Is THRB p.Arg46His (c.137G>A) pathogenic?

THRB p.Arg46His (c.137G>A) is classified Likely benign in THRB (ClinVar, Single submitter, 1 submitter; last evaluated 2026-03-16). AlphaMissense: likely benign (0.0723); Ultra-rare (popmax 0.0165%, mid); Associated with thyroid hormone resistance, generalized, autosomal recessive.

What condition is associated with THRB p.Arg46His (c.137G>A)?

THRB p.Arg46His (c.137G>A) is associated with thyroid hormone resistance, generalized, autosomal recessive (ClinVar).

How common is THRB p.Arg46His (c.137G>A) in the general population?

THRB p.Arg46His (c.137G>A) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about THRB p.Arg46His (c.137G>A)?

AlphaMissense predicts likely benign (score 0.0723) — an in-silico prediction, not a clinical call.

THRB p.Arg46His

c.137G>A · VCV4819971

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0723 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

thyroid hormone resistance, generalized, autosomal recessive

Computational evidence

Protein change
AlphaMissense	0.0723	likely benign
REVEL	0.24	benign-leaning
SaProt	LLR -6.36	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.4	GERP 0.6, phastCons 1
Regional constraint	o/e 1.21	unconstrained · MANE · 76 kb · p 0.02 · regional, not allelic
Overall
CADD	16.22	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 0.0165% Middle Eastern · 1/6,062 alleles

Filtering AF 0.00623% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00467%

Overall 0.00229% 37/1,614,052 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,062
African / African-American	0.012%	8,335
East Asian	0.00446%	22,436
Remaining individualsnot grpmax-eligible	0.0032%	31,254
European (non-Finnish)	0.00178%	56,190
Admixed American	0.00167%	59,996
South Asian	0.0011%	91,076

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.Arg46His
Coding: c.137G>A
MANE Select: NM_001354712
Type: single nucleotide variant
Location: chr3:24190220 (GRCh38)
Gene constraint: LOEUF 0.43 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 80.24 · 34 PDB
Residue 46: the 'modulating' region

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

Disease context

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

Similar variants

PRSS1 p.His46Arg Uncertain significance ★ ⚠ same residue
THRB p.Arg46Cys Uncertain significance ★ ⚠ same residue
THRB p.Ala268Gly Pathogenic/Likely pathogenic ★★ ⚠ same condition
THRB p.Arg320Cys Pathogenic ★★ same condition
THRB p.Arg338Trp Pathogenic ★★ same condition
THRB p.Lys50Gln Uncertain significance ★★ ⚠ same condition
THRB p.Ile59Val Benign/Likely benign ★★ same condition
PRSS1 p.His46del Uncertain significance ★ same residue

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-arg46his (accessed [today's date]).

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