Is TH p.Pro67Thr (c.199C>A) pathogenic?

TH p.Pro67Thr (c.199C>A) is classified Uncertain significance in TH (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-05). AlphaMissense: likely benign (0.0732); Ultra-rare (popmax 0.0296%, sas); Associated with Inborn genetic diseases.

What condition is associated with TH p.Pro67Thr (c.199C>A)?

TH p.Pro67Thr (c.199C>A) is associated with Inborn genetic diseases (ClinVar).

How common is TH p.Pro67Thr (c.199C>A) in the general population?

TH p.Pro67Thr (c.199C>A) is ultra-rare (popmax 0.0296%, sas) (gnomAD).

What do computational predictors say about TH p.Pro67Thr (c.199C>A)?

AlphaMissense predicts likely benign (score 0.0732) — an in-silico prediction, not a clinical call.

TH p.Pro67Thr

c.199C>A · VCV4183788

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0732 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0296%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0732	likely benign
REVEL	0.263	benign-leaning
SaProt	LLR -7.07	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.5	GERP -0.63, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 7,550 bp · p 0.38 · regional, not allelic
Overall
CADD	4.287	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 P98T vs ClinVar P67T) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0296% South Asian · 27/91,064 alleles

Filtering AF 0.0208% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.018%

Overall 0.00186% 30/1,612,156 alleles · ultra-rare exomes 27/1,459,978 · genomes 3/152,178 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0296%	3,373
Remaining individualsnot grpmax-eligible	0.0016%	62,406
European (non-Finnish)	0.00017%	589,856

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.Pro67Thr
Coding: c.199C>A
MANE Select: NM_000360
Type: single nucleotide variant
Location: chr11:2169763 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TH p.Pro67Leu Uncertain significance ★★ ⚠ same residue
TH p.Tyr224Ter Pathogenic ★★ same condition
TH c.91-853C>T Uncertain significance ★★ ⚠ same condition
TH c.91-892C>T Uncertain significance ★★ ⚠ same condition
TH p.Ala210Ser Uncertain significance ★★ ⚠ same condition
TH p.Ala317Gly Uncertain significance ★★ ⚠ same condition
TH p.Ala492Val Uncertain significance ★★ ⚠ same condition
TH p.Ala56Val Uncertain significance ★★ ⚠ 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-pro67thr (accessed [today's date]).

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