Is TH p.Lys240= (c.720G>A) pathogenic?

TH p.Lys240= (c.720G>A) is classified Benign in TH (ClinVar, Multiple submitters, 14 submitters; last evaluated 2026-02-04). Common (popmax 32.3%, nfe) — too common for a highly-penetrant pathogenic allele; Associated with TH-deficient dopa-responsive dystonia.

What condition is associated with TH p.Lys240= (c.720G>A)?

TH p.Lys240= (c.720G>A) is associated with TH-deficient dopa-responsive dystonia (ClinVar).

How is Autosomal recessive dopa-responsive dystonia inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

TH p.Lys240=

Q: How common is TH p.Lys240= (c.720G>A) in the general population?

TH p.Lys240= (c.720G>A) is common (popmax 32.3%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.720G>A · rs6357 · VCV263258

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 14 submitters

gnomAD v4.1

Common

common (popmax 32.3%, nfe) — too common for a highly-penetrant pathogenic allele

Conditions

TH-deficient dopa-responsive dystonia

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.95	GERP 0.55
Overall
CADD	11.29	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 32.3% European (non-Finnish) · 376,841/1,166,066 alleles

Filtering AF 32.2% ClinGen BA1/BS1 input FAF95, joint · FAF99 32.2%

Overall 28.5% 452,107/1,585,578 alleles · common exomes 416,356/1,433,358 · genomes 35,751/152,220 · joint denominator

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	43.8%	2
European (non-Finnish)grpmax	32.3%	3
Finnishnot grpmax-eligible	29.1%	3
Remaining individualsnot grpmax-eligible	25.7%	4
Ashkenazi Jewishnot grpmax-eligible	25.2%	4
Admixed American	17.6%	6
South Asian	14.6%	7
Middle Eastern	12.6%	8
African / African-American	12.3%	8
East Asian	3.51%	28

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.Lys240=
Coding: c.720G>A
MANE Select: NM_000360
dbSNP: rs6357
Type: single nucleotide variant
Location: chr11:2167008 (GRCh38)
Gene constraint: LOEUF 1.27 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.75 · 7 PDB
Residue 240: 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.Lys240Arg Uncertain significance ⚠ 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-lys240 (accessed [today's date]).

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