# NM_006852.6(TLK2):c.1039CCT[1] (p.Pro348del)

https://sugi.bio/variant/tlk2-p-pro348del

## Summary

**TLK2 p.Pro348del (c.1039CCT[1])** is classified **Uncertain significance** in TLK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-05). No gnomAD frequency available for this variant.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs2080462905 · 1 submitter · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the TLK2 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, 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 | [TLK2](https://sugi.bio/atlas/gene/TLK2/) |
| Protein change (HGVS p.) | p.Pro348del |
| Coding change (HGVS c.) | c.1039CCT[1] |
| MANE Select transcript | [NM_006852](https://www.ncbi.nlm.nih.gov/nuccore/NM_006852) |
| dbSNP | [rs2080462905](https://www.ncbi.nlm.nih.gov/snp/rs2080462905/) |
| Variant type | Microsatellite |
| Location | chr17:62573285-62573287 (GRCh38) |
| ClinVar | [VCV2136019](https://www.ncbi.nlm.nih.gov/clinvar/variation/2136019/) |

**All HGVS expressions:** `NC_000017.10:g.60650646CCT[1]`, `NC_000017.11:g.62573285CCT[1]`, `NM_001284333.3:c.1039CCT[1]`, `NM_001284363.1:c.943CCT[1]`, `NM_001330418.3:c.592CCT[1]`, `NM_001375269.1:c.1081CCT[1]`, `NM_001375270.1:c.1039CCT[1]`, `NM_001375271.1:c.1039CCT[1]`, `NM_001375272.1:c.943CCT[1]`, `NM_001375273.1:c.592CCT[1]`, `NM_001411074.1:c.754_756CCT[1]`, `NM_006852.6:c.1039CCT[1]`

## 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 (below), not from a missing predictor score.
- Conservation: phyloP 6.923, GERP 0.742, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **in-frame indel**.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no microsatellite variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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}

**TLK2** population constraint: LOEUF 0.103, pLI 1, missense-Z 6.5465. *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):

- **complex neurodevelopmental disorder** — Definitive (AD)

## Protein context {#protein}

Residue **348** lies in a UniProt-annotated variant site (in mrd57); the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 73.15, 50% of residues very-high.

**2 experimental structure(s)** (PDB): [5O0Y](https://www.rcsb.org/structure/5O0Y), [7LO0](https://www.rcsb.org/structure/7LO0).

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

*Describes the biological roles of TLK2 (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:** TLK2's established molecular role includes protein serine/threonine kinase activity. p.Pro348del falls in the disordered region.


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

**Molecular function:** protein serine/threonine kinase activity, ATP binding, identical protein binding.

**Biological process:** protein phosphorylation, DNA damage response, chromosome segregation, peptidyl-serine phosphorylation, negative regulation of proteasomal ubiquitin-dependent protein catabolic process, intracellular signal transduction.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-11-05.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-11-05 |

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

## Similar variants {#similar}

Related TLK2 variant pages (same residue, condition, or type): [TLK2 p.Arg286_Asp287insTer](/variant/tlk2-p-arg286-asp287inster), [TLK2 p.Thr161fs](/variant/tlk2-p-thr161fs), [TLK2 p.Asp601_Ser602insAsp](/variant/tlk2-p-asp601-ser602insasp).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-06); 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 2136019). 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.*