# NM_006852.6(TLK2):c.1263G>C (p.Arg421Ser)

https://sugi.bio/variant/tlk2-p-arg421ser

## Summary

**TLK2 p.Arg421Ser (c.1263G>C)** is classified **Uncertain significance** in TLK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-12-24). AlphaMissense: likely pathogenic (0.9999); Absent from gnomAD v4.1.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs2545779002 · 1 submitter · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## 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.Arg421Ser |
| Coding change (HGVS c.) | c.1263G>C |
| MANE Select transcript | [NM_006852](https://www.ncbi.nlm.nih.gov/nuccore/NM_006852) |
| dbSNP | [rs2545779002](https://www.ncbi.nlm.nih.gov/snp/rs2545779002/) |
| Variant type | single nucleotide variant |
| Location | chr17:62578551-62578551 (GRCh38) |
| ClinVar | [VCV2058006](https://www.ncbi.nlm.nih.gov/clinvar/variation/2058006/) |

**All HGVS expressions:** `NC_000017.10:g.60655912G>C`, `NC_000017.11:g.62578551G>C`, `NM_001284333.3:c.1329G>C`, `NM_001284363.1:c.1167G>C`, `NM_001330418.3:c.816G>C`, `NM_001375269.1:c.1305G>C`, `NM_001375270.1:c.1263G>C`, `NM_001375271.1:c.1263G>C`, `NM_001375272.1:c.1167G>C`, `NM_001375273.1:c.816G>C`, `NM_001411074.1:c.978G>C`, `NM_006852.6:c.1263G>C`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.9999)
- REVEL 0.443 (indeterminate)
- SaProt LLR -16.122 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this damaging; REVEL is indeterminate
- Conservation: phyloP 7.609, GERP 0.184, phastCons 1 — highly conserved (agrees)
- ⚠ **Isoform check:** AlphaMissense is numbered on a different transcript (AM **R443S** vs ClinVar **R421S**) — the AlphaMissense read here may be for a different residue; verify against the ClinVar transcript.
- AlphaMissense ranks this among the **top 7%** most-pathogenic-predicted substitutions in TLK2 (of 4,511 modeled).
- CADD: **PHRED 28.9**. 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 0.22** across the covering region of the MANE Select transcript (62,578,533–62,612,489), spanning 33,956 bp — the region is depleted of missense variation. Chi-square p 3.2e-51. 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, Δ0.35 donor 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.*
- Pangolin: Δ**0.24** (loss), gain 0.01 / loss 0.24. 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: **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}

**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 **443** lies in a UniProt-annotated variant site (in mrd57).

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.


### 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 2021-12-24.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-12-24 |

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

## Similar variants {#similar}

Related TLK2 variant pages (same residue, condition, or type): [TLK2 p.Arg421Lys](/variant/tlk2-p-arg421lys), [TLK2 p.Arg421Met](/variant/tlk2-p-arg421met), [TLK2 c.1121+1G>A](/variant/tlk2-c-1121-plus-1g-a), [TLK2 c.1550+1G>A](/variant/tlk2-c-1550-plus-1g-a), [TLK2 p.Arg11Ter](/variant/tlk2-p-arg11ter), [TLK2 p.Arg122Ter](/variant/tlk2-p-arg122ter), [TLK2 p.Arg123Ter](/variant/tlk2-p-arg123ter), [TLK2 p.Arg262Ter](/variant/tlk2-p-arg262ter).

### 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 2058006). 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.*