Is TH p.Gly497Asp (c.1490G>A) pathogenic?

TH p.Gly497Asp (c.1490G>A) is classified Uncertain significance in TH (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-04-07). AlphaMissense: likely benign (0.1132); Ultra-rare (popmax 0.0179%, eas); Associated with Inborn genetic diseases.

What condition is associated with TH p.Gly497Asp (c.1490G>A)?

TH p.Gly497Asp (c.1490G>A) is associated with Inborn genetic diseases, TH-deficient dopa-responsive dystonia (ClinVar).

How common is TH p.Gly497Asp (c.1490G>A) in the general population?

TH p.Gly497Asp (c.1490G>A) is ultra-rare (popmax 0.0179%, eas) (gnomAD).

What do computational predictors say about TH p.Gly497Asp (c.1490G>A)?

AlphaMissense predicts likely benign (score 0.1132) — an in-silico prediction, not a clinical call.

TH p.Gly497Asp

c.1490G>A · rs753632777 · VCV936679

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1132 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0179%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1132	likely benign
REVEL	0.395	indeterminate
SaProt	LLR -7.40	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.29	gain · loss 0.00 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 7.3	GERP 1.2, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 7,550 bp · p 0.38 · regional, not allelic
Overall
CADD	22.8	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 G528D vs ClinVar G497D) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0179% East Asian · 7/39,132 alleles

Filtering AF 0.0083% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00595%

Overall 0.000753% 11/1,460,946 alleles · ultra-rare exomes 9/1,308,738 · genomes 2/152,208 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0179%	5,590
Remaining individualsnot grpmax-eligible	0.00721%	13,875

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.Gly497Asp
Coding: c.1490G>A
MANE Select: NM_000360
dbSNP: rs753632777
Type: single nucleotide variant
Location: chr11:2164237 (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.Gly497Ser Uncertain significance ★ ⚠ same residue
TH p.Gly497Val Uncertain significance ★ ⚠ 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
TH c.644+1G>A Likely pathogenic ★★ same condition
TH c.695+1G>C 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/th-p-gly497asp (accessed [today's date]).

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