Is THAP1 p.Val183Phe (c.547G>T) pathogenic?

THAP1 p.Val183Phe (c.547G>T) is classified Uncertain significance in THAP1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-21). AlphaMissense: likely benign (0.1366); Very rare (popmax 0.00533%, afr); Associated with Inborn genetic diseases.

What condition is associated with THAP1 p.Val183Phe (c.547G>T)?

THAP1 p.Val183Phe (c.547G>T) is associated with Inborn genetic diseases, torsion dystonia 6 (ClinVar).

How common is THAP1 p.Val183Phe (c.547G>T) in the general population?

THAP1 p.Val183Phe (c.547G>T) is very rare (popmax 0.00533%, afr) (gnomAD).

What do computational predictors say about THAP1 p.Val183Phe (c.547G>T)?

AlphaMissense predicts likely benign (score 0.1366) — an in-silico prediction, not a clinical call.

THAP1 p.Val183Phe

c.547G>T · rs370082539 · VCV1696664

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1366 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00533%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1366	likely benign
REVEL	0.374	indeterminate
SaProt	LLR -7.18	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 7.6	GERP 2.3, phastCons 1
Regional constraint	o/e 0.70	unconstrained · MANE · 5,129 bp · p 1.3e-06 · regional, not allelic
Overall
CADD	20.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.00533% African / African-American · 4/74,982 alleles

Filtering AF 0.00175% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.00031% 5/1,613,984 alleles · very rare exomes 3/1,461,746 · genomes 2/152,238 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00533%	18,746
Remaining individualsnot grpmax-eligible	0.0016%	62,492

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.Val183Phe
Coding: c.547G>T
MANE Select: NM_018105
dbSNP: rs370082539
Type: single nucleotide variant
Location: chr8:42838057 (GRCh38)
Gene constraint: LOEUF 0.571 · pLI 0.90 (gnomAD)
Structure: AlphaFold pLDDT 71.61 · 3 PDB
Residue 183: the 'involved in homodimer formation' region

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.Val183Ala Uncertain significance ★ ⚠ 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
THAP1 p.Ser21Phe 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-val183phe (accessed [today's date]).

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