Is GNAS p.Pro179= (c.537G>A) pathogenic?

GNAS p.Pro179= (c.537G>A) is classified Likely benign in GNAS (ClinVar, Multiple submitters, 7 submitters; last evaluated 2025-11-01). Rare (popmax 0.436%, sas); Associated with pseudohypoparathyroidism type 1C.

What condition is associated with GNAS p.Pro179= (c.537G>A)?

GNAS p.Pro179= (c.537G>A) is associated with pseudohypoparathyroidism type 1C, pseudohypoparathyroidism type 1A, progressive osseous heteroplasia (ClinVar).

How common is GNAS p.Pro179= (c.537G>A) in the general population?

GNAS p.Pro179= (c.537G>A) is rare (popmax 0.436%, sas) (gnomAD).

How is Pseudohypoparathyroidism type 1C inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

GNAS p.Pro179=

c.537G>A · rs181594534 · VCV1284575

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

rare (popmax 0.436%, sas)

Conditions

pseudohypoparathyroidism type 1C

⚠ Built without this gene's context — gene constraint and dosage, protein structure, pathways, panels and related-variant links were not looked up for this page. why

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.151	moderately benign-leaning
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 4.1	GERP -0.74, phastCons 1
Overall
CADD	12.04	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.436% South Asian · 397/91,020 alleles

Filtering AF 0.401% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.387%

Overall 0.0268% 431/1,606,386 alleles · rare exomes 414/1,454,210 · genomes 17/152,176 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.436%	229
Remaining individualsnot grpmax-eligible	0.0401%	2,495
Middle Eastern	0.0165%	6,052
East Asian	0.0112%	8,957
Admixed American	0.00167%	59,856
African / African-American	0.00134%	74,882
European (non-Finnish)	8.48e-05%	1,178,837

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.Pro179=
Coding: c.537G>A
MANE Select: NM_000516 · reported on NM_016592
dbSNP: rs181594534
Type: single nucleotide variant
Location: chr20:58840643 (GRCh38)

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

Disease context

pseudohypoparathyroidism type 1C — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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

For Pseudohypoparathyroidism type 1C (Orphanet):

Inheritance: Autosomal dominant
Onset: Childhood, Infancy, Neonatal

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-pro179 (accessed [today's date]).

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