Is GNAS p.Phe290= (c.870C>T) pathogenic?

GNAS p.Phe290= (c.870C>T) is classified Uncertain significance in GNAS (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-09). Very rare (popmax 8.48e-05%, nfe); Associated with pseudopseudohypoparathyroidism.

What condition is associated with GNAS p.Phe290= (c.870C>T)?

GNAS p.Phe290= (c.870C>T) is associated with pseudopseudohypoparathyroidism, pseudohypoparathyroidism type 1A, progressive osseous heteroplasia (ClinVar).

How common is GNAS p.Phe290= (c.870C>T) in the general population?

GNAS p.Phe290= (c.870C>T) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

How is Pseudopseudohypoparathyroidism inherited?

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

GNAS p.Phe290=

c.870C>T · VCV3587589

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Conditions

pseudopseudohypoparathyroidism

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 4.9	GERP 1.9, phastCons 1
Overall
CADD	13.46	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,566 alleles

Overall 6.2e-05% 1/1,613,718 alleles · very rare exomes 1/1,461,340 · genomes 0/152,378 · joint denominator

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.Phe290=
Coding: c.870C>T
MANE Select: NM_000516
Type: single nucleotide variant
Location: chr20:58909981 (GRCh38)
Gene constraint: LOEUF 0.302 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 59.47 · 200 PDB
Residue 290: a β-strand; the g-alpha domain; the 'g4 motif' region; 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

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

For Pseudopseudohypoparathyroidism (Orphanet):

Inheritance: Autosomal dominant
Onset: All ages

Similar variants

GNAS p.Arg290Ser Uncertain significance ★ ⚠ 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-phe290 (accessed [today's date]).

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