Is THRB p.Arg383His (c.1148G>A) pathogenic?

THRB p.Arg383His (c.1148G>A) is classified Pathogenic/Likely pathogenic in THRB (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-10-10). AlphaMissense: likely pathogenic (0.9768); Very rare (popmax 8.47e-05%, nfe); Associated with THRB-related disorder.

What condition is associated with THRB p.Arg383His (c.1148G>A)?

THRB p.Arg383His (c.1148G>A) is associated with THRB-related disorder, thyroid hormone resistance, generalized, autosomal dominant (ClinVar).

How common is THRB p.Arg383His (c.1148G>A) in the general population?

THRB p.Arg383His (c.1148G>A) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about THRB p.Arg383His (c.1148G>A)?

AlphaMissense predicts likely pathogenic (score 0.9768) — an in-silico prediction, not a clinical call.

THRB p.Arg383His

c.1148G>A · rs121918708 · VCV12568

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.9768 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

THRB-related disorder

Computational evidence

Protein change
AlphaMissense	0.9768	likely pathogenic ✓ concordant with ClinVar
REVEL	0.929	moderately pathogenic-leaning
SaProt	LLR -12.34	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 7.7	GERP 2.1, phastCons 1
Regional constraint	o/e 0.29	constrained · MANE · 10 kb · p 5.8e-19 · regional, not allelic
Overall
CADD	32.0	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 8.47e-05% European (non-Finnish) · 1/1,180,024 alleles

Overall 0.000658% 1/151,984 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.Arg383His
Coding: c.1148G>A
MANE Select: NM_001354712
dbSNP: rs121918708
Type: single nucleotide variant
Location: chr3:24123122 (GRCh38)
Gene constraint: LOEUF 0.43 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 80.24 · 34 PDB
Residue 383: the nr lbd domain; the 'interaction with nr2f6' region; a β-strand

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

Disease context

THRB-related disorder

Also linked: thyroid hormone resistance, generalized, autosomal dominant

Similar variants

THRB p.Arg383Ser Uncertain significance ★ ⚠ same residue
THRB p.Arg383Cys Conflicting classifications of pathogenicity ★ ⚠ 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

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-arg383his (accessed [today's date]).

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