Is GNAS p.Met1Val (c.1A>G) pathogenic?

GNAS p.Met1Val (c.1A>G) is classified Pathogenic in GNAS (ClinVar, Multiple submitters, 5 submitters; last evaluated 2024-11-20). Very rare (popmax 9.96e-05%); Associated with GNAS-related disorder.

What condition is associated with GNAS p.Met1Val (c.1A>G)?

GNAS p.Met1Val (c.1A>G) is associated with GNAS-related disorder, progressive osseous heteroplasia, pseudohypoparathyroidism type 1B (ClinVar).

How common is GNAS p.Met1Val (c.1A>G) in the general population?

GNAS p.Met1Val (c.1A>G) is very rare (popmax 9.96e-05%) (gnomAD).

GNAS p.Met1Val

c.1A>G · rs137854530 · VCV15927

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

Consequence

start-loss

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 9.96e-05%)

Conditions

GNAS-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	start-loss	predicted loss-of-function in a haploinsufficient gene (ClinGen)
REVEL	0.774	moderately pathogenic-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.2	GERP -3.1, phastCons 1
Overall
CADD	23.3	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 9.96e-05%

Overall 9.96e-05% 1/1,004,328 alleles · very rare

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.Met1Val
Coding: c.1A>G
MANE Select: NM_000516
dbSNP: rs137854530
Type: single nucleotide variant
Location: chr20:58891727 (GRCh38)
Gene constraint: LOEUF 0.302 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 59.47 · 200 PDB
Residue 1: the 'disordered' region

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

Disease context

Also linked: progressive osseous heteroplasia pseudohypoparathyroidism type 1B pseudohypoparathyroidism type 1C pseudopseudohypoparathyroidism Cushing syndrome McCune-Albright syndrome pseudohypoparathyroidism pituitary adenoma 3, multiple types

Similar variants

GNAS p.Met1Leu Pathogenic ★★ same residue
GNAS p.Met1Ala Pathogenic ★★ same residue
GNAS p.Met1_Asp2delinsIleIle Uncertain significance same residue
GNAS p.Met1Thr Pathogenic ★★ same residue
GNAS p.Met1Ile Pathogenic ★ same residue
GNAS c.139+1G>C Pathogenic ★★ same condition
GNAS c.432+1G>A Pathogenic ★★ same condition
GNAS c.433-2A>C Pathogenic/Likely pathogenic ★★ 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-met1val (accessed [today's date]).

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