GNAS p.Ala366=
c.1098T>C · VCV3680568
Likely benign
Multiple submitters
Classification
Likely benign
ClinVar
Review
Multiple submitters ★★☆☆
ClinVar · 2 submitters
gnomAD v4.1
Rare
very rare (popmax 0.00223%, eas)
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 -3.7 | GERP -2.9 |
| Overall | ||
| CADD | 6.783 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.00223%
East Asian · 1/44,884 alleles
Filtering AF
6.8e-05%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 1.9e-05%
Overall
0.000372%
6/1,614,076 alleles · very rare
exomes 6/1,461,768 · genomes 0/152,308 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| East Asiangrpmax | 0.00223% | 44,884 |
| Remaining individualsnot grpmax-eligible | 0.0016% | 62,504 |
| African / African-American | 0.00133% | 75,052 |
| European (non-Finnish) | 0.000254% | 393,307 |
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
- GNAS
- Protein
- p.Ala366=
- Coding
- c.1098T>C
- MANE Select
- NM_000516
- Type
- single nucleotide variant
- Location
- chr20:58910742 (GRCh38)
- Gene constraint
- LOEUF 0.302 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
- Structure
- AlphaFold pLDDT 59.47 · 200 PDB
- Residue 366
- a β-strand; a binding site; the g-alpha domain; a UniProt-annotated variant site (in php1a; the patient also shows testotoxicosis; constitutively activates adenylyl cyclase in vitro; rapidly degraded at 37 degrees resulting in loss of gs activity); the 'g5 motif' region; the 'disordered' region
Similar variants
- GNAS p.Ala366Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
- GNAS p.Ala366Ser Pathogenic same residue
- GNAS c.139+1G>C Pathogenic ★★ same type
- GNAS c.139+2T>C Pathogenic ★★ same type
- GNAS c.312+5G>A Pathogenic ★★ same type
- GNAS c.432+1G>A Pathogenic ★★ same type
- GNAS c.433-2A>C Pathogenic/Likely pathogenic ★★ same type
- GNAS p.Ala102Thr 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/gnas-p-ala366 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown