# NM_004614.5(TK2):c.744T>C (p.Phe248=)

https://sugi.bio/variant/tk2-p-phe248

## Summary

**TK2 p.Phe248= (c.744T>C)** is classified **Likely benign** in TK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-30). Ultra-rare (popmax 0.0853%, afr).

**At a glance:** Likely benign · review: Single submitter · rsID rs147834546 · 1 submitter · ultra-rare (popmax 0.0853%, afr)

## For patients & families {#patients}

This is a change in the TK2 gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter.

*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.Phe248= |
| Coding change (HGVS c.) | c.744T>C |
| MANE Select transcript | [NM_004614](https://www.ncbi.nlm.nih.gov/nuccore/NM_004614) |
| dbSNP | [rs147834546](https://www.ncbi.nlm.nih.gov/snp/rs147834546/) |
| Variant type | single nucleotide variant |
| Location | chr16:66512022-66512022 (GRCh38) |
| ClinVar | [VCV702829](https://www.ncbi.nlm.nih.gov/clinvar/variation/702829/) |

**All HGVS expressions:** `NC_000016.10:g.66512022A>G`, `NC_000016.9:g.66545925A>G`, `NG_016862.1:g.43391T>C`, `NM_001172643.1:c.651T>C`, `NM_001172644.2:c.669T>C`, `NM_001172645.2:c.690T>C`, `NM_001271934.2:c.597T>C`, `NM_001271935.1:c.*41T>C`, `NM_001272050.2:c.453T>C`, `NM_004614.5:c.744T>C`, `NR_073520.2:n.1733T>C`

## Computational & population evidence {#evidence}

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

- **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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **acceptor gain** (Δ 0.20) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 1.411, GERP -3.9, phastCons 0.999 — weakly conserved position
- CADD: **PHRED 8.64**. 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 deltas (raw): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.20**, donor gain **0.00**. Largest is acceptor gain, 44 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Pangolin: Δ**0.22** (gain), gain 0.22 / loss 0.00. Agrees with SpliceAI. 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 **0.0853%** (afr) · FAF95 0.0685% · FAF99 0.0624% · 64/75,052 in the highest group · 67/1,614,214 alleles overall — ultra-rare (popmax 0.0853%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.0853% | 1,173 |
| Admixed American | 0.00167% | 60,018 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,512 |
| European (non-Finnish) | 8.47e-05% | 1,180,045 |

*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 benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-12-30.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-12-30 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Similar variants {#similar}

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

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 702829). 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.*