Is GNAS p.Pro474= (c.1422C>T) pathogenic?

GNAS p.Pro474= (c.1422C>T) is classified Uncertain significance in GNAS (ClinVar, Single submitter, 2 submitters; last evaluated 2017-06-28). Ultra-rare (popmax 0.0325%, afr); Associated with pseudopseudohypoparathyroidism.

What condition is associated with GNAS p.Pro474= (c.1422C>T)?

GNAS p.Pro474= (c.1422C>T) is associated with pseudopseudohypoparathyroidism (ClinVar).

How common is GNAS p.Pro474= (c.1422C>T) in the general population?

GNAS p.Pro474= (c.1422C>T) is ultra-rare (popmax 0.0325%, afr) (gnomAD).

How is Pseudopseudohypoparathyroidism inherited?

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

GNAS p.Pro474=

c.1422C>T · rs532475771 · VCV584449

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0325%, afr)

Conditions

pseudopseudohypoparathyroidism

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.015	strongly benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -4.1	GERP -2.1
Overall
CADD	0.942	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0325% African / African-American · 23/70,790 alleles

Filtering AF 0.0222% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0188%

Overall 0.00177% 27/1,525,254 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0325%	3,078
Admixed American	0.00201%	49,640
European (non-Finnish)	0.000262%	381,054

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.Pro474=
Coding: c.1422C>T
MANE Select: NM_000516 · reported on NM_080425
dbSNP: rs532475771
Type: single nucleotide variant
Location: chr20:58854687 (GRCh38)
Gene constraint: LOEUF 0.302 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 59.47 · 200 PDB
Residue 474: 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 p.Pro474Ser Uncertain significance ⚠ same residue
GNAS c.432+1G>A Pathogenic ★★ same condition
GNAS c.433-2A>C Pathogenic/Likely pathogenic ★★ same condition
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

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-pro474 (accessed [today's date]).

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