Is TH p.Val457Met (c.1369G>A) pathogenic?

TH p.Val457Met (c.1369G>A) is classified Uncertain significance in TH (ClinVar, Single submitter, 1 submitter; last evaluated 2022-03-24). AlphaMissense: likely benign (0.2902); Ultra-rare (popmax 0.0139%, afr); Associated with TH-deficient dopa-responsive dystonia.

What condition is associated with TH p.Val457Met (c.1369G>A)?

TH p.Val457Met (c.1369G>A) is associated with TH-deficient dopa-responsive dystonia (ClinVar).

How common is TH p.Val457Met (c.1369G>A) in the general population?

TH p.Val457Met (c.1369G>A) is ultra-rare (popmax 0.0139%, afr) (gnomAD).

How is Autosomal recessive dopa-responsive dystonia inherited?

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

What do computational predictors say about TH p.Val457Met (c.1369G>A)?

AlphaMissense predicts likely benign (score 0.2902) — an in-silico prediction, not a clinical call.

TH p.Val457Met

c.1369G>A · rs760675839 · VCV2082116

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2902 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0139%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

TH-deficient dopa-responsive dystonia

Computational evidence

Protein change
AlphaMissense	0.2902	likely benign
REVEL	0.864	moderately pathogenic-leaning
SaProt	LLR -12.82	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.4	GERP 1.7, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 7,550 bp · p 0.38 · regional, not allelic
Overall
CADD	26.0	PHRED · no single calibrated threshold — expert panels disagree

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM V488M vs ClinVar V457M) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0139% African / African-American · 10/72,000 alleles

Filtering AF 0.0075% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0057%

Overall 0.00439% 68/1,549,966 alleles · ultra-rare exomes 58/1,397,788 · genomes 10/152,178 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0139%	7,200
South Asian	0.00957%	10,444
East Asian	0.00718%	13,933
Remaining individualsnot grpmax-eligible	0.00503%	19,865
Admixed American	0.00381%	26,244
European (non-Finnish)	0.00367%	27,278

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.Val457Met
Coding: c.1369G>A
MANE Select: NM_000360
dbSNP: rs760675839
Type: single nucleotide variant
Location: chr11:2164358 (GRCh38)
Gene constraint: LOEUF 1.27 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.75 · 7 PDB
Residue 488 UniProt numbering: a β-strand

Full TH gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

TH-deficient dopa-responsive dystonia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Autosomal recessive dopa-responsive dystonia (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

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
TH c.90+10C>T Pathogenic/Likely pathogenic ★★ same condition
TH c.90+13G>A 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-val457met (accessed [today's date]).

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