Is GNAS p.Ser305Pro (c.913T>C) pathogenic?

GNAS p.Ser305Pro (c.913T>C) is classified Likely benign in GNAS (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-03-01). AlphaMissense: likely benign (0.0648); Rare (popmax 0.111%, eas); Associated with McCune-Albright syndrome.

What condition is associated with GNAS p.Ser305Pro (c.913T>C)?

GNAS p.Ser305Pro (c.913T>C) is associated with McCune-Albright syndrome, pseudohypoparathyroidism type 1A, progressive osseous heteroplasia (ClinVar).

How common is GNAS p.Ser305Pro (c.913T>C) in the general population?

GNAS p.Ser305Pro (c.913T>C) is rare (popmax 0.111%, eas) (gnomAD).

How is McCune-Albright syndrome inherited?

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

What do computational predictors say about GNAS p.Ser305Pro (c.913T>C)?

AlphaMissense predicts likely benign (score 0.0648) — an in-silico prediction, not a clinical call.

GNAS p.Ser305Pro

c.913T>C · rs376517306 · VCV719213

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0648 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.111%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

McCune-Albright syndrome

Computational evidence

Protein change
AlphaMissense	0.0648	likely benign
REVEL	0.409	indeterminate
SaProt	LLR -7.64	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.23	GERP -0.33, phastCons 1
Overall
CADD	14.94	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.111% East Asian · 50/44,862 alleles

Filtering AF 0.0868% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0781%

Overall 0.00508% 82/1,612,702 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.111%	897
Remaining individualsnot grpmax-eligible	0.0416%	2,402
African / African-American	0.00668%	14,980
European (non-Finnish)	8.48e-05%	1,179,830

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.Ser305Pro
Coding: c.913T>C
MANE Select: NM_000516 · reported on NM_080425
dbSNP: rs376517306
Type: single nucleotide variant
Location: chr20:58854178 (GRCh38)
Gene constraint: LOEUF 0.302 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 59.47 · 200 PDB
Residue 305: a β-strand; the g-alpha domain; the 'disordered' region

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 p.Lys305Arg Uncertain significance ★ ⚠ same residue
GNAS p.Lys305= Likely benign ★ 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
GNAS p.Arg165Cys Pathogenic ★★ same condition
GNAS p.Arg201Cys Pathogenic/Likely pathogenic ★★ same condition
GNAS p.Arg201His 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-ser305pro (accessed [today's date]).

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