Is GNAS p.Pro144= (c.432C>T) pathogenic?

GNAS p.Pro144= (c.432C>T) is classified Benign/Likely benign in GNAS (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-02-01). Low-frequency (popmax 2.66%, afr); Associated with pseudohypoparathyroidism type 1C.

What condition is associated with GNAS p.Pro144= (c.432C>T)?

GNAS p.Pro144= (c.432C>T) is associated with pseudohypoparathyroidism type 1C, pseudohypoparathyroidism type 1A, progressive osseous heteroplasia (ClinVar).

How common is GNAS p.Pro144= (c.432C>T) in the general population?

GNAS p.Pro144= (c.432C>T) is low-frequency (popmax 2.66%, afr) (gnomAD).

How is Pseudohypoparathyroidism type 1C inherited?

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

GNAS p.Pro144=

c.432C>T · rs11554266 · VCV134475

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

gnomAD v4.1

Rare

low-frequency (popmax 2.66%, afr)

Conditions

pseudohypoparathyroidism type 1C

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.3	GERP -0.39
Overall
CADD	11.56	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 2.66% African / African-American · 1,997/74,974 alleles

Filtering AF 2.57% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.53%

Overall 0.155% 2,508/1,614,008 alleles · low-frequency exomes 1,304/1,461,812 · genomes 1,204/152,196 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	2.66%	38
Admixed American	0.303%	330
Remaining individualsnot grpmax-eligible	0.237%	422
Middle Eastern	0.116%	866
European (non-Finnish)	0.0136%	7,375
South Asian	0.011%	9,107
East Asian	0.00891%	11,220

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.Pro144=
Coding: c.432C>T
MANE Select: NM_000516
dbSNP: rs11554266
Type: single nucleotide variant
Location: chr20:58903791 (GRCh38)
Gene constraint: LOEUF 0.302 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 59.47 · 200 PDB
Residue 144: the 'disordered' region; the g-alpha domain; an α-helix

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-pro144 (accessed [today's date]).

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