Is THRB p.Ala231= (c.693G>A) pathogenic?

THRB p.Ala231= (c.693G>A) is classified Uncertain significance in THRB (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-13). Very rare (popmax 0.00322%, nfe); Associated with thyroid hormone resistance, generalized, autosomal dominant.

What condition is associated with THRB p.Ala231= (c.693G>A)?

THRB p.Ala231= (c.693G>A) is associated with thyroid hormone resistance, generalized, autosomal dominant (ClinVar).

How common is THRB p.Ala231= (c.693G>A) in the general population?

THRB p.Ala231= (c.693G>A) is very rare (popmax 0.00322%, nfe) (gnomAD).

THRB p.Ala231=

c.693G>A · rs115360190 · VCV902713

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00322%, nfe)

Conditions

thyroid hormone resistance, generalized, autosomal dominant

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.2	GERP -3.4, phastCons 1
Overall
CADD	9.868	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00322% European (non-Finnish) · 38/1,180,038 alleles

Filtering AF 0.00239% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0021%

Overall 0.00254% 41/1,614,188 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00322%	31,054
East Asian	0.00223%	44,880
Remaining individualsnot grpmax-eligible	0.0016%	62,508
African / African-American	0.00133%	75,056

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.Ala231=
Coding: c.693G>A
MANE Select: NM_001354712
dbSNP: rs115360190
Type: single nucleotide variant
Location: chr3:24143546 (GRCh38)
Gene constraint: LOEUF 0.43 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 80.24 · 34 PDB
Residue 231: the nr lbd domain

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

PRSS1 p.Lys231Asn 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-ala231 (accessed [today's date]).

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