Is TH p.Pro324Leu (c.971C>T) pathogenic?

TH p.Pro324Leu (c.971C>T) is classified Likely pathogenic in TH (ClinVar, Single submitter, 1 submitter; last evaluated 2019-01-01). AlphaMissense: likely pathogenic (0.8147); No allele count reported in gnomAD v4.1 (AN 1,580,018).

How common is TH p.Pro324Leu (c.971C>T) in the general population?

TH p.Pro324Leu (c.971C>T) is no allele count reported in gnomAD v4.1 (AN 1,580,018) (gnomAD).

What do computational predictors say about TH p.Pro324Leu (c.971C>T)?

AlphaMissense predicts likely pathogenic (score 0.8147) — an in-silico prediction, not a clinical call.

TH p.Pro324Leu

c.971C>T · rs777379609 · VCV546656

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8147 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,580,018)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8147	likely pathogenic ✓ concordant with ClinVar
REVEL	0.916	moderately pathogenic-leaning
SaProt	LLR -12.51	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.72 · evaluated, not missing
Constraint at this position
Conservation	phyloP 11	GERP 1.8, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 7,550 bp · p 0.38 · regional, not allelic
Overall
CADD	33.0	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 P355L vs ClinVar P324L) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

No allele count reported in gnomAD v4.1 (AN 1,580,018). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: TH
Protein: p.Pro324Leu
Coding: c.971C>T
MANE Select: NM_000360
dbSNP: rs777379609
Type: single nucleotide variant
Location: chr11:2166639 (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

Similar variants

TH p.Pro324Ser Uncertain significance ★★ ⚠ 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
TH c.90+10C>T Pathogenic/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-pro324leu (accessed [today's date]).

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