Is TH p.Ile229Phe (c.685A>T) pathogenic?

TH p.Ile229Phe (c.685A>T) is classified Likely benign in TH (ClinVar, Single submitter, 3 submitters; last evaluated 2026-02-02). AlphaMissense: likely benign (0.3319); Rare (popmax 0.167%, amr); Associated with TH-deficient dopa-responsive dystonia.

What condition is associated with TH p.Ile229Phe (c.685A>T)?

TH p.Ile229Phe (c.685A>T) is associated with TH-deficient dopa-responsive dystonia (ClinVar).

How common is TH p.Ile229Phe (c.685A>T) in the general population?

TH p.Ile229Phe (c.685A>T) is rare (popmax 0.167%, amr) (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.Ile229Phe (c.685A>T)?

AlphaMissense predicts likely benign (score 0.3319) — an in-silico prediction, not a clinical call.

TH p.Ile229Phe

c.685A>T · rs778613708 · VCV571044

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.3319 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.167%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

TH-deficient dopa-responsive dystonia

Computational evidence

Protein change
AlphaMissense	0.3319	likely benign
REVEL	0.607	indeterminate
SaProt	LLR -10.51	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.5	GERP 0.32, phastCons 0.97
Regional constraint	o/e 1.03	unconstrained · MANE · 7,550 bp · p 0.38 · regional, not allelic
Overall
CADD	17.93	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 I260F vs ClinVar I229F) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.167% Admixed American · 88/52,614 alleles

Filtering AF 0.139% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.129%

Overall 0.00569% 89/1,562,782 alleles · rare exomes 78/1,410,806 · genomes 11/151,976 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.167%	598
African / African-American	0.00135%	73,812

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.Ile229Phe
Coding: c.685A>T
MANE Select: NM_000360
dbSNP: rs778613708
Type: single nucleotide variant
Location: chr11:2167445 (GRCh38)
Gene constraint: LOEUF 1.27 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.75 · 7 PDB
Residue 260 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 p.Ile229Thr Uncertain significance ★★ ⚠ same residue
TH p.Ile229Leu 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-ile229phe (accessed [today's date]).

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