Is TH p.Glu253Val (c.758A>T) pathogenic?

TH p.Glu253Val (c.758A>T) is classified Uncertain significance in TH (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-09-23). AlphaMissense: likely benign (0.2156); Very rare (popmax 0.00804%, afr); Associated with Inborn genetic diseases.

What condition is associated with TH p.Glu253Val (c.758A>T)?

TH p.Glu253Val (c.758A>T) is associated with Inborn genetic diseases, TH-deficient dopa-responsive dystonia (ClinVar).

How common is TH p.Glu253Val (c.758A>T) in the general population?

TH p.Glu253Val (c.758A>T) is very rare (popmax 0.00804%, afr) (gnomAD).

What do computational predictors say about TH p.Glu253Val (c.758A>T)?

AlphaMissense predicts likely benign (score 0.2156) — an in-silico prediction, not a clinical call.

TH p.Glu253Val

c.758A>T · rs369397659 · VCV1346759

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2156 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00804%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2156	likely benign
REVEL	0.479	indeterminate
SaProt	LLR -10.67	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.9	GERP 1.8, phastCons 0.73
Regional constraint	o/e 1.03	unconstrained · MANE · 7,550 bp · p 0.38 · regional, not allelic
Overall
CADD	21.0	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 E284V vs ClinVar E253V) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00804% African / African-American · 6/74,654 alleles

Filtering AF 0.00348% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00239%

Overall 0.000502% 8/1,593,994 alleles · very rare exomes 5/1,441,786 · genomes 3/152,208 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00804%	12,442
Admixed American	0.00174%	57,378
South Asian	0.00114%	87,900

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.Glu253Val
Coding: c.758A>T
MANE Select: NM_000360
dbSNP: rs369397659
Type: single nucleotide variant
Location: chr11:2166970 (GRCh38)
Gene constraint: LOEUF 1.27 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.75 · 7 PDB
Residue 284 UniProt numbering: 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.Glu253= 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
TH c.90+10C>T Pathogenic/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-glu253val (accessed [today's date]).

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