Is GNAS p.Pro465= (c.1395A>C) pathogenic?

GNAS p.Pro465= (c.1395A>C) is classified Likely benign in GNAS (ClinVar, Multiple submitters, 5 submitters; last evaluated 2024-06-24). Rare (popmax 0.233%, afr); Associated with pseudohypoparathyroidism type 1C.

What condition is associated with GNAS p.Pro465= (c.1395A>C)?

GNAS p.Pro465= (c.1395A>C) is associated with pseudohypoparathyroidism type 1C, pseudohypoparathyroidism type 1A, progressive osseous heteroplasia (ClinVar).

How common is GNAS p.Pro465= (c.1395A>C) in the general population?

GNAS p.Pro465= (c.1395A>C) is rare (popmax 0.233%, afr) (gnomAD).

How is Pseudohypoparathyroidism type 1C inherited?

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

GNAS p.Pro465=

c.1395A>C · rs56213454 · VCV1203026

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

rare (popmax 0.233%, afr)

Conditions

pseudohypoparathyroidism type 1C

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.011	strongly benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -7.4	GERP -2.2
Overall
CADD	0.553	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.233% African / African-American · 137/58,752 alleles

Filtering AF 0.201% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.189%

Overall 0.0172% 257/1,494,356 alleles · rare exomes 221/1,356,232 · genomes 36/138,124 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.233%	429
Admixed American	0.0846%	1,183
Middle Eastern	0.0194%	5,154
East Asian	0.0177%	5,643
South Asian	0.0147%	6,787
Remaining individualsnot grpmax-eligible	0.0138%	7,231
European (non-Finnish)	0.00442%	22,631
Ashkenazi Jewishnot grpmax-eligible	0.00357%	28,036
Finnishnot grpmax-eligible	0.00228%	43,880

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.Pro465=
Coding: c.1395A>C
MANE Select: NM_000516 · reported on NM_080425
dbSNP: rs56213454
Type: single nucleotide variant
Location: chr20:58854660 (GRCh38)
Gene constraint: LOEUF 0.302 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 59.47 · 200 PDB
Residue 465: the 'disordered' region

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

Disease context

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

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

For Pseudohypoparathyroidism type 1C (Orphanet):

Inheritance: Autosomal dominant
Onset: 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-pro465 (accessed [today's date]).

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