Is THRB p.Pro453Ala (c.1357C>G) pathogenic?

THRB p.Pro453Ala (c.1357C>G) is classified Pathogenic/Likely pathogenic in THRB (ClinVar, Multiple submitters, 8 submitters; last evaluated 2025-12-30). AlphaMissense: likely pathogenic (0.7133); Very rare (popmax 0.00223%, eas); Associated with THRB-related disorder.

What condition is associated with THRB p.Pro453Ala (c.1357C>G)?

THRB p.Pro453Ala (c.1357C>G) is associated with THRB-related disorder, thyroid hormone resistance, generalized, autosomal dominant (ClinVar).

How common is THRB p.Pro453Ala (c.1357C>G) in the general population?

THRB p.Pro453Ala (c.1357C>G) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about THRB p.Pro453Ala (c.1357C>G)?

AlphaMissense predicts likely pathogenic (score 0.7133) — an in-silico prediction, not a clinical call.

THRB p.Pro453Ala

c.1357C>G · rs28933408 · VCV492924

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

AlphaMissense

likely pathogenic

0.7133 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

THRB-related disorder

Computational evidence

Protein change
AlphaMissense	0.7133	likely pathogenic ✓ concordant with ClinVar
REVEL	0.903	moderately pathogenic-leaning
SaProt	LLR -9.93	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 12	GERP 2.1, phastCons 1
Regional constraint	o/e 0.15	constrained · MANE · 103 bp · p 5.9e-09 · regional, not allelic
Overall
CADD	26.1	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 0.00223% East Asian · 1/44,896 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000496% 8/1,614,162 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,608
Finnishnot grpmax-eligible	0.00312%	32,015
East Asiangrpmax	0.00223%	44,896
European (non-Finnish)	0.000339%	295,008

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro453Ala
Coding: c.1357C>G
MANE Select: NM_001354712
dbSNP: rs28933408
Type: single nucleotide variant
Location: chr3:24122913 (GRCh38)
Gene constraint: LOEUF 0.43 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 80.24 · 34 PDB
Residue 453: the nr lbd domain; an α-helix; 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

THRB-related disorder

Also linked: thyroid hormone resistance, generalized, autosomal dominant

Similar variants

THRB p.Pro453Ser Pathogenic ★★ same residue
THRB p.Pro453Thr Pathogenic ★★ same residue
THRB p.Pro453Leu Likely pathogenic ★ same residue
THRB p.Pro453His Pathogenic same residue
THRB p.Pro453Asn Likely pathogenic ★★ same residue
THRB p.Ala268Gly Pathogenic/Likely pathogenic ★★ ⚠ same condition
THRB p.Ala317Thr Pathogenic ★★ ⚠ same condition
THRB p.Arg316His 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-pro453ala (accessed [today's date]).

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