Is GNAS p.Pro115Arg (c.344C>G) pathogenic?

GNAS p.Pro115Arg (c.344C>G) is classified Likely pathogenic in GNAS (ClinVar, Single submitter, 1 submitter; last evaluated 2019-11-16). AlphaMissense: likely pathogenic (0.9653); Absent from gnomAD v4.1; Associated with skeletal dysplasia.

What condition is associated with GNAS p.Pro115Arg (c.344C>G)?

GNAS p.Pro115Arg (c.344C>G) is associated with skeletal dysplasia (ClinVar).

How common is GNAS p.Pro115Arg (c.344C>G) in the general population?

GNAS p.Pro115Arg (c.344C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about GNAS p.Pro115Arg (c.344C>G)?

AlphaMissense predicts likely pathogenic (score 0.9653) — an in-silico prediction, not a clinical call.

GNAS p.Pro115Arg

c.344C>G · VCV4074923

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9653 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

skeletal dysplasia

Computational evidence

Protein change
AlphaMissense	0.9653	likely pathogenic ✓ concordant with ClinVar
REVEL	0.888	moderately pathogenic-leaning
SaProt	LLR -17.84	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.2	GERP 1.9, phastCons 1
Regional constraint	o/e 0.31	constrained · MANE · 18 kb · p 9.1e-28 · regional, not allelic
Overall
CADD	27.8	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P758R vs ClinVar P115R) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: GNAS
Protein: p.Pro115Arg
Coding: c.344C>G
MANE Select: NM_000516
Type: single nucleotide variant
Location: chr20:58903703 (GRCh38)
Gene constraint: LOEUF 0.302 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 59.47 · 200 PDB
Residue 115: the 'disordered' region; the g-alpha domain; a UniProt-annotated variant site (in aho); a β-strand

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

Disease context

skeletal dysplasia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

GNAS p.Pro115Leu Pathogenic/Likely pathogenic ★★ same residue
GNAS p.Pro115Ser Pathogenic ★★ same residue
GNAS p.Trp115Ter Uncertain significance ★ same residue
GNAS p.Pro115= Likely benign ★ same residue
GNAS c.139+1G>C Pathogenic ★★ same type
GNAS c.139+2T>C Pathogenic ★★ same type
GNAS c.312+5G>A Pathogenic ★★ same type
GNAS c.432+1G>A Pathogenic ★★ same type

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-pro115arg (accessed [today's date]).

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