# NM_018105.3(THAP1):c.576C>T (p.Asp192=)

https://sugi.bio/variant/thap1-p-asp192

## Summary

**THAP1 p.Asp192= (c.576C>T)** is classified **Likely benign** in THAP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-07). Ultra-rare (popmax 0.016%, afr); Associated with torsion dystonia 6.

**At a glance:** Likely benign · review: Single submitter · rsID rs570575495 · 1 submitter · 1 linked condition · ultra-rare (popmax 0.016%, afr)

## For patients & families {#patients}

This is a change in the THAP1 gene that is classified as likely benign — not considered disease-causing, 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.Asp192= |
| Coding change (HGVS c.) | c.576C>T |
| MANE Select transcript | [NM_018105](https://www.ncbi.nlm.nih.gov/nuccore/NM_018105) |
| dbSNP | [rs570575495](https://www.ncbi.nlm.nih.gov/snp/rs570575495/) |
| Variant type | single nucleotide variant |
| Location | chr8:42838028-42838028 (GRCh38) |
| ClinVar | [VCV2026656](https://www.ncbi.nlm.nih.gov/clinvar/variation/2026656/) |

**All HGVS expressions:** `NC_000008.10:g.42693171G>A`, `NC_000008.11:g.42838028G>A`, `NG_011837.2:g.10297C>T`, `NM_018105.3:c.576C>T`, `NM_199003.2:c.*218C>T`

## 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 -0.913, GERP -2.55 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 4.507**. 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: **not assessed** — this absence is genuinely unknown. Where a position sits between the lowest and the highest record the release holds for its gene, an absent score is a result and we state it as one; this position falls outside them, or the gene has no scored position at all, so that test did not reach here. It may lie outside the scored MANE transcript scope, or it may have been scored with all four deltas below Δ0.2 just past the last surviving record. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.016%** (afr) · FAF95 0.00921% · FAF99 0.00721% · 12/74,982 in the highest group · 16/1,613,644 alleles overall — ultra-rare (popmax 0.016%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.016% | 6,249 |
| Admixed American | 0.00167% | 59,906 |
| South Asian | 0.0011% | 90,968 |
| European (non-Finnish) | 0.00017% | 589,964 |

*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}

Residue **192** lies in a UniProt-annotated variant site (in dyt6).

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}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-03-07.

**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 | 2024-03-07 |

## 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.Asp192Asn](/variant/thap1-p-asp192asn), [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 2026-10-15); 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 2026656). 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.*