# NM_004614.5(TK2):c.547C>T (p.Arg183Trp)

https://sugi.bio/variant/tk2-p-arg183trp

## Summary

**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.

**At a glance:** Pathogenic · review: Multiple submitters · rsID rs137886900 · 9 submitters · 5 linked conditions · AlphaMissense likely benign · very rare (popmax 0.00801%, afr)

## For patients & families {#patients}

This is a change in the TK2 gene that is reported as disease-causing, though the computational evidence is not fully concordant, submitted by 9 submitters, and is linked to TK2-related disorder.

*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.*

**Support & next steps:** [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.Arg183Trp |
| Coding change (HGVS c.) | c.547C>T |
| MANE Select transcript | [NM_004614](https://www.ncbi.nlm.nih.gov/nuccore/NM_004614) |
| dbSNP | [rs137886900](https://www.ncbi.nlm.nih.gov/snp/rs137886900/) |
| Variant type | single nucleotide variant |
| Location | chr16:66517207-66517207 (GRCh38) |
| ClinVar | [VCV38992](https://www.ncbi.nlm.nih.gov/clinvar/variation/38992/) |

**All HGVS expressions:** `NC_000016.10:g.66517207G>A`, `NC_000016.9:g.66551110G>A`, `NG_016862.1:g.38206C>T`, `NM_001172643.1:c.454C>T`, `NM_001172644.2:c.472C>T`, `NM_001172645.2:c.493C>T`, `NM_001271934.2:c.400C>T`, `NM_001271935.1:c.357-3396C>T`, `NM_001272050.2:c.256C>T`, `NM_004614.5:c.547C>T`, `NR_073520.2:n.1536C>T`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — AlphaMissense predicts likely-benign.

- AlphaMissense **likely benign** (0.2929) — ⚠ discordant with the pathogenic call
- REVEL 0.92 (moderately pathogenic-leaning) — differs from AlphaMissense
- SaProt LLR -14.363 (damaging) — differs from AlphaMissense
- → **In-silico consensus:** REVEL and SaProt call this damaging; AlphaMissense does not
- Conservation: phyloP 9.864, GERP 1.52, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 34.0**. 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.*
- 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 (G>T, Δ0.45 acceptor gain), 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.*
- Pangolin: Δ**0.27** (loss), gain 0.00 / loss 0.27. SpliceAI below 0.2. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.00801%** (afr) · FAF95 0.00394% · FAF99 0.00361% · 6/74,914 in the highest group · 126/1,613,922 alleles overall — very rare (popmax 0.00801%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Finnish (not grpmax-eligible) | 0.0813% | 1,231 |
| Remaining individuals (not grpmax-eligible) | 0.0128% | 7,811 |
| African / African-American (grpmax) | 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. 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.

*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 **183** lies in a UniProt-annotated variant site (in mtdps2 and peob3; reduction of activity; reduced affinity for atp).

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}

**Pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-11-24.

**Submitter consensus:** conflicting (8 Pathogenic, 1 not provided).

**Submission history:** 9 submissions (2012–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneReviews | not provided | no classification provided | literature only |  |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Pathogenic | criteria provided, single submitter | clinical testing | 2023-04-13 |
| Revvity Omics, Revvity | Pathogenic | criteria provided, single submitter | clinical testing | 2022-01-29 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2024-12-24 |
| Blueprint Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2024-03-20 |
| Baylor Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2017-09-01 |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 2012-01-01 |
| Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre | Pathogenic | criteria provided, single submitter | clinical testing | 2024-04-04 |
| Genomenon, Inc, Genomenon, Inc | Pathogenic | criteria provided, single submitter | curation | 2025-11-24 |

## Associated conditions {#conditions}

[TK2-related disorder](https://sugi.bio/atlas/disease/tk2-related-disorder/), [mitochondrial DNA depletion syndrome, myopathic form](https://sugi.bio/atlas/disease/mitochondrial-dna-depletion-syndrome-myopathic-form/), [progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 3](https://sugi.bio/atlas/disease/progressive-external-ophthalmoplegia-with-mitochondrial-dna-deletions-autosomal-recessive-3/), [mitochondrial DNA depletion syndrome](https://sugi.bio/atlas/disease/mitochondrial-dna-depletion-syndrome/), [mitochondrial disease](https://sugi.bio/atlas/disease/mitochondrial-disease/).

**Reported phenotype names (ClinVar):** TK2-related disorder, Mitochondrial DNA depletion syndrome, myopathic form, Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 3, not provided, Mitochondrial DNA depletion syndrome, Mitochondrial disease, TK2-related condition, PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA, AUTOSOMAL RECESSIVE 3, mitochondrial DNA depletion, none provided.

## Same-residue context {#hotspot}

Residue **183** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [TK2 p.Arg183Gly](/variant/tk2-p-arg183gly). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related TK2 variant pages (same residue, condition, or type): [TK2 p.Arg183Gly](/variant/tk2-p-arg183gly), [TK2 p.Arg183Gln](/variant/tk2-p-arg183gln), [TK2 p.Arg183=](/variant/tk2-p-arg183), [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).

### 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 38992). 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.*