TSHR p.Phe423=
c.1269C>T · rs780475606 · VCV2891092
Likely benign
Single submitter
Classification
Likely benign
ClinVar
Review
Single submitter ★☆☆☆
ClinVar · 1 submitter
gnomAD v4.1
Rare
very rare (popmax 0.00333%, amr)
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 0.32 | GERP -0.13, phastCons 1 |
| Overall | ||
| CADD | 8.409 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.00333%
Admixed American · 2/59,994 alleles
Filtering AF
0.000553%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.000207%
Overall
0.000434%
7/1,614,010 alleles · very rare
| Ancestry group | Frequency | 1 in |
|---|---|---|
| Admixed Americangrpmax | 0.00333% | 29,997 |
| East Asian | 0.00223% | 44,890 |
| Remaining individualsnot grpmax-eligible | 0.0016% | 62,490 |
| South Asian | 0.0011% | 91,078 |
| European (non-Finnish) | 0.000169% | 590,026 |
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
- TSHR
- Protein
- p.Phe423=
- Coding
- c.1269C>T
- MANE Select
- NM_000369
- dbSNP
- rs780475606
- Type
- single nucleotide variant
- Location
- chr14:81143327 (GRCh38)
- Gene constraint
- LOEUF 1.012 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 73.67 · 9 PDB
- Residue 423
- an α-helix
Similar variants
- TSHR p.Phe423Tyr Uncertain significance ★ ⚠ same residue
- TSHR c.881+1G>A Pathogenic/Likely pathogenic ★★ same type
- TSHR c.881+1G>T Pathogenic/Likely pathogenic ★★ same type
- TSHR p.Ala553Thr Pathogenic/Likely pathogenic ★★ same type
- TSHR p.Arg109Gln Pathogenic/Likely pathogenic ★★ ⚠ same type
- TSHR p.Arg450His Pathogenic/Likely pathogenic ★★ ⚠ same type
- TSHR p.Arg519Cys Pathogenic ★★ same type
- TSHR p.Arg519His Pathogenic/Likely 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/tshr-p-phe423 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown