Is GNAS p.Ala46= (c.138C>A) pathogenic?

GNAS p.Ala46= (c.138C>A) is classified Uncertain significance in GNAS (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-28). Ultra-rare (popmax 0.0681%, afr).

How common is GNAS p.Ala46= (c.138C>A) in the general population?

GNAS p.Ala46= (c.138C>A) is ultra-rare (popmax 0.0681%, afr) (gnomAD).

GNAS p.Ala46=

c.138C>A · VCV4812891

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0681%, afr)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 3.3	GERP 0.65, phastCons 1
Overall
CADD	14.69	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0681% African / African-American · 51/74,930 alleles

Filtering AF 0.0531% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0478%

Overall 0.00565% 91/1,611,156 alleles · ultra-rare exomes 55/1,458,956 · genomes 36/152,200 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0681%	1,469
Admixed American	0.0333%	2,999
Middle Eastern	0.0329%	3,041
Remaining individualsnot grpmax-eligible	0.00801%	12,490
European (non-Finnish)	0.0011%	90,756

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: GNAS
Protein: p.Ala46=
Coding: c.138C>A
MANE Select: NM_000516 · reported on NM_016592
Type: single nucleotide variant
Location: chr20:58840244 (GRCh38)

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

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-ala46 (accessed [today's date]).

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