Is THRB p.Cys446Arg (c.1336T>C) pathogenic?

THRB p.Cys446Arg (c.1336T>C) is classified Pathogenic in THRB (ClinVar, Single submitter, 2 submitters; last evaluated 2022-12-12). AlphaMissense: likely pathogenic (0.9925); Absent from gnomAD v4.1; Associated with thyroid hormone resistance, generalized, autosomal dominant.

What condition is associated with THRB p.Cys446Arg (c.1336T>C)?

THRB p.Cys446Arg (c.1336T>C) is associated with thyroid hormone resistance, generalized, autosomal dominant (ClinVar).

How common is THRB p.Cys446Arg (c.1336T>C) in the general population?

THRB p.Cys446Arg (c.1336T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about THRB p.Cys446Arg (c.1336T>C)?

AlphaMissense predicts likely pathogenic (score 0.9925) — an in-silico prediction, not a clinical call.

THRB p.Cys446Arg

c.1336T>C · rs121918703 · VCV12563

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9925 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

thyroid hormone resistance, generalized, autosomal dominant

Computational evidence

Protein change
AlphaMissense	0.9925	likely pathogenic ✓ concordant with ClinVar
REVEL	0.924	moderately pathogenic-leaning
SaProt	LLR -9.30	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 11	GERP 2.1, phastCons 1
Regional constraint	o/e 0.15	constrained · MANE · 103 bp · p 5.9e-09 · regional, not allelic
Overall
CADD	28.2	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.Cys446Arg
Coding: c.1336T>C
MANE Select: NM_001354712
dbSNP: rs121918703
Type: single nucleotide variant
Location: chr3:24122934 (GRCh38)
Gene constraint: LOEUF 0.43 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 80.24 · 34 PDB
Residue 446: 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

Disease context

thyroid hormone resistance, generalized, autosomal dominant — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

THRB p.Cys446Gly Uncertain significance ★ ⚠ 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-cys446arg (accessed [today's date]).

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