arg130trp), [TK2 p.Arg183Trp](/variant/tk2-p-arg183trp), [TK2 p.Arg192Lys](/variant/tk2-p-arg192lys), [TK2 p.Asn58Ser](/variant/tk2-p-asn58ser).

### 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 887674). 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.*