Is GNAS p.Ala458= (c.1374C>G) pathogenic?

GNAS p.Ala458= (c.1374C>G) is classified Uncertain significance in GNAS (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-01). Absent from gnomAD v4.1.

How common is GNAS p.Ala458= (c.1374C>G) in the general population?

GNAS p.Ala458= (c.1374C>G) is absent from gnomAD v4.1 (gnomAD).

GNAS p.Ala458=

c.1374C>G · VCV4822866

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Absent

absent from gnomAD v4.1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.025	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.68	GERP -2.8
Overall
CADD	6.042	PHRED · no single calibrated threshold — expert panels disagree

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.Ala458=
Coding: c.1374C>G
MANE Select: NM_000516 · reported on NM_080425
Type: single nucleotide variant
Location: chr20:58854639 (GRCh38)
Gene constraint: LOEUF 0.302 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 59.47 · 200 PDB
Residue 458: the 'disordered' region

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

Similar variants

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
GNAS p.Arg160Cys 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-ala458 (accessed [today's date]).

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