Is THAP1 p.Phe45= (c.135T>C) pathogenic?

THAP1 p.Phe45= (c.135T>C) is classified Likely benign in THAP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-13). Very rare (popmax 8.47e-05%, nfe); Associated with torsion dystonia 6.

What condition is associated with THAP1 p.Phe45= (c.135T>C)?

THAP1 p.Phe45= (c.135T>C) is associated with torsion dystonia 6 (ClinVar).

How common is THAP1 p.Phe45= (c.135T>C) in the general population?

THAP1 p.Phe45= (c.135T>C) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

How is Primary dystonia, DYT6 type inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

THAP1 p.Phe45=

c.135T>C · rs1563644836 · VCV1900876

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Conditions

torsion dystonia 6

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.53	GERP 1.3, phastCons 0.83
Overall
CADD	10.16	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,179,994 alleles

Overall 6.2e-05% 1/1,614,090 alleles · very rare exomes 1/1,461,764 · genomes 0/152,326 · joint denominator

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: THAP1
Protein: p.Phe45=
Coding: c.135T>C
MANE Select: NM_018105
dbSNP: rs1563644836
Type: single nucleotide variant
Location: chr8:42839318 (GRCh38)
Gene constraint: LOEUF 0.571 · pLI 0.90 (gnomAD)
Structure: AlphaFold pLDDT 71.61 · 3 PDB

Full THAP1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

torsion dystonia 6 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Primary dystonia, DYT6 type (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Adult, Childhood
Prevalence: <1 / 1 000 000 (Worldwide)

Similar variants

THAP1 p.Phe45Cys Pathogenic ★ same residue
THAP1 p.Phe45fs Pathogenic ★★ same residue
THAP1 p.Arg169Ter Pathogenic/Likely pathogenic ★★ same condition
THAP1 p.Arg29Pro Pathogenic/Likely pathogenic ★★ same condition
THAP1 p.Arg29Ter Pathogenic/Likely pathogenic ★★ same condition
THAP1 p.Gly9Ser Likely pathogenic ★★ same condition
THAP1 p.Pro26Leu Pathogenic/Likely pathogenic ★★ same condition
THAP1 p.Ser130Ter Pathogenic/Likely pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/thap1-p-phe45 (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown