Is GNAS p.Pro188fs (c.562_569del) pathogenic?

GNAS p.Pro188fs (c.562569del) is classified Uncertain significance in GNAS (ClinVar, Single submitter, 1 submitter; last evaluated 2026-06-18). Associated with Early onset severe obesity.

What condition is associated with GNAS p.Pro188fs (c.562_569del)?

GNAS p.Pro188fs (c.562_569del) is associated with Early onset severe obesity (ClinVar).

GNAS p.Pro188fs

c.562_569del · VCV4876248

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

Conditions

Early onset severe obesity

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function in a haploinsufficient gene (ClinGen); NMD-escape possible for C-terminal truncations
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 3.3	GERP 1.4, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Variant & gene context

Gene: GNAS
Protein: p.Pro188fs
Coding: c.562_569del
MANE Select: NM_000516 · reported on NM_016592
Type: Deletion
Location: chr20:58840668 (GRCh38)
Gene constraint: LOEUF 0.302 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 59.47 · 200 PDB
Residue 188: the 'disordered' region; the g-alpha domain

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

Disease context

Early onset severe obesity — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

GNAS p.Ala188fs Pathogenic ★ same residue
GNAS p.Thr415_Gly423del Benign/Likely benign ★★ same condition
GNAS p.Asn66fs Pathogenic ★ same condition
GNAS p.Gly188Asp Uncertain significance ★ ⚠ same residue
GNAS p.Ala400_Asp401insAlaProAla Benign/Likely benign ★★ same condition
GNAS p.Ala470Thr Uncertain significance ★ ⚠ same condition
GNAS p.Gln59His Uncertain significance ★ ⚠ same condition
GNAS p.Met386Thr Uncertain significance ★ ⚠ 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-pro188fs (accessed [today's date]).

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