# NM_018105.3(THAP1):c.316C>T (p.Pro106Ser)

https://sugi.bio/variant/thap1-p-pro106ser

## Summary

**THAP1 p.Pro106Ser (c.316C>T)** is classified **Uncertain significance** in THAP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-19). AlphaMissense: likely benign (0.0798); Very rare (popmax 8.48e-05%, nfe); Associated with torsion dystonia 6.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs2487027505 · 1 submitter · 1 linked condition · AlphaMissense likely benign · very rare (popmax 8.48e-05%, nfe)

## For patients & families {#patients}

This is a change in the THAP1 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to torsion dystonia 6.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal dominant |
| Age of onset (of this condition) | Adolescent, Adult, Childhood |
| Prevalence | <1 / 1 000 000 (Worldwide) |
| Clinical trials | 1 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | THAP1 is a diagnostic-grade gene on 6 Genomics England panels |

**Commonly reported features of Primary dystonia, DYT6 type** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Dystonia — Very frequent (99-80%)
- Generalized dystonia — Very frequent (99-80%)
- Dysarthria — Frequent (79-30%)
- Torticollis — Occasional (29-5%)
- Blepharospasm — Occasional (29-5%)
- Laryngeal dystonia — Occasional (29-5%)
- Craniofacial dystonia — Occasional (29-5%)
- Lingual dystonia — Occasional (29-5%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0009630/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [THAP1](https://sugi.bio/atlas/gene/THAP1/) |
| Protein change (HGVS p.) | p.Pro106Ser |
| Coding change (HGVS c.) | c.316C>T |
| MANE Select transcript | [NM_018105](https://www.ncbi.nlm.nih.gov/nuccore/NM_018105) |
| dbSNP | [rs2487027505](https://www.ncbi.nlm.nih.gov/snp/rs2487027505/) |
| Variant type | single nucleotide variant |
| Location | chr8:42838288-42838288 (GRCh38) |
| ClinVar | [VCV2881162](https://www.ncbi.nlm.nih.gov/clinvar/variation/2881162/) |

**All HGVS expressions:** `NC_000008.10:g.42693431G>A`, `NC_000008.11:g.42838288G>A`, `NG_011837.1:g.10044C>T`, `NG_011837.2:g.10037C>T`, `NM_018105.3:c.316C>T`, `NM_199003.2:c.120C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.0798)
- REVEL 0.243 (benign-leaning) — agrees with AlphaMissense
- SaProt LLR -7.989 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 2.19, GERP -0.056, phastCons 0.996 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 6.351**. 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 0.70** across the covering region of the MANE Select transcript (42,837,965–42,843,094), spanning 5,129 bp. Chi-square p 1.3e-06. 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>C, Δ0.24 acceptor 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.*
- Population frequency (gnomAD v4.1): grpmax **8.48e-05%** (nfe) · 1/1,179,936 in the highest group · 2/1,614,058 alleles overall — very rare (popmax 8.48e-05%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Finnish (not grpmax-eligible) | 0.00156% | 64,020 |
| European (non-Finnish) (grpmax) | 8.48e-05% | 1,179,935 |

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}

**THAP1** population constraint: LOEUF 0.571, pLI 0.90189, missense-Z 2.0539. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 71.61, 18% of residues very-high.

**3 experimental structure(s)** (PDB): [2JTG](https://www.rcsb.org/structure/2JTG), [2KO0](https://www.rcsb.org/structure/2KO0), [2L1G](https://www.rcsb.org/structure/2L1G).

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

*Describes the biological roles of THAP1 (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:** THAP1's established molecular role includes RNA polymerase II cis-regulatory region sequence-specific DNA binding.


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

**Molecular function:** RNA polymerase II cis-regulatory region sequence-specific DNA binding, DNA-binding transcription repressor activity, RNA polymerase II-specific, zinc ion binding, identical protein binding, protein homodimerization activity, sequence-specific DNA binding.

**Biological process:** negative regulation of transcription by RNA polymerase II, endothelial cell proliferation, DNA-templated transcription, regulation of DNA-templated transcription, regulation of mitotic cell cycle.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-10-19.

**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 | 2022-10-19 |

## Associated conditions {#conditions}

[torsion dystonia 6](https://sugi.bio/atlas/disease/torsion-dystonia-6/).

**Reported phenotype names (ClinVar):** Torsion dystonia 6, DYT-THAP1.

## Similar variants {#similar}

Related THAP1 variant pages (same residue, condition, or type): [THAP1 p.Pro106=](/variant/thap1-p-pro106), [THAP1 p.Arg169Ter](/variant/thap1-p-arg169ter), [THAP1 p.Arg29Pro](/variant/thap1-p-arg29pro), [THAP1 p.Arg29Ter](/variant/thap1-p-arg29ter), [THAP1 p.Gly9Ser](/variant/thap1-p-gly9ser), [THAP1 p.Pro26Leu](/variant/thap1-p-pro26leu), [THAP1 p.Ser130Ter](/variant/thap1-p-ser130ter), [THAP1 p.Ser21Phe](/variant/thap1-p-ser21phe).

### 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 2881162). 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.*