TSHR p.Ala705=
c.2115A>C · rs375078827 · VCV2789737
Likely benign
Single submitter
Classification
Likely benign
ClinVar
Review
Single submitter ★☆☆☆
ClinVar · 1 submitter
gnomAD v4.1
Rare
ultra-rare (popmax 0.0164%, mid)
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 -0.52 | GERP -5.5 |
| Overall | ||
| CADD | 4.459 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.0164%
Middle Eastern · 1/6,084 alleles
Filtering AF
7.9e-05%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 5.4e-05%
Overall
0.00031%
5/1,613,964 alleles · ultra-rare
| Ancestry group | Frequency | 1 in |
|---|---|---|
| Middle Easterngrpmax | 0.0164% | 6,084 |
| European (non-Finnish) | 0.000339% | 294,989 |
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.Ala705=
- Coding
- c.2115A>C
- MANE Select
- NM_000369
- dbSNP
- rs375078827
- Type
- single nucleotide variant
- Location
- chr14:81144173 (GRCh38)
- Gene constraint
- LOEUF 1.012 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 73.67 · 9 PDB
Similar variants
- 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
- TSHR p.Cys390Trp 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-ala705 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown