Is RRAS p.Ser27= (c.81C>T) pathogenic?

RRAS p.Ser27= (c.81C>T) is classified Conflicting classifications of pathogenicity in RRAS (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-01-27). Ultra-rare (popmax 0.0442%, nfe); Associated with RRAS-related disorder.

What condition is associated with RRAS p.Ser27= (c.81C>T)?

RRAS p.Ser27= (c.81C>T) is associated with RRAS-related disorder, Noonan syndrome (ClinVar).

How common is RRAS p.Ser27= (c.81C>T) in the general population?

RRAS p.Ser27= (c.81C>T) is ultra-rare (popmax 0.0442%, nfe) (gnomAD).

RRAS p.Ser27=

c.81C>T · rs375821724 · VCV1503389

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0442%, nfe)

Conditions

RRAS-related disorder

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 5.2	GERP 0.29, phastCons 1
Overall
CADD	17.28	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0442% European (non-Finnish) · 515/1,164,036 alleles

Filtering AF 0.0411% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0398%

Overall 0.0339% 530/1,565,370 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0442%	2,260
Remaining individualsnot grpmax-eligible	0.0165%	6,061
African / African-American	0.00418%	23,895
Admixed American	0.00179%	55,956
South Asian	0.00114%	87,734

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.Ser27=
Coding: c.81C>T
MANE Select: NM_006270
dbSNP: rs375821724
Type: single nucleotide variant
Location: chr19:49640018 (GRCh38)
Gene constraint: LOEUF 1.175 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.79 · 2 PDB
Residue 27: an α-helix; the 'disordered' region

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

Disease context

RRAS-related disorder

Also linked: Noonan syndrome

Similar variants

RRAS p.Ser27Cys 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-ser27 (accessed [today's date]).

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