Is TH p.Arg98Gln (c.293G>A) pathogenic?

TH p.Arg98Gln (c.293G>A) is classified Uncertain significance in TH (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-22). AlphaMissense: likely benign (0.1031); Very rare (popmax 0.00237%, nfe); Associated with Inborn genetic diseases.

What condition is associated with TH p.Arg98Gln (c.293G>A)?

TH p.Arg98Gln (c.293G>A) is associated with Inborn genetic diseases, TH-deficient dopa-responsive dystonia (ClinVar).

How common is TH p.Arg98Gln (c.293G>A) in the general population?

TH p.Arg98Gln (c.293G>A) is very rare (popmax 0.00237%, nfe) (gnomAD).

What do computational predictors say about TH p.Arg98Gln (c.293G>A)?

AlphaMissense predicts likely benign (score 0.1031) — an in-silico prediction, not a clinical call.

TH p.Arg98Gln

c.293G>A · rs375214998 · VCV2201146

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1031 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00237%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1031	likely benign
REVEL	0.441	indeterminate
SaProt	LLR -6.68	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.5	GERP -0.5, phastCons 0.99
Regional constraint	o/e 1.03	unconstrained · MANE · 7,550 bp · p 0.38 · regional, not allelic
Overall
CADD	18.95	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R129Q vs ClinVar R98Q) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00237% European (non-Finnish) · 28/1,179,968 alleles

Filtering AF 0.00164% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00142%

Overall 0.00186% 30/1,613,452 alleles · very rare exomes 29/1,461,364 · genomes 1/152,088 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00237%	42,142
Remaining individualsnot grpmax-eligible	0.0016%	62,482
South Asian	0.0011%	91,086

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: TH
Protein: p.Arg98Gln
Coding: c.293G>A
MANE Select: NM_000360
dbSNP: rs375214998
Type: single nucleotide variant
Location: chr11:2169669 (GRCh38)
Gene constraint: LOEUF 1.27 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.75 · 7 PDB

Full TH 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: TH-deficient dopa-responsive dystonia

Similar variants

TH p.Arg98Ter Pathogenic/Likely pathogenic ★★ same residue
TH p.Arg98Pro Uncertain significance ★★ ⚠ same residue
TH p.Arg98_Ala99insGly Likely pathogenic ★ same residue
TH p.Arg98fs Likely pathogenic ★ same residue
TH c.1200+2T>C Likely pathogenic ★★ same condition
TH c.1334+1G>A Likely pathogenic ★★ same condition
TH c.312+1G>A Likely pathogenic ★★ same condition
TH c.488-1G>A 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/th-p-arg98gln (accessed [today's date]).

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