Is GNAS p.Val128= (c.384G>A) pathogenic?

GNAS p.Val128= (c.384G>A) is classified Benign/Likely benign in GNAS (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-01-28). Low-frequency (popmax 2.09%, afr); Associated with McCune-Albright syndrome.

What condition is associated with GNAS p.Val128= (c.384G>A)?

GNAS p.Val128= (c.384G>A) is associated with McCune-Albright syndrome, pseudohypoparathyroidism type 1A, progressive osseous heteroplasia (ClinVar).

How common is GNAS p.Val128= (c.384G>A) in the general population?

GNAS p.Val128= (c.384G>A) is low-frequency (popmax 2.09%, afr) (gnomAD).

How is McCune-Albright syndrome inherited?

Typically Not applicable (Orphanet). A genetic counselor can assess individual risk for a family.

GNAS p.Val128=

c.384G>A · rs3730166 · VCV729219

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

low-frequency (popmax 2.09%, afr)

Conditions

McCune-Albright syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.114	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.6	GERP 0.84, phastCons 1
Overall
CADD	13.78	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 2.09% African / African-American · 1,565/74,934 alleles

Filtering AF 2% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.97%

Overall 0.108% 1,736/1,613,668 alleles · low-frequency exomes 880/1,461,606 · genomes 856/152,062 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	2.09%	48
Remaining individualsnot grpmax-eligible	0.13%	772
Admixed American	0.123%	811
Middle Eastern	0.033%	3,031
South Asian	0.00439%	22,763
European (non-Finnish)	0.000848%	117,972

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.Val128=
Coding: c.384G>A
MANE Select: NM_000516
dbSNP: rs3730166
Type: single nucleotide variant
Location: chr20:58903743 (GRCh38)
Gene constraint: LOEUF 0.302 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 59.47 · 200 PDB
Residue 128: the 'disordered' region; the g-alpha domain; an α-helix

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

Disease context

McCune-Albright syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: pseudohypoparathyroidism type 1A progressive osseous heteroplasia pseudohypoparathyroidism type 1B pseudohypoparathyroidism type 1C pseudopseudohypoparathyroidism ACTH-independent macronodular adrenal hyperplasia 1 pituitary adenoma 3, multiple types

For McCune-Albright syndrome (Orphanet):

Inheritance: Not applicable
Onset: Childhood
Prevalence: 1-9 / 1 000 000 (Europe)

Similar variants

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
GNAS p.Arg165Cys Pathogenic ★★ same condition
GNAS p.Arg201Cys Pathogenic/Likely pathogenic ★★ same condition
GNAS p.Arg201His Pathogenic/Likely pathogenic ★★ same condition
GNAS p.Arg228Cys Pathogenic ★★ same condition
GNAS p.Arg231Cys 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-val128 (accessed [today's date]).

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