Is TH p.Phe376= (c.1128C>T) pathogenic?

TH p.Phe376= (c.1128C>T) is classified Likely benign in TH (ClinVar, Single submitter, 2 submitters; last evaluated 2025-11-25). Ultra-rare (popmax 0.0582%, sas); Associated with TH-deficient dopa-responsive dystonia.

What condition is associated with TH p.Phe376= (c.1128C>T)?

TH p.Phe376= (c.1128C>T) is associated with TH-deficient dopa-responsive dystonia (ClinVar).

How common is TH p.Phe376= (c.1128C>T) in the general population?

TH p.Phe376= (c.1128C>T) is ultra-rare (popmax 0.0582%, sas) (gnomAD).

How is Autosomal recessive dopa-responsive dystonia inherited?

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

TH p.Phe376=

c.1128C>T · rs769329337 · VCV702397

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0582%, sas)

Conditions

TH-deficient dopa-responsive dystonia

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.078	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -7.1	GERP -3.7
Overall
CADD	1.874	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0582% South Asian · 53/91,062 alleles

Filtering AF 0.0457% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0412%

Overall 0.00509% 82/1,612,570 alleles · ultra-rare exomes 80/1,460,464 · genomes 2/152,106 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0582%	1,718
Admixed American	0.005%	19,999
Remaining individualsnot grpmax-eligible	0.0048%	20,819
European (non-Finnish)	0.00186%	53,635
African / African-American	0.00134%	74,872

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.Phe376=
Coding: c.1128C>T
MANE Select: NM_000360
dbSNP: rs769329337
Type: single nucleotide variant
Location: chr11:2165740 (GRCh38)
Gene constraint: LOEUF 1.27 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.75 · 7 PDB
Residue 376: a UniProt-annotated variant site (in arsegs; loss of over 80% of tyrosine 3-monooxygenase activity); 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-phe376 (accessed [today's date]).

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