Is GNAS p.Pro195= (c.585C>T) pathogenic?

GNAS p.Pro195= (c.585C>T) is classified Uncertain significance in GNAS (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-16). Very rare (popmax 0.00226%, sas).

How common is GNAS p.Pro195= (c.585C>T) in the general population?

GNAS p.Pro195= (c.585C>T) is very rare (popmax 0.00226%, sas) (gnomAD).

GNAS p.Pro195=

c.585C>T · VCV4945456

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00226%, sas)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.144	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2.2	GERP -3.9
Overall
CADD	8.99	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00226% South Asian · 2/88,522 alleles

Filtering AF 0.000375% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00014%

Overall 0.000314% 5/1,593,956 alleles · very rare exomes 4/1,441,772 · genomes 1/152,184 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00226%	44,261
European (non-Finnish)	0.000256%	390,314

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.Pro195=
Coding: c.585C>T
MANE Select: NM_000516 · reported on NM_080425
Type: single nucleotide variant
Location: chr20:58853850 (GRCh38)
Gene constraint: LOEUF 0.302 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 59.47 · 200 PDB
Residue 195: the 'disordered' region; the g-alpha domain; an α-helix

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

Similar variants

GNAS p.Gln195His Uncertain significance ★ ⚠ same residue
GNAS p.Pro195Ser Uncertain significance ★ ⚠ same residue
GNAS c.139+1G>C Pathogenic ★★ same type
GNAS c.139+2T>C Pathogenic ★★ same type
GNAS c.312+5G>A Pathogenic ★★ same type
GNAS c.432+1G>A Pathogenic ★★ same type
GNAS c.433-2A>C Pathogenic/Likely pathogenic ★★ same type
GNAS p.Ala102Thr Pathogenic/Likely pathogenic ★★ same type

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-pro195 (accessed [today's date]).

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