Is TH p.Ala210Ser (c.628G>T) pathogenic?

TH p.Ala210Ser (c.628G>T) is classified Uncertain significance in TH (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-06-23). AlphaMissense: likely benign (0.3065); Ultra-rare (popmax 0.0165%, mid); Associated with Inborn genetic diseases.

What condition is associated with TH p.Ala210Ser (c.628G>T)?

TH p.Ala210Ser (c.628G>T) is associated with Inborn genetic diseases, TH-deficient dopa-responsive dystonia (ClinVar).

How common is TH p.Ala210Ser (c.628G>T) in the general population?

TH p.Ala210Ser (c.628G>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about TH p.Ala210Ser (c.628G>T)?

AlphaMissense predicts likely benign (score 0.3065) — an in-silico prediction, not a clinical call.

TH p.Ala210Ser

c.628G>T · rs1260455415 · VCV1437804

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.3065 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3065	likely benign
REVEL	0.899	moderately pathogenic-leaning
SaProt	LLR -9.35	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.30 · evaluated, not missing
Constraint at this position
Conservation	phyloP 5.7	GERP 1.2, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 7,550 bp · p 0.38 · regional, not allelic
Overall
CADD	26.8	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 A241S vs ClinVar A210S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,052 alleles

Overall 6.22e-05% 1/1,608,190 alleles · ultra-rare exomes 1/1,455,900 · genomes 0/152,290 · joint denominator

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.Ala210Ser
Coding: c.628G>T
MANE Select: NM_000360
dbSNP: rs1260455415
Type: single nucleotide variant
Location: chr11:2167882 (GRCh38)
Gene constraint: LOEUF 1.27 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.75 · 7 PDB
Residue 241 UniProt numbering: 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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: TH-deficient dopa-responsive dystonia

Similar variants

TH p.Ala210Thr Pathogenic/Likely pathogenic ★★ same residue
TH p.Ala210= Likely benign ★ same residue
TH p.Ala210Gly Uncertain significance ★ ⚠ same residue
TH p.Ala210Val 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

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-ala210ser (accessed [today's date]).

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