Is GNAS p.Asp223= (c.669C>T) pathogenic?

GNAS p.Asp223= (c.669C>T) is classified Likely benign in GNAS (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-02). Ultra-rare (popmax 0.025%, amr).

How common is GNAS p.Asp223= (c.669C>T) in the general population?

GNAS p.Asp223= (c.669C>T) is ultra-rare (popmax 0.025%, amr) (gnomAD).

GNAS p.Asp223=

c.669C>T · rs779338481 · VCV1574124

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.025%, 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 -1.1	GERP -3.8, phastCons 0.002
Overall
CADD	12.21	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.025% Admixed American · 15/60,034 alleles

Filtering AF 0.0153% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0124%

Overall 0.00254% 41/1,614,160 alleles · ultra-rare exomes 33/1,461,824 · genomes 8/152,336 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.025%	4,002
African / African-American	0.00933%	10,722
European (non-Finnish)	0.00153%	65,554
South Asian	0.0011%	91,086

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.Asp223=
Coding: c.669C>T
MANE Select: NM_000516
dbSNP: rs779338481
Type: single nucleotide variant
Location: chr20:58909530 (GRCh38)
Gene constraint: LOEUF 0.302 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 59.47 · 200 PDB
Residue 223: the 'disordered' region; a binding site; the g-alpha domain; the 'g3 motif' region; a β-strand

Full GNAS gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

GNAS p.Asp223Gly Uncertain significance ★ ⚠ same residue
GNAS p.Asp223Val Uncertain significance ★ ⚠ same residue
GNAS p.Thr223= Uncertain significance ★ same residue
GNAS p.Lys223= Likely benign same residue
GNAS p.Asp223Ter Likely 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

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-asp223 (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown