Is TH p.Lys240Arg (c.719A>G) pathogenic?

TH p.Lys240Arg (c.719A>G) is classified Uncertain significance in TH (ClinVar, No assertion criteria, 1 submitter; last evaluated 2025-02-19). AlphaMissense: likely benign (0.0604); No allele count reported in gnomAD v4.1 (AN 1,585,860); Associated with TH-deficient dopa-responsive dystonia.

What condition is associated with TH p.Lys240Arg (c.719A>G)?

TH p.Lys240Arg (c.719A>G) is associated with TH-deficient dopa-responsive dystonia (ClinVar).

How common is TH p.Lys240Arg (c.719A>G) in the general population?

TH p.Lys240Arg (c.719A>G) is no allele count reported in gnomAD v4.1 (AN 1,585,860) (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.Lys240Arg (c.719A>G)?

AlphaMissense predicts likely benign (score 0.0604) — an in-silico prediction, not a clinical call.

TH p.Lys240Arg

c.719A>G · VCV4062318

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0604 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,585,860)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

TH-deficient dopa-responsive dystonia

Computational evidence

Protein change
AlphaMissense	0.0604	likely benign
REVEL	0.32	indeterminate
SaProt	LLR -7.23	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.27	GERP -1.1
Regional constraint	o/e 1.03	unconstrained · MANE · 7,550 bp · p 0.38 · regional, not allelic
Overall
CADD	13.39	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM K271R vs ClinVar K240R) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

No allele count reported in gnomAD v4.1 (AN 1,585,860). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: TH
Protein: p.Lys240Arg
Coding: c.719A>G
MANE Select: NM_000360
Type: single nucleotide variant
Location: chr11:2167009 (GRCh38)
Gene constraint: LOEUF 1.27 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.75 · 7 PDB
Residue 271 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.Lys240= Benign ★★ same residue
TH p.Lys240fs Likely pathogenic same residue
TH p.Lys240Asn 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

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-lys240arg (accessed [today's date]).

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