Is THAP1 p.Ser21Ala (c.61T>G) pathogenic?

THAP1 p.Ser21Ala (c.61T>G) is classified Uncertain significance in THAP1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-04-09). AlphaMissense: likely pathogenic (0.8687); Very rare (popmax 0.00267%, afr); Associated with torsion dystonia 6.

What condition is associated with THAP1 p.Ser21Ala (c.61T>G)?

THAP1 p.Ser21Ala (c.61T>G) is associated with torsion dystonia 6 (ClinVar).

How common is THAP1 p.Ser21Ala (c.61T>G) in the general population?

THAP1 p.Ser21Ala (c.61T>G) is very rare (popmax 0.00267%, afr) (gnomAD).

How is Primary dystonia, DYT6 type inherited?

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

What do computational predictors say about THAP1 p.Ser21Ala (c.61T>G)?

AlphaMissense predicts likely pathogenic (score 0.8687) — an in-silico prediction, not a clinical call.

THAP1 p.Ser21Ala

c.61T>G · rs1421233354 · VCV448687

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.8687 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

torsion dystonia 6

Computational evidence

Protein change
AlphaMissense	0.8687	likely pathogenic
REVEL	0.863	moderately pathogenic-leaning
SaProt	LLR -11.41	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 9.2	GERP 1.9, phastCons 1
Regional constraint	o/e 0.70	unconstrained · MANE · 5,129 bp · p 1.3e-06 · regional, not allelic
Overall
CADD	28.6	PHRED · no single calibrated threshold — expert panels disagree

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

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00267% African / African-American · 2/74,894 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000124% 2/1,613,480 alleles · very rare exomes 0/1,461,390 · genomes 2/152,090 · 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.Ser21Ala
Coding: c.61T>G
MANE Select: NM_018105
dbSNP: rs1421233354
Type: single nucleotide variant
Location: chr8:42843034 (GRCh38)
Gene constraint: LOEUF 0.571 · pLI 0.90 (gnomAD)
Structure: AlphaFold pLDDT 71.61 · 3 PDB
Residue 21: a UniProt-annotated variant site (in dyt6)

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.Ser21Phe Likely pathogenic ★★ same residue
THAP1 p.Ser21Cys 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-ser21ala (accessed [today's date]).

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