Is THRB p.Arg243Trp (c.727C>T) pathogenic?

THRB p.Arg243Trp (c.727C>T) is classified Pathogenic in THRB (ClinVar, Multiple submitters, 8 submitters; last evaluated 2025-08-06). AlphaMissense: likely pathogenic (0.9085); Very rare (popmax 0.000169%, nfe); Associated with hyperthyroidism.

What condition is associated with THRB p.Arg243Trp (c.727C>T)?

THRB p.Arg243Trp (c.727C>T) is associated with hyperthyroidism, thyroid hormone resistance, generalized, autosomal dominant (ClinVar).

How common is THRB p.Arg243Trp (c.727C>T) in the general population?

THRB p.Arg243Trp (c.727C>T) is very rare (popmax 0.000169%, nfe) (gnomAD).

What do computational predictors say about THRB p.Arg243Trp (c.727C>T)?

AlphaMissense predicts likely pathogenic (score 0.9085) — an in-silico prediction, not a clinical call.

THRB p.Arg243Trp

c.727C>T · rs121918707 · VCV12567

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

AlphaMissense

likely pathogenic

0.9085 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hyperthyroidism

Computational evidence

Protein change
AlphaMissense	0.9085	likely pathogenic ✓ concordant with ClinVar
REVEL	0.811	moderately pathogenic-leaning
SaProt	LLR -14.68	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 7.2	GERP 2.1, phastCons 1
Regional constraint	o/e 0.53	unconstrained · MANE · 19 kb · p 5.8e-12 · regional, not allelic
Overall
CADD	34.0	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

Grpmax group 0.000169% European (non-Finnish) · 2/1,180,014 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,614,182 alleles · very rare

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: THRB
Protein: p.Arg243Trp
Coding: c.727C>T
dbSNP: rs121918707
Type: single nucleotide variant
Location: chr3:24143512 (GRCh38)

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

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-arg243trp (accessed [today's date]).

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