# NM_004614.5(TK2):c.548G>A (p.Arg183Gln)

https://sugi.bio/variant/tk2-p-arg183gln

## Summary

**TK2 p.Arg183Gln (c.548G>A)** is classified **Conflicting classifications of pathogenicity** in TK2 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-01-11). AlphaMissense: likely benign (0.0774); Rare (popmax 0.145%, sas); Associated with Inborn genetic diseases.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs780333412 · 5 submitters · 2 linked conditions · AlphaMissense likely benign · rare (popmax 0.145%, sas)

## For patients & families {#patients}

This is a change in the TK2 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 5 submitters, and is linked to Inborn genetic diseases.

*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.Arg183Gln |
| Coding change (HGVS c.) | c.548G>A |
| MANE Select transcript | [NM_004614](https://www.ncbi.nlm.nih.gov/nuccore/NM_004614) |
| dbSNP | [rs780333412](https://www.ncbi.nlm.nih.gov/snp/rs780333412/) |
| Variant type | single nucleotide variant |
| Location | chr16:66517206-66517206 (GRCh38) |
| ClinVar | [VCV1516956](https://www.ncbi.nlm.nih.gov/clinvar/variation/1516956/) |

**All HGVS expressions:** `NC_000016.10:g.66517206C>T`, `NC_000016.9:g.66551109C>T`, `NG_016862.1:g.38207G>A`, `NM_001172643.1:c.455G>A`, `NM_001172644.2:c.473G>A`, `NM_001172645.2:c.494G>A`, `NM_001271934.2:c.401G>A`, `NM_001271935.1:c.357-3395G>A`, `NM_001272050.2:c.257G>A`, `NM_004614.5:c.548G>A`, `NR_073520.2:n.1537G>A`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely benign** (0.0774)
- REVEL 0.462 (indeterminate)
- SaProt LLR -10.442 (damaging) — differs from AlphaMissense
- → **In-silico consensus:** SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate
- SpliceAI predicts **acceptor gain** (Δ 0.57) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 1.393, GERP -1.87, phastCons 1 — weakly conserved position
- CADD: **PHRED 23.6**. 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 deltas (raw): acceptor loss **0.12**, donor loss **0.00**, acceptor gain **0.57**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.12**, donor loss **0.00**, acceptor gain **0.57**, donor gain **0.00**.
- Pangolin: Δ**0.26** (loss), gain 0.21 / loss 0.26. SpliceAI calls gain. 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 **0.145%** (sas) · FAF95 0.125% · FAF99 0.117% · 132/91,084 in the highest group · 148/1,613,916 alleles overall — rare (popmax 0.145%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.145% | 690 |
| Remaining individuals (not grpmax-eligible) | 0.0064% | 15,621 |
| Admixed American | 0.005% | 19,994 |
| European (non-Finnish) | 0.000763% | 131,107 |

*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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2026-01-11.

**Submitter consensus:** conflicting (4 Uncertain significance, 1 Likely benign).

**Submission history:** 5 submissions (2020–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2020-12-28 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-04-02 |
| Revvity Omics, Revvity | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-05-12 |
| Genomenon, Inc, Genomenon, Inc | Uncertain significance | criteria provided, single submitter | curation | 2025-11-24 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2026-01-11 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/), [mitochondrial disease](https://sugi.bio/atlas/disease/mitochondrial-disease/).

**Reported phenotype names (ClinVar):** Inborn genetic diseases, not provided, not specified, Mitochondrial disease, AllHighlyPenetrant, none provided, Mitochondrial disorders, Mitochondrial disorder.

## Same-residue context {#hotspot}

Residue **183** carries **2 other pathogenic ClinVar variants** — a recurrently-mutated position: [TK2 p.Arg183Gly](/variant/tk2-p-arg183gly), [TK2 p.Arg183Trp](/variant/tk2-p-arg183trp). *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.Arg183Trp](/variant/tk2-p-arg183trp), [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 1516956). 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.*