Is THRB p.Pro447Leu (c.1340C>T) pathogenic?

THRB p.Pro447Leu (c.1340C>T) is classified Uncertain significance in THRB (ClinVar, Single submitter, 1 submitter; last evaluated 2018-05-15). AlphaMissense: likely pathogenic (0.9614); Absent from gnomAD v4.1.

How common is THRB p.Pro447Leu (c.1340C>T) in the general population?

THRB p.Pro447Leu (c.1340C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about THRB p.Pro447Leu (c.1340C>T)?

AlphaMissense predicts likely pathogenic (score 0.9614) — an in-silico prediction, not a clinical call.

THRB p.Pro447Leu

c.1340C>T · rs865994135 · VCV619917

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9614 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9614	likely pathogenic
REVEL	0.787	moderately pathogenic-leaning
SaProt	LLR -12.87	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 10	GERP 2.1, phastCons 1
Regional constraint	o/e 0.15	constrained · MANE · 103 bp · p 5.9e-09 · regional, not allelic
Overall
CADD	29.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

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: THRB
Protein: p.Pro447Leu
Coding: c.1340C>T
MANE Select: NM_001354712
dbSNP: rs865994135
Type: single nucleotide variant
Location: chr3:24122930 (GRCh38)
Gene constraint: LOEUF 0.43 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 80.24 · 34 PDB
Residue 447: the nr lbd domain; a UniProt-annotated variant site (in grthd); the 'interaction with nr2f6' region

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

Similar variants

PRSS1 p.Asn29Thr Pathogenic ★★ ⚠ same type
PRSS1 p.Lys23Arg Likely pathogenic ★★ ⚠ same type
THRB p.Ala268Gly Pathogenic/Likely pathogenic ★★ same type
THRB p.Ala317Thr Pathogenic ★★ same type
THRB p.Arg316His Pathogenic ★★ same type
THRB p.Arg320Cys Pathogenic ★★ same type
THRB p.Arg320His Pathogenic/Likely pathogenic ★★ same type
THRB p.Arg338Trp 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/thrb-p-pro447leu (accessed [today's date]).

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