Is GNAS p.Pro335= (c.1005G>T) pathogenic?

GNAS p.Pro335= (c.1005G>T) is classified Uncertain significance in GNAS (ClinVar, Single submitter, 1 submitter; last evaluated 2019-01-01). Very rare (popmax 0.00223%, eas); Associated with pseudohypoparathyroidism type 1B.

What condition is associated with GNAS p.Pro335= (c.1005G>T)?

GNAS p.Pro335= (c.1005G>T) is associated with pseudohypoparathyroidism type 1B (ClinVar).

How common is GNAS p.Pro335= (c.1005G>T) in the general population?

GNAS p.Pro335= (c.1005G>T) is very rare (popmax 0.00223%, eas) (gnomAD).

How is Pseudohypoparathyroidism type 1B inherited?

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

GNAS p.Pro335=

c.1005G>T · rs536976542 · VCV982908

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Conditions

pseudohypoparathyroidism type 1B

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.066	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.8	GERP 1.8, phastCons 1
Overall
CADD	22.0	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,768 alleles

Overall 0.000657% 1/152,312 alleles · very rare

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.Pro335=
Coding: c.1005G>T
MANE Select: NM_000516 · reported on NM_080425
dbSNP: rs536976542
Type: single nucleotide variant
Location: chr20:58854270 (GRCh38)
Gene constraint: LOEUF 0.302 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 59.47 · 200 PDB
Residue 335: an α-helix; the g-alpha domain; the 'disordered' region

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

Disease context

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

For Pseudohypoparathyroidism type 1B (Orphanet):

Inheritance: Autosomal dominant, Not applicable
Onset: Adolescent, Childhood, Infancy, Neonatal

Similar variants

GNAS c.139+1G>C Pathogenic ★★ same condition
GNAS c.433-2A>C Pathogenic/Likely pathogenic ★★ same condition
GNAS p.Arg201Cys Pathogenic/Likely pathogenic ★★ same condition
GNAS p.Arg201His Pathogenic/Likely pathogenic ★★ same condition
GNAS p.Arg228Cys Pathogenic ★★ same condition
GNAS p.Arg231Cys Pathogenic/Likely pathogenic ★★ same condition
GNAS p.Arg342Ter Pathogenic ★★ same condition
GNAS p.Gln12Ter 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-pro335 (accessed [today's date]).

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