Is GNAS p.Pro141Arg (c.422C>G) pathogenic?

GNAS p.Pro141Arg (c.422C>G) is classified Uncertain significance in GNAS (ClinVar, No assertion criteria, 1 submitter). AlphaMissense: likely benign (0.1065); Absent from gnomAD v4.1.

How common is GNAS p.Pro141Arg (c.422C>G) in the general population?

GNAS p.Pro141Arg (c.422C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about GNAS p.Pro141Arg (c.422C>G)?

AlphaMissense predicts likely benign (score 0.1065) — an in-silico prediction, not a clinical call.

GNAS p.Pro141Arg

c.422C>G · rs942980796 · VCV1050690

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1065 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.1065	likely benign
REVEL	0.449	indeterminate
SaProt	LLR -9.73	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.4	GERP 0.84, phastCons 0.99
Overall
CADD	17.34	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

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.Pro141Arg
Coding: c.422C>G
MANE Select: NM_000516 · reported on NM_080425
dbSNP: rs942980796
Type: single nucleotide variant
Location: chr20:58853687 (GRCh38)
Gene constraint: LOEUF 0.302 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 59.47 · 200 PDB
Residue 141: the 'disordered' region; the g-alpha domain

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

Similar variants

GNAS p.Pro141= 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
GNAS c.433-2A>C Pathogenic/Likely pathogenic ★★ same type
GNAS p.Ala102Thr Pathogenic/Likely pathogenic ★★ same type
GNAS p.Ala102Val Pathogenic/Likely 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-pro141arg (accessed [today's date]).

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