Is GNAS p.Arg561Phe (c.1681_1682delinsTT) pathogenic?

GNAS p.Arg561Phe (c.16811682delinsTT) is classified Uncertain significance in GNAS (ClinVar, Single submitter, 2 submitters; last evaluated 2024-04-18). No gnomAD frequency available for this variant; Associated with pseudopseudohypoparathyroidism.

What condition is associated with GNAS p.Arg561Phe (c.1681_1682delinsTT)?

GNAS p.Arg561Phe (c.1681_1682delinsTT) is associated with pseudopseudohypoparathyroidism (ClinVar).

How common is GNAS p.Arg561Phe (c.1681_1682delinsTT) in the general population?

GNAS p.Arg561Phe (c.1681_1682delinsTT) is no gnomAD frequency available for this variant (gnomAD).

How is Pseudopseudohypoparathyroidism inherited?

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

GNAS p.Arg561Phe

c.1681_1682delinsTT · rs2516392460 · VCV2637129

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Not reported

no gnomAD frequency available for this variant

Conditions

pseudopseudohypoparathyroidism

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.8	GERP -2.5, phastCons 0.74

Population frequency

dbSNP / gnomAD

No gnomAD frequency available for this variant. This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: GNAS
Protein: p.Arg561Phe
Coding: c.1681_1682delinsTT
MANE Select: NM_000516 · reported on NM_080425
dbSNP: rs2516392460
Type: Indel
Location: chr20:58854946 (GRCh38)
Gene constraint: LOEUF 0.302 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 59.47 · 200 PDB
Residue 561: 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

For Pseudopseudohypoparathyroidism (Orphanet):

Inheritance: Autosomal dominant
Onset: All ages

Similar variants

GNAS p.Arg561His Uncertain significance ★ ⚠ same residue
GNAS p.Arg258Ala Pathogenic same condition
GNAS c.212+1_212+3del Likely pathogenic ★★ same condition
GNAS c.432+1G>A Pathogenic ★★ same condition
GNAS c.433-2A>C Pathogenic/Likely pathogenic ★★ same condition
GNAS p.Arg201His Pathogenic/Likely pathogenic ★★ same condition
GNAS p.Arg231Cys Pathogenic/Likely pathogenic ★★ same condition
GNAS p.Arg342Ter 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-arg561phe (accessed [today's date]).

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