Is TH p.Val275Ile (c.823G>A) pathogenic?

TH p.Val275Ile (c.823G>A) is classified Uncertain significance in TH (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-16). AlphaMissense: likely benign (0.0913); Very rare (popmax 0.00509%, amr); Associated with TH-deficient dopa-responsive dystonia.

What condition is associated with TH p.Val275Ile (c.823G>A)?

TH p.Val275Ile (c.823G>A) is associated with TH-deficient dopa-responsive dystonia (ClinVar).

How common is TH p.Val275Ile (c.823G>A) in the general population?

TH p.Val275Ile (c.823G>A) is very rare (popmax 0.00509%, 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.Val275Ile (c.823G>A)?

AlphaMissense predicts likely benign (score 0.0913) — an in-silico prediction, not a clinical call.

TH p.Val275Ile

c.823G>A · rs770941754 · VCV1505895

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0913 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00509%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

TH-deficient dopa-responsive dystonia

Computational evidence

Protein change
AlphaMissense	0.0913	likely benign
REVEL	0.714	pathogenic-leaning
SaProt	LLR -7.05	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.3	GERP 1.9, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 7,550 bp · p 0.38 · regional, not allelic
Overall
CADD	24.9	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 V306I vs ClinVar V275I) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00509% Admixed American · 3/58,986 alleles

Filtering AF 0.00135% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000719%

Overall 0.00137% 22/1,604,668 alleles · very rare exomes 20/1,452,434 · genomes 2/152,234 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00509%	19,662
South Asian	0.00224%	44,645
European (non-Finnish)	0.00144%	69,222

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.Val275Ile
Coding: c.823G>A
MANE Select: NM_000360
dbSNP: rs770941754
Type: single nucleotide variant
Location: chr11:2166905 (GRCh38)
Gene constraint: LOEUF 1.27 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.75 · 7 PDB
Residue 306 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.Val275Gly Uncertain significance ★ ⚠ same residue
TH p.Val275= 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-val275ile (accessed [today's date]).

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