Is TH p.Ile35Thr (c.104T>C) pathogenic?

TH p.Ile35Thr (c.104T>C) is classified Uncertain significance in TH (ClinVar, Multiple submitters, 6 submitters; last evaluated 2024-12-15). AlphaMissense: likely benign (0.1298); Ultra-rare (popmax 0.02%, amr); Associated with Inborn genetic diseases.

What condition is associated with TH p.Ile35Thr (c.104T>C)?

TH p.Ile35Thr (c.104T>C) is associated with Inborn genetic diseases, TH-deficient dopa-responsive dystonia (ClinVar).

How common is TH p.Ile35Thr (c.104T>C) in the general population?

TH p.Ile35Thr (c.104T>C) is ultra-rare (popmax 0.02%, amr) (gnomAD).

What do computational predictors say about TH p.Ile35Thr (c.104T>C)?

AlphaMissense predicts likely benign (score 0.1298) — an in-silico prediction, not a clinical call.

TH p.Ile35Thr

c.104T>C · rs747420332 · VCV1210008

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.1298 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.02%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1298	likely benign
REVEL	0.356	indeterminate
SaProt	LLR -5.42	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	Δ0.25	acceptor loss, 10 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 6.6	GERP 0.7, phastCons 0.97
Regional constraint	o/e 1.03	unconstrained · MANE · 7,550 bp · p 0.38 · regional, not allelic
Overall
CADD	15.49	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 I66T vs ClinVar I35T) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.02% Admixed American · 12/59,886 alleles

Filtering AF 0.0115% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.009%

Overall 0.00491% 79/1,609,678 alleles · ultra-rare exomes 71/1,457,596 · genomes 8/152,082 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.02%	4,990
East Asian	0.00669%	14,938
European (non-Finnish)	0.00509%	19,658
Remaining individualsnot grpmax-eligible	0.00322%	31,089
African / African-American	0.00267%	37,413

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.Ile35Thr
Coding: c.104T>C
MANE Select: NM_000360
dbSNP: rs747420332
Type: single nucleotide variant
Location: chr11:2169858 (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

Also linked: TH-deficient dopa-responsive dystonia

Similar variants

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
TH c.90+13G>A 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-ile35thr (accessed [today's date]).

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