Is GNAS p.Leu99Pro (c.296T>C) pathogenic?

GNAS p.Leu99Pro (c.296T>C) is classified Pathogenic in GNAS (ClinVar, No assertion criteria, 1 submitter; last evaluated 2013-09-30). AlphaMissense: likely pathogenic (0.9995); Absent from gnomAD v4.1; Associated with pseudohypoparathyroidism.

What condition is associated with GNAS p.Leu99Pro (c.296T>C)?

GNAS p.Leu99Pro (c.296T>C) is associated with pseudohypoparathyroidism (ClinVar).

How common is GNAS p.Leu99Pro (c.296T>C) in the general population?

GNAS p.Leu99Pro (c.296T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about GNAS p.Leu99Pro (c.296T>C)?

AlphaMissense predicts likely pathogenic (score 0.9995) — an in-silico prediction, not a clinical call.

GNAS p.Leu99Pro

c.296T>C · rs137854531 · VCV15931

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9995 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

pseudohypoparathyroidism

Computational evidence

Protein change
AlphaMissense	0.9995	likely pathogenic ✓ concordant with ClinVar · top 2% in GNAS
REVEL	0.906	moderately pathogenic-leaning
SaProt	LLR -13.37	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.1	GERP 1.7, phastCons 1
Regional constraint	o/e 0.31	constrained · MANE · 18 kb · p 9.1e-28 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM L742P vs ClinVar L99P) — verify the residue.

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.Leu99Pro
Coding: c.296T>C
MANE Select: NM_000516
dbSNP: rs137854531
Type: single nucleotide variant
Location: chr20:58903569 (GRCh38)
Gene constraint: LOEUF 0.302 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 59.47 · 200 PDB
Residue 742 UniProt numbering: the g-alpha domain

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

Disease context

pseudohypoparathyroidism — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

GNAS p.Leu99= Likely benign ★ same residue
GNAS p.Arg165Cys Pathogenic ★★ same condition
GNAS p.Arg231Cys Pathogenic/Likely pathogenic ★★ same condition
GNAS p.Arg231His Pathogenic ★★ same condition
GNAS p.Gln12Ter Pathogenic ★★ same condition
GNAS p.Gln294Ter Pathogenic/Likely pathogenic ★★ same condition
GNAS p.Gln29Ter Pathogenic ★★ same condition
GNAS p.Met1Val 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-leu99pro (accessed [today's date]).

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