Is THAP1 p.Ala115Pro (c.343G>C) pathogenic?

THAP1 p.Ala115Pro (c.343G>C) is classified Conflicting classifications of pathogenicity in THAP1 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-05-04). AlphaMissense: likely benign (0.2177); Ultra-rare (popmax 0.0178%, eas); Associated with Inborn genetic diseases.

What condition is associated with THAP1 p.Ala115Pro (c.343G>C)?

THAP1 p.Ala115Pro (c.343G>C) is associated with Inborn genetic diseases, torsion dystonia 6 (ClinVar).

How common is THAP1 p.Ala115Pro (c.343G>C) in the general population?

THAP1 p.Ala115Pro (c.343G>C) is ultra-rare (popmax 0.0178%, eas) (gnomAD).

What do computational predictors say about THAP1 p.Ala115Pro (c.343G>C)?

AlphaMissense predicts likely benign (score 0.2177) — an in-silico prediction, not a clinical call.

THAP1 p.Ala115Pro

c.343G>C · rs761376417 · VCV1002296

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.2177 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0178%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2177	likely benign
REVEL	0.403	indeterminate
SaProt	LLR -5.88	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.3	GERP 1.4, phastCons 1
Regional constraint	o/e 0.70	unconstrained · MANE · 5,129 bp · p 1.3e-06 · regional, not allelic
Overall
CADD	20.1	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0178% East Asian · 8/44,902 alleles

Filtering AF 0.00883% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00641%

Overall 0.000805% 13/1,613,968 alleles · ultra-rare exomes 12/1,461,798 · genomes 1/152,170 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0178%	5,613
Remaining individualsnot grpmax-eligible	0.008%	12,496

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.Ala115Pro
Coding: c.343G>C
MANE Select: NM_018105
dbSNP: rs761376417
Type: single nucleotide variant
Location: chr8:42838261 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: torsion dystonia 6

Similar variants

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
THAP1 p.Ser21Phe Likely pathogenic ★★ same condition
THAP1 p.Arg169Gln Uncertain significance ★★ ⚠ 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-ala115pro (accessed [today's date]).

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