Is TH p.Ala6Thr (c.16G>A) pathogenic?

TH p.Ala6Thr (c.16G>A) is classified Benign/Likely benign in TH (ClinVar, Multiple submitters, 12 submitters; last evaluated 2026-06-01). AlphaMissense: likely benign (0.0695); Rare (popmax 0.552%, nfe); Associated with TH-deficient dopa-responsive dystonia.

What condition is associated with TH p.Ala6Thr (c.16G>A)?

TH p.Ala6Thr (c.16G>A) is associated with TH-deficient dopa-responsive dystonia (ClinVar).

How common is TH p.Ala6Thr (c.16G>A) in the general population?

TH p.Ala6Thr (c.16G>A) is rare (popmax 0.552%, 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.Ala6Thr (c.16G>A)?

AlphaMissense predicts likely benign (score 0.0695) — an in-silico prediction, not a clinical call.

TH p.Ala6Thr

c.16G>A · rs74555599 · VCV242252

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 12 submitters

AlphaMissense

likely benign

0.0695 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.552%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

TH-deficient dopa-responsive dystonia

Computational evidence

Protein change
AlphaMissense	0.0695	likely benign
REVEL	0.277	benign-leaning
SaProt	LLR -7.14	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.67	GERP -0.26
Regional constraint	o/e 1.03	unconstrained · MANE · 7,550 bp · p 0.38 · regional, not allelic
Overall
CADD	7.811	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.552% European (non-Finnish) · 6,517/1,179,772 alleles

Filtering AF 0.541% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.537%

Overall 0.484% 7,810/1,612,174 alleles · rare exomes 7,150/1,459,936 · genomes 660/152,238 · joint denominator

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	5.59%	18
Finnishnot grpmax-eligible	1.52%	66
European (non-Finnish)grpmax	0.552%	181
Remaining individualsnot grpmax-eligible	0.319%	314
African / African-American	0.0813%	1,230
Admixed American	0.0417%	2,400
Ashkenazi Jewishnot grpmax-eligible	0.0135%	7,390
East Asian	0.00223%	44,858

Amish 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.Ala6Thr
Coding: c.16G>A
MANE Select: NM_000360
dbSNP: rs74555599
Type: single nucleotide variant
Location: chr11:2171771 (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

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.Ala6Ser Uncertain significance ★ ⚠ same residue
TH p.Ala6= Likely benign ★ 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-ala6thr (accessed [today's date]).

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