Is GNAS p.Pro192= (c.576G>T) pathogenic?

GNAS p.Pro192= (c.576G>T) is classified Likely benign in GNAS (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-11-01). Very rare (popmax 0.00348%, nfe); Associated with McCune-Albright syndrome.

What condition is associated with GNAS p.Pro192= (c.576G>T)?

GNAS p.Pro192= (c.576G>T) is associated with McCune-Albright syndrome, pseudohypoparathyroidism type 1A, progressive osseous heteroplasia (ClinVar).

How common is GNAS p.Pro192= (c.576G>T) in the general population?

GNAS p.Pro192= (c.576G>T) is very rare (popmax 0.00348%, nfe) (gnomAD).

How is McCune-Albright syndrome inherited?

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

GNAS p.Pro192=

c.576G>T · rs558915293 · VCV1299925

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00348%, nfe)

Conditions

McCune-Albright syndrome

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 0.071	GERP -3.8, phastCons 0.52
Overall
CADD	11.0	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00348% European (non-Finnish) · 41/1,179,844 alleles

Filtering AF 0.00259% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00233%

Overall 0.00254% 41/1,613,814 alleles · very rare exomes 40/1,461,672 · genomes 1/152,142 · joint denominator

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.Pro192=
Coding: c.576G>T
MANE Select: NM_000516
dbSNP: rs558915293
Type: single nucleotide variant
Location: chr20:58909207 (GRCh38)
Gene constraint: LOEUF 0.302 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 59.47 · 200 PDB
Residue 192: the 'disordered' region; the g-alpha domain

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.Glu192Gln Uncertain significance ★ same residue
GNAS p.Pro192Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
GNAS p.Pro192Thr Uncertain significance ★ ⚠ same residue
GNAS p.Glu192Gly Uncertain significance 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

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-pro192 (accessed [today's date]).

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