Is TH p.Pro414Thr (c.1240C>A) pathogenic?

TH p.Pro414Thr (c.1240C>A) is classified Uncertain significance in TH (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-12). AlphaMissense: ambiguous (0.3762); Absent from gnomAD v4.1.

How common is TH p.Pro414Thr (c.1240C>A) in the general population?

TH p.Pro414Thr (c.1240C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TH p.Pro414Thr (c.1240C>A)?

AlphaMissense predicts ambiguous (score 0.3762) — an in-silico prediction, not a clinical call.

TH p.Pro414Thr

c.1240C>A · VCV3777668

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3762 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.3762	ambiguous
REVEL	0.908	moderately pathogenic-leaning
SaProt	LLR -12.37	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 11	GERP -1.1, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 7,550 bp · p 0.38 · regional, not allelic
Overall
CADD	25.6	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 P445T vs ClinVar P414T) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: TH
Protein: p.Pro414Thr
Coding: c.1240C>A
MANE Select: NM_000360
Type: single nucleotide variant
Location: chr11:2165326 (GRCh38)
Gene constraint: LOEUF 1.27 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.75 · 7 PDB
Residue 445 UniProt numbering: an α-helix

Full TH gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

TH p.Pro414Ser Uncertain significance ★ ⚠ same residue
TH p.Pro414= Likely benign ★ same residue
TH c.1200+2T>C Likely pathogenic ★★ same type
TH c.1334+1G>A Likely pathogenic ★★ same type
TH c.312+1G>A Likely pathogenic ★★ same type
TH c.488-1G>A Pathogenic ★★ same type
TH c.644+1G>A Likely pathogenic ★★ same type
TH c.695+1G>C Likely pathogenic ★★ same type

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-pro414thr (accessed [today's date]).

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