Is THRB p.Ile431Met (c.1293A>G) pathogenic?

THRB p.Ile431Met (c.1293A>G) is classified Pathogenic in THRB (ClinVar, Single submitter, 2 submitters; last evaluated 2025-01-23). AlphaMissense: likely pathogenic (0.9154); Absent from gnomAD v4.1; Associated with hyperthyroidism.

What condition is associated with THRB p.Ile431Met (c.1293A>G)?

THRB p.Ile431Met (c.1293A>G) is associated with hyperthyroidism, thyroid hormone resistance, generalized, autosomal dominant (ClinVar).

How common is THRB p.Ile431Met (c.1293A>G) in the general population?

THRB p.Ile431Met (c.1293A>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about THRB p.Ile431Met (c.1293A>G)?

AlphaMissense predicts likely pathogenic (score 0.9154) — an in-silico prediction, not a clinical call.

THRB p.Ile431Met

c.1293A>G · rs1553609195 · VCV492920

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9154 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hyperthyroidism

Computational evidence

Protein change
AlphaMissense	0.9154	likely pathogenic ✓ concordant with ClinVar
REVEL	0.742	pathogenic-leaning
SaProt	LLR -8.17	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -4.3	GERP -4.1
Regional constraint	o/e 0.15	constrained · MANE · 103 bp · p 5.9e-09 · regional, not allelic
Overall
CADD	13.51	PHRED · no single calibrated threshold — expert panels disagree

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.Ile431Met
Coding: c.1293A>G
MANE Select: NM_001354712
dbSNP: rs1553609195
Type: single nucleotide variant
Location: chr3:24122977 (GRCh38)
Gene constraint: LOEUF 0.43 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 80.24 · 34 PDB
Residue 431: 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

Disease context

hyperthyroidism — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: thyroid hormone resistance, generalized, autosomal dominant

Similar variants

THRB p.Ile431Thr Likely pathogenic ★★ ⚠ same residue
THRB p.Ala268Gly Pathogenic/Likely pathogenic ★★ ⚠ same condition
THRB p.Ala317Thr Pathogenic ★★ ⚠ same condition
THRB p.Arg316His Pathogenic ★★ same condition
THRB p.Arg320Cys Pathogenic ★★ same condition
THRB p.Arg320His Pathogenic/Likely pathogenic ★★ same condition
THRB p.Arg338Trp Pathogenic ★★ same condition
THRB p.Arg383His Pathogenic/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/thrb-p-ile431met (accessed [today's date]).

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