THRB p.Met442Arg
c.1325T>G · VCV3572086
Uncertain significance
Single submitter
Classification
Uncertain significance
ClinVar
Review
Single submitter ★☆☆☆
ClinVar · 1 submitter
AlphaMissense
likely pathogenic
0.9896 · ACMG-weighted
gnomAD v4.1
Absent
absent from gnomAD v4.1
Missense predictors
2/3 damaging
AlphaMissense, REVEL, SaProt
Computational evidence
| Protein change | ||
| AlphaMissense | 0.9896 | likely pathogenic |
|---|---|---|
| REVEL | 0.936 | strongly pathogenic-leaning |
| SaProt | LLR -9.22 | 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 11 | GERP 2.1, phastCons 1 |
| Regional constraint | o/e 0.15 | constrained · MANE · 103 bp · p 5.9e-09 · regional, not allelic |
| Overall | ||
| CADD | 25.5 | 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
Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.
Variant & gene context
- Gene
- THRB
- Protein
- p.Met442Arg
- Coding
- c.1325T>G
- MANE Select
- NM_001354712
- Type
- single nucleotide variant
- Location
- chr3:24122945 (GRCh38)
- Gene constraint
- LOEUF 0.43 · pLI 1.00 (gnomAD)
- Structure
- AlphaFold pLDDT 80.24 · 34 PDB
- Residue 442
- the nr lbd domain; a UniProt-annotated variant site (in grthd); the 'interaction with nr2f6' region; an α-helix
Similar variants
- THRB p.Met442Val Likely pathogenic ★★ ⚠ same residue
- THRB p.Met442Thr Likely pathogenic ★ ⚠ same residue
- THRB p.Met442_Lys443delinsIleTer Pathogenic ★ same residue
- PRSS1 p.Asn29Thr Pathogenic ★★ ⚠ same type
- PRSS1 p.Lys23Arg Likely pathogenic ★★ ⚠ same type
- THRB p.Ala268Gly Pathogenic/Likely pathogenic ★★ ⚠ same type
- THRB p.Ala317Thr Pathogenic ★★ ⚠ same type
- THRB p.Arg316His Pathogenic ★★ same type
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-met442arg (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown