# NM_018105.3(THAP1):c.135_139delinsGGGTTTA (p.Phe45fs)

https://sugi.bio/variant/thap1-p-phe45fs

## Summary

**THAP1 p.Phe45fs (c.135_139delinsGGGTTTA)** is classified **Pathogenic** in THAP1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-05-22). No gnomAD frequency available for this variant; Associated with torsion dystonia 6.

**At a glance:** Pathogenic · review: Multiple submitters · rsID rs1586457060 · 3 submitters · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the THAP1 gene that is considered disease-causing, submitted by 3 submitters, 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.Phe45fs |
| Coding change (HGVS c.) | c.135_139delinsGGGTTTA |
| MANE Select transcript | [NM_018105](https://www.ncbi.nlm.nih.gov/nuccore/NM_018105) |
| dbSNP | [rs1586457060](https://www.ncbi.nlm.nih.gov/snp/rs1586457060/) |
| Variant type | Indel |
| Location | chr8:42839314-42839318 (GRCh38) |
| ClinVar | [VCV817036](https://www.ncbi.nlm.nih.gov/clinvar/variation/817036/) |

**All HGVS expressions:** `NC_000008.10:g.42694457_42694461delinsTAAACCC`, `NC_000008.11:g.42839314_42839318delinsTAAACCC`, `NG_011837.1:g.9014_9018delinsGGGTTTA`, `NM_018105.2:c.135_139delinsGGGTTTA`, `NM_018105.3:c.135_139delinsGGGTTTA`, `NM_199003.2:c.72-982_72-978delinsGGGTTTA`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **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 11.708, GERP 2.42, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. the gene is **loss-of-function-intolerant** (LOEUF 0.571, pLI 0.90189), supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 2 of 3**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no indel 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}

**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}

**Pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-05-22.

**Submitter consensus:** unanimous (3/3 Pathogenic).

**Submission history:** 3 submissions (2009–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 2009-03-01 |
| GeneDx | Pathogenic | criteria provided, single submitter | clinical testing | 2024-06-03 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-05-22 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Torsion dystonia 6, not provided, DYT-THAP1, none provided.

## Same-residue context {#hotspot}

Residue **45** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [THAP1 p.Phe45Cys](/variant/thap1-p-phe45cys). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related THAP1 variant pages (same residue, condition, or type): [THAP1 p.Phe45Cys](/variant/thap1-p-phe45cys), [THAP1 p.Phe45=](/variant/thap1-p-phe45), [THAP1 c.72-10_72-9delinsGC](/variant/thap1-c-72-minus-10-72-minus-9delinsgc), [THAP1 c.270_273del](/variant/thap1-c-270-273del), [THAP1 p.Arg169Ter](/variant/thap1-p-arg169ter), [THAP1 p.Arg29Pro](/variant/thap1-p-arg29pro), [THAP1 p.Arg29Ter](/variant/thap1-p-arg29ter), [THAP1 p.Asn69del](/variant/thap1-p-asn69del).

### 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 817036). 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.*