Is GNAS p.Pro441= (c.1323C>T) pathogenic?

GNAS p.Pro441= (c.1323C>T) is classified Uncertain significance in GNAS (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-10-16). Very rare (popmax 0.00189%, amr); Associated with pseudohypoparathyroidism type 1B.

What condition is associated with GNAS p.Pro441= (c.1323C>T)?

GNAS p.Pro441= (c.1323C>T) is associated with pseudohypoparathyroidism type 1B, pseudohypoparathyroidism type 1A, progressive osseous heteroplasia (ClinVar).

How common is GNAS p.Pro441= (c.1323C>T) in the general population?

GNAS p.Pro441= (c.1323C>T) is very rare (popmax 0.00189%, amr) (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.Pro441=

c.1323C>T · rs146744182 · VCV930718

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00189%, amr)

Conditions

pseudohypoparathyroidism type 1B

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.044	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -15	GERP -2.6
Overall
CADD	0.464	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00189% Admixed American · 1/52,936 alleles

Filtering AF 0.00051% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000373%

Overall 0.000774% 12/1,550,382 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00189%	52,936
European (non-Finnish)	0.000951%	105,161

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.Pro441=
Coding: c.1323C>T
MANE Select: NM_000516 · reported on NM_080425
dbSNP: rs146744182
Type: single nucleotide variant
Location: chr20:58854588 (GRCh38)
Gene constraint: LOEUF 0.302 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 59.47 · 200 PDB
Residue 441: 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

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

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.432+1G>A Pathogenic ★★ same condition
GNAS c.433-2A>C Pathogenic/Likely pathogenic ★★ same condition
GNAS p.Arg165Cys 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

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-pro441 (accessed [today's date]).

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