Is TH p.Val374Ala (c.1121T>C) pathogenic?

TH p.Val374Ala (c.1121T>C) is classified Uncertain significance in TH (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-12). AlphaMissense: likely pathogenic (0.8015); Very rare (popmax 8.48e-05%, nfe); Associated with TH-deficient dopa-responsive dystonia.

What condition is associated with TH p.Val374Ala (c.1121T>C)?

TH p.Val374Ala (c.1121T>C) is associated with TH-deficient dopa-responsive dystonia (ClinVar).

How common is TH p.Val374Ala (c.1121T>C) in the general population?

TH p.Val374Ala (c.1121T>C) is very rare (popmax 8.48e-05%, nfe) (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.Val374Ala (c.1121T>C)?

AlphaMissense predicts likely pathogenic (score 0.8015) — an in-silico prediction, not a clinical call.

TH p.Val374Ala

c.1121T>C · rs1846072496 · VCV856884

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8015 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

TH-deficient dopa-responsive dystonia

Computational evidence

Protein change
AlphaMissense	0.8015	likely pathogenic
REVEL	0.921	moderately pathogenic-leaning
SaProt	LLR -11.61	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.9, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 7,550 bp · p 0.38 · regional, not allelic
Overall
CADD	26.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 V405A vs ClinVar V374A) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,926 alleles

Overall 0.000124% 2/1,612,606 alleles · very rare exomes 2/1,460,420 · genomes 0/152,186 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,482
European (non-Finnish)grpmax	8.48e-05%	1,179,926

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Val374Ala
Coding: c.1121T>C
MANE Select: NM_000360
dbSNP: rs1846072496
Type: single nucleotide variant
Location: chr11:2165747 (GRCh38)
Gene constraint: LOEUF 1.27 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.75 · 7 PDB
Residue 405 UniProt numbering: an α-helix

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-val374ala (accessed [today's date]).

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