Is GNAS p.Pro58Ser (c.172C>T) pathogenic?

GNAS p.Pro58Ser (c.172C>T) is classified Uncertain significance in GNAS (ClinVar, Single submitter, 1 submitter; last evaluated 2026-03-25). AlphaMissense: likely benign (0.111); Very rare (popmax 0.00337%, amr); Associated with pseudopseudohypoparathyroidism.

What condition is associated with GNAS p.Pro58Ser (c.172C>T)?

GNAS p.Pro58Ser (c.172C>T) is associated with pseudopseudohypoparathyroidism (ClinVar).

How common is GNAS p.Pro58Ser (c.172C>T) in the general population?

GNAS p.Pro58Ser (c.172C>T) is very rare (popmax 0.00337%, amr) (gnomAD).

How is Pseudopseudohypoparathyroidism inherited?

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

What do computational predictors say about GNAS p.Pro58Ser (c.172C>T)?

AlphaMissense predicts likely benign (score 0.111) — an in-silico prediction, not a clinical call.

GNAS p.Pro58Ser

c.172C>T · VCV4974637

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.111 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00337%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

pseudopseudohypoparathyroidism

Computational evidence

Protein change
AlphaMissense	0.111	likely benign
REVEL	0.329	indeterminate
SaProt	LLR -6.63	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.4	GERP -0.48, phastCons 1
Overall
CADD	19.94	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00337% Admixed American · 2/59,374 alleles

Filtering AF 0.000559% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000209%

Overall 0.000187% 3/1,607,528 alleles · very rare exomes 2/1,455,336 · genomes 1/152,192 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00337%	29,687
European (non-Finnish)	8.49e-05%	1,177,270

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.Pro58Ser
Coding: c.172C>T
MANE Select: NM_000516 · reported on NM_080425
Type: single nucleotide variant
Location: chr20:58853437 (GRCh38)
Gene constraint: LOEUF 0.302 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 59.47 · 200 PDB
Residue 58: the g-alpha domain; an α-helix; the 'disordered' region

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

Disease context

pseudopseudohypoparathyroidism — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Pseudopseudohypoparathyroidism (Orphanet):

Inheritance: Autosomal dominant
Onset: All ages

Similar variants

GNAS c.432+1G>A Pathogenic ★★ same condition
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GNAS p.Arg201His Pathogenic/Likely pathogenic ★★ same condition
GNAS p.Arg231Cys Pathogenic/Likely pathogenic ★★ same condition
GNAS p.Arg342Ter Pathogenic ★★ same condition
GNAS p.Gln12Ter Pathogenic ★★ same condition
GNAS p.Gln29Ter Pathogenic ★★ same condition
GNAS p.Gln31Ter 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-pro58ser (accessed [today's date]).

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