Is GNAS p.Ala476= (c.1428C>G) pathogenic?

GNAS p.Ala476= (c.1428C>G) is classified Likely benign in GNAS (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-08-01). Rare (popmax 0.58%, sas); Associated with pseudohypoparathyroidism type 1C.

What condition is associated with GNAS p.Ala476= (c.1428C>G)?

GNAS p.Ala476= (c.1428C>G) is associated with pseudohypoparathyroidism type 1C, pseudohypoparathyroidism type 1A, progressive osseous heteroplasia (ClinVar).

How common is GNAS p.Ala476= (c.1428C>G) in the general population?

GNAS p.Ala476= (c.1428C>G) is rare (popmax 0.58%, sas) (gnomAD).

How is Pseudohypoparathyroidism type 1C inherited?

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

GNAS p.Ala476=

c.1428C>G · rs559714658 · VCV1205936

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

rare (popmax 0.58%, sas)

Conditions

pseudohypoparathyroidism type 1C

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	GERP -2.4
Overall
CADD	5.3	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.58% South Asian · 484/83,474 alleles

Filtering AF 0.537% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.52%

Overall 0.0333% 509/1,529,040 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.58%	172
Remaining individualsnot grpmax-eligible	0.0352%	2,838
Middle Eastern	0.0193%	5,170
East Asian	0.00247%	40,496
African / African-American	0.00138%	72,216
European (non-Finnish)	8.74e-05%	1,144,146

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.Ala476=
Coding: c.1428C>G
MANE Select: NM_000516 · reported on NM_080425
dbSNP: rs559714658
Type: single nucleotide variant
Location: chr20:58854693 (GRCh38)
Gene constraint: LOEUF 0.302 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 59.47 · 200 PDB
Residue 476: 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 p.Ala476Val Conflicting classifications of pathogenicity ★ ⚠ same residue
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

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-ala476 (accessed [today's date]).

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