Is THRB p.Leu341Pro (c.1022T>C) pathogenic?

THRB p.Leu341Pro (c.1022T>C) is classified Uncertain significance in THRB (ClinVar, Single submitter, 1 submitter; last evaluated 2019-12-06). AlphaMissense: likely pathogenic (0.9999); Absent from gnomAD v4.1.

How common is THRB p.Leu341Pro (c.1022T>C) in the general population?

THRB p.Leu341Pro (c.1022T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about THRB p.Leu341Pro (c.1022T>C)?

AlphaMissense predicts likely pathogenic (score 0.9999) — an in-silico prediction, not a clinical call.

THRB p.Leu341Pro

c.1022T>C · rs2033110557 · VCV993157

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9999 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9999	likely pathogenic · top 8% in THRB
REVEL	0.975	strongly pathogenic-leaning
SaProt	LLR -13.33	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 11	GERP 2.1, phastCons 1
Regional constraint	o/e 0.29	constrained · MANE · 10 kb · p 5.8e-19 · regional, not allelic
Overall
CADD	33.0	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.Leu341Pro
Coding: c.1022T>C
MANE Select: NM_001354712
dbSNP: rs2033110557
Type: single nucleotide variant
Location: chr3:24127621 (GRCh38)
Gene constraint: LOEUF 0.43 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 80.24 · 34 PDB
Residue 341: the nr lbd domain; a UniProt-annotated variant site (in grthd); the 'interaction with nr2f6' region; an α-helix

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

Similar variants

THRB p.Leu341Val Likely pathogenic ★ same residue
THRB p.Leu341Gln Uncertain significance ★ same residue
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

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-leu341pro (accessed [today's date]).

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