Is RRAS p.Ser172= (c.516G>A) pathogenic?

RRAS p.Ser172= (c.516G>A) is classified Likely benign in RRAS (ClinVar, Multiple submitters, 3 submitters; last evaluated 2023-10-19). Ultra-rare (popmax 0.0338%, mid); Associated with Noonan syndrome.

What condition is associated with RRAS p.Ser172= (c.516G>A)?

RRAS p.Ser172= (c.516G>A) is associated with Noonan syndrome (ClinVar).

How common is RRAS p.Ser172= (c.516G>A) in the general population?

RRAS p.Ser172= (c.516G>A) is ultra-rare (popmax 0.0338%, mid) (gnomAD).

RRAS p.Ser172=

c.516G>A · rs199924228 · VCV1554536

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0338%, mid)

Conditions

Noonan syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -20	GERP -3.4
Overall
CADD	0.098	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0338% Middle Eastern · 2/5,910 alleles

Filtering AF 0.00596% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00247%

Overall 0.00125% 18/1,436,288 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0338%	2,955
Remaining individualsnot grpmax-eligible	0.00329%	30,387
East Asian	0.0023%	43,560
European (non-Finnish)	0.00112%	89,333

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: RRAS
Protein: p.Ser172=
Coding: c.516G>A
MANE Select: NM_006270
dbSNP: rs199924228
Type: single nucleotide variant
Location: chr19:49635790 (GRCh38)
Gene constraint: LOEUF 1.175 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.79 · 2 PDB
Residue 172: a binding site

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

Disease context

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

Similar variants

RRAS p.Ser172Leu Uncertain significance ★ ⚠ same residue
RRAS p.Ala109Thr Uncertain significance ★★ ⚠ same condition
RRAS p.Ala162Thr Uncertain significance ★★ ⚠ same condition
RRAS p.Ala205Val Uncertain significance ★★ ⚠ same condition
RRAS p.Ala85Val Uncertain significance ★★ ⚠ same condition
RRAS p.Arg113Gln Uncertain significance ★★ ⚠ same condition
RRAS p.Arg128Gln Uncertain significance ★★ ⚠ same condition
RRAS p.Arg132Cys 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/rras-p-ser172 (accessed [today's date]).

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