Is GNAS p.Arg228= (c.684C>T) pathogenic?

GNAS p.Arg228= (c.684C>T) is classified Likely benign in GNAS (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-12-02). Very rare (popmax 0.00988%, sas); Associated with McCune-Albright syndrome.

What condition is associated with GNAS p.Arg228= (c.684C>T)?

GNAS p.Arg228= (c.684C>T) is associated with McCune-Albright syndrome, pseudohypoparathyroidism type 1A, progressive osseous heteroplasia (ClinVar).

How common is GNAS p.Arg228= (c.684C>T) in the general population?

GNAS p.Arg228= (c.684C>T) is very rare (popmax 0.00988%, sas) (gnomAD).

How is McCune-Albright syndrome inherited?

Typically Not applicable (Orphanet). A genetic counselor can assess individual risk for a family.

GNAS p.Arg228=

c.684C>T · rs147984566 · VCV744959

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00988%, sas)

Conditions

McCune-Albright syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -9.7	GERP -3.8
Overall
CADD	0.926	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00988% South Asian · 9/91,090 alleles

Filtering AF 0.00639% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00592%

Overall 0.00638% 103/1,614,016 alleles · very rare exomes 98/1,461,854 · genomes 5/152,162 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00988%	10,121
European (non-Finnish)	0.00771%	12,967
East Asian	0.00223%	44,900
Remaining individualsnot grpmax-eligible	0.0016%	62,488
African / African-American	0.00133%	74,908

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.Arg228=
Coding: c.684C>T
MANE Select: NM_000516
dbSNP: rs147984566
Type: single nucleotide variant
Location: chr20:58909545 (GRCh38)
Gene constraint: LOEUF 0.302 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 59.47 · 200 PDB
Residue 228: the 'disordered' region; the g-alpha domain; the 'g3 motif' region; an α-helix

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

Disease context

McCune-Albright syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: pseudohypoparathyroidism type 1A progressive osseous heteroplasia pseudohypoparathyroidism type 1B pseudohypoparathyroidism type 1C pseudopseudohypoparathyroidism ACTH-independent macronodular adrenal hyperplasia 1 pituitary adenoma 3, multiple types

For McCune-Albright syndrome (Orphanet):

Inheritance: Not applicable
Onset: Childhood
Prevalence: 1-9 / 1 000 000 (Europe)

Similar variants

GNAS p.Arg228Cys Pathogenic ★★ same residue
GNAS p.Arg228His Uncertain significance ★★ ⚠ same residue
GNAS p.Arg228Ser Likely pathogenic ★ same residue
GNAS c.139+1G>C Pathogenic ★★ same condition
GNAS c.432+1G>A Pathogenic ★★ same condition
GNAS c.433-2A>C Pathogenic/Likely pathogenic ★★ same condition
GNAS p.Arg165Cys Pathogenic ★★ same condition
GNAS p.Arg201Cys Pathogenic/Likely pathogenic ★★ same condition

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-arg228 (accessed [today's date]).

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