Is TH p.Glu27Asp (c.81G>T) pathogenic?

TH p.Glu27Asp (c.81G>T) is classified Conflicting classifications of pathogenicity in TH (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2026-01-31). AlphaMissense: likely benign (0.2083); Rare (popmax 0.59%, afr); Associated with TH-deficient dopa-responsive dystonia.

What condition is associated with TH p.Glu27Asp (c.81G>T)?

TH p.Glu27Asp (c.81G>T) is associated with TH-deficient dopa-responsive dystonia (ClinVar).

How common is TH p.Glu27Asp (c.81G>T) in the general population?

TH p.Glu27Asp (c.81G>T) is rare (popmax 0.59%, afr) (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.Glu27Asp (c.81G>T)?

AlphaMissense predicts likely benign (score 0.2083) — an in-silico prediction, not a clinical call.

TH p.Glu27Asp

c.81G>T · rs139742336 · VCV695326

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.2083 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.59%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

TH-deficient dopa-responsive dystonia

Computational evidence

Protein change
AlphaMissense	0.2083	likely benign
REVEL	0.373	indeterminate
SaProt	LLR -7.59	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.2	GERP 0.9, phastCons 0.97
Regional constraint	o/e 1.03	unconstrained · MANE · 7,550 bp · p 0.38 · regional, not allelic
Overall
CADD	16.23	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 0.59% African / African-American · 443/75,030 alleles

Filtering AF 0.545% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.527%

Overall 0.0317% 511/1,612,396 alleles · rare exomes 246/1,460,062 · genomes 265/152,334 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.59%	169
Middle Eastern	0.0524%	1,908
Remaining individualsnot grpmax-eligible	0.0481%	2,081
Admixed American	0.03%	3,334
South Asian	0.0022%	45,529
European (non-Finnish)	0.00127%	78,655

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.Glu27Asp
Coding: c.81G>T
MANE Select: NM_000360
dbSNP: rs139742336
Type: single nucleotide variant
Location: chr11:2171706 (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.Glu27= Likely benign ★ same residue
TH p.Glu27fs Pathogenic ★ 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-glu27asp (accessed [today's date]).

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