Is GNAS p.Arg258Pro (c.773G>C) pathogenic?

GNAS p.Arg258Pro (c.773G>C) is classified Likely pathogenic in GNAS (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-28). AlphaMissense: likely pathogenic (0.997); Absent from gnomAD v4.1; Associated with pseudohypoparathyroidism type 1A.

What condition is associated with GNAS p.Arg258Pro (c.773G>C)?

GNAS p.Arg258Pro (c.773G>C) is associated with pseudohypoparathyroidism type 1A (ClinVar).

How common is GNAS p.Arg258Pro (c.773G>C) in the general population?

GNAS p.Arg258Pro (c.773G>C) is absent from gnomAD v4.1 (gnomAD).

How is Pseudohypoparathyroidism type 1A inherited?

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

What do computational predictors say about GNAS p.Arg258Pro (c.773G>C)?

AlphaMissense predicts likely pathogenic (score 0.997) — an in-silico prediction, not a clinical call.

GNAS p.Arg258Pro

c.773G>C · rs1555891584 · VCV3571461

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.997 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

pseudohypoparathyroidism type 1A

Computational evidence

Protein change
AlphaMissense	0.997	likely pathogenic ✓ concordant with ClinVar · top 7% in GNAS
REVEL	0.875	moderately pathogenic-leaning
SaProt	LLR -14.22	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.16	constrained · MANE · 1,269 bp · p 5.6e-36 · regional, not allelic
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R901P vs ClinVar R258P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: GNAS
Protein: p.Arg258Pro
Coding: c.773G>C
MANE Select: NM_000516
dbSNP: rs1555891584
Type: single nucleotide variant
Location: chr20:58909738 (GRCh38)
Gene constraint: LOEUF 0.302 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 59.47 · 200 PDB
Residue 901 UniProt numbering: the g-alpha domain

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

Disease context

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

For Pseudohypoparathyroidism type 1A (Orphanet):

Inheritance: Autosomal dominant
Onset: Childhood, Infancy, Neonatal

Similar variants

GNAS p.Arg258Leu Pathogenic ★ same residue
GNAS p.Arg258Trp Conflicting classifications of pathogenicity ★ ⚠ same residue
GNAS p.Arg258Gln Pathogenic/Likely pathogenic ★★ same residue
GNAS p.Val258= Likely benign same residue
GNAS c.433-2A>C Pathogenic/Likely pathogenic ★★ same condition
GNAS p.Arg165Cys Pathogenic ★★ same condition
GNAS p.Arg201His Pathogenic/Likely pathogenic ★★ same condition
GNAS p.Arg228Cys 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-arg258pro (accessed [today's date]).

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