THRB p.Ala433=
c.1299C>T · rs144206187 · VCV901811
Benign/Likely benign
Multiple submitters
Classification
Benign/Likely benign
ClinVar
Review
Multiple submitters ★★☆☆
ClinVar · 3 submitters
gnomAD v4.1
Rare
rare (popmax 0.132%, mid)
Conditions
1
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 5.2 | GERP 0.13, phastCons 1 |
| Overall | ||
| CADD | 10.13 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.132%
Middle Eastern · 8/6,062 alleles
Filtering AF
0.0656%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.0478%
Overall
0.0252%
407/1,614,198 alleles · rare
| Ancestry group | Frequency | 1 in |
|---|---|---|
| Middle Easterngrpmax | 0.132% | 758 |
| European (non-Finnish) | 0.0299% | 3,343 |
| Remaining individualsnot grpmax-eligible | 0.0256% | 3,907 |
| Admixed American | 0.0183% | 5,457 |
| South Asian | 0.0165% | 6,072 |
| African / African-American | 0.00533% | 18,763 |
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.Ala433=
- Coding
- c.1299C>T
- MANE Select
- NM_001354712
- dbSNP
- rs144206187
- Type
- single nucleotide variant
- Location
- chr3:24122971 (GRCh38)
- Gene constraint
- LOEUF 0.43 · pLI 1.00 (gnomAD)
- Structure
- AlphaFold pLDDT 80.24 · 34 PDB
- Residue 433
- the nr lbd domain; the 'interaction with nr2f6' region; an α-helix
Similar variants
- 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
- THRB p.Arg429Gln 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-ala433 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown