Is GNAS p.Ser555Pro (c.1663T>C) pathogenic?

GNAS p.Ser555Pro (c.1663T>C) is classified Uncertain significance in GNAS (ClinVar, Single submitter, 1 submitter; last evaluated 2021-11-15). AlphaMissense: likely benign (0.0958); Very rare (popmax 0.00341%, amr); Associated with Inborn genetic diseases.

What condition is associated with GNAS p.Ser555Pro (c.1663T>C)?

GNAS p.Ser555Pro (c.1663T>C) is associated with Inborn genetic diseases (ClinVar).

How common is GNAS p.Ser555Pro (c.1663T>C) in the general population?

GNAS p.Ser555Pro (c.1663T>C) is very rare (popmax 0.00341%, amr) (gnomAD).

What do computational predictors say about GNAS p.Ser555Pro (c.1663T>C)?

AlphaMissense predicts likely benign (score 0.0958) — an in-silico prediction, not a clinical call.

GNAS p.Ser555Pro

c.1663T>C · rs1423926275 · VCV2261667

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0958 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00341%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0958	likely benign
REVEL	0.255	benign-leaning
SaProt	LLR -6.05	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.4	GERP -3.2
Overall
CADD	8.642	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00341% Admixed American · 2/58,720 alleles

Filtering AF 0.000565% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000211%

Overall 0.000125% 2/1,601,940 alleles · very rare exomes 2/1,449,604 · genomes 0/152,336 · joint denominator

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.Ser555Pro
Coding: c.1663T>C
MANE Select: NM_000516 · reported on NM_080425
dbSNP: rs1423926275
Type: single nucleotide variant
Location: chr20:58854928 (GRCh38)
Gene constraint: LOEUF 0.302 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 59.47 · 200 PDB
Residue 555: the 'disordered' region

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

GNAS p.Ser555Tyr Uncertain significance ⚠ same residue
GNAS c.432+1G>A Pathogenic ★★ same condition
GNAS p.Arg265Cys Pathogenic/Likely pathogenic ★★ same condition
GNAS p.Arg385His Pathogenic ★★ same condition
GNAS p.Arg42Cys Pathogenic ★★ same condition
GNAS p.Arg385Cys Uncertain significance ★★ ⚠ same condition
GNAS p.Asn239Ser Uncertain significance ★★ same condition
GNAS p.Asp401Asn Uncertain significance ★★ ⚠ 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-ser555pro (accessed [today's date]).

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