Is TH p.Phe131Val (c.391T>G) pathogenic?

TH p.Phe131Val (c.391T>G) is classified Uncertain significance in TH (ClinVar, Multiple submitters, 8 submitters; last evaluated 2025-03-31). AlphaMissense: likely benign (0.2924); Ultra-rare (popmax 0.0364%, nfe); Associated with TH-deficient dopa-responsive dystonia.

What condition is associated with TH p.Phe131Val (c.391T>G)?

TH p.Phe131Val (c.391T>G) is associated with TH-deficient dopa-responsive dystonia (ClinVar).

How common is TH p.Phe131Val (c.391T>G) in the general population?

TH p.Phe131Val (c.391T>G) is ultra-rare (popmax 0.0364%, nfe) (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.Phe131Val (c.391T>G)?

AlphaMissense predicts likely benign (score 0.2924) — an in-silico prediction, not a clinical call.

TH p.Phe131Val

c.391T>G · rs200536568 · VCV643112

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.2924 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0364%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

TH-deficient dopa-responsive dystonia

Computational evidence

Protein change
AlphaMissense	0.2924	likely benign
REVEL	0.61	indeterminate
SaProt	LLR -8.09	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 2.8	GERP -1.1, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 7,550 bp · p 0.38 · regional, not allelic
Overall
CADD	20.9	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 F162V vs ClinVar F131V) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0364% European (non-Finnish) · 429/1,179,742 alleles

Filtering AF 0.0335% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0323%

Overall 0.0286% 461/1,611,804 alleles · ultra-rare exomes 435/1,459,666 · genomes 26/152,138 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0364%	2,750
Remaining individualsnot grpmax-eligible	0.0241%	4,156
Middle Eastern	0.0167%	5,972
Admixed American	0.015%	6,664
African / African-American	0.00668%	14,980
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,568
South Asian	0.0011%	91,006

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.Phe131Val
Coding: c.391T>G
MANE Select: NM_000360
dbSNP: rs200536568
Type: single nucleotide variant
Location: chr11:2168587 (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.Phe131= Conflicting classifications of pathogenicity ★ same residue
TH p.Phe131Ser 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
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-phe131val (accessed [today's date]).

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