Is TH p.Pro2Leu (c.5C>T) pathogenic?

TH p.Pro2Leu (c.5C>T) is classified Conflicting classifications of pathogenicity in TH (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-02-01). AlphaMissense: likely benign (0.2106); Rare (popmax 0.238%, sas); Associated with TH-deficient dopa-responsive dystonia.

What condition is associated with TH p.Pro2Leu (c.5C>T)?

TH p.Pro2Leu (c.5C>T) is associated with TH-deficient dopa-responsive dystonia (ClinVar).

How common is TH p.Pro2Leu (c.5C>T) in the general population?

TH p.Pro2Leu (c.5C>T) is rare (popmax 0.238%, sas) (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.Pro2Leu (c.5C>T)?

AlphaMissense predicts likely benign (score 0.2106) — an in-silico prediction, not a clinical call.

TH p.Pro2Leu

c.5C>T · rs139474171 · VCV304087

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.2106 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.238%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

TH-deficient dopa-responsive dystonia

Computational evidence

Protein change
AlphaMissense	0.2106	likely benign
REVEL	0.591	indeterminate
SaProt	LLR -6.57	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.22	gain · loss 0.00 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 9.6	GERP -0.25, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 7,550 bp · p 0.38 · regional, not allelic
Overall
CADD	24.8	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 0.238% South Asian · 217/91,044 alleles

Filtering AF 0.212% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.202%

Overall 0.0143% 230/1,611,720 alleles · rare exomes 222/1,459,444 · genomes 8/152,276 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.238%	420
Middle Eastern	0.0168%	5,942
Remaining individualsnot grpmax-eligible	0.0112%	8,922
African / African-American	0.00666%	15,007

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.Pro2Leu
Coding: c.5C>T
MANE Select: NM_000360
dbSNP: rs139474171
Type: single nucleotide variant
Location: chr11:2171782 (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.Pro2= 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-pro2leu (accessed [today's date]).

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