Is RRAS p.Pro26fs (c.74dup) pathogenic?

RRAS p.Pro26fs (c.74dup) is classified Uncertain significance in RRAS (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-22). Very rare (popmax 0.00499%, eas); Associated with Noonan syndrome.

What condition is associated with RRAS p.Pro26fs (c.74dup)?

RRAS p.Pro26fs (c.74dup) is associated with Noonan syndrome (ClinVar).

How common is RRAS p.Pro26fs (c.74dup) in the general population?

RRAS p.Pro26fs (c.74dup) is very rare (popmax 0.00499%, eas) (gnomAD).

RRAS p.Pro26fs

c.74dup · rs755237250 · VCV1489940

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00499%, eas)

Conditions

Noonan syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 1 of 6
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.82	GERP -3.3, phastCons 1
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00499% East Asian · 2/40,062 alleles

Filtering AF 0.00156% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00133%

Overall 0.00199% 31/1,554,938 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00499%	20,031
Admixed American	0.00369%	27,127
European (non-Finnish)	0.00224%	44,586
African / African-American	0.0014%	71,296

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.Pro26fs
Coding: c.74dup
MANE Select: NM_006270
dbSNP: rs755237250
Type: Duplication
Location: chr19:49640024 (GRCh38)
Gene constraint: LOEUF 1.175 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.79 · 2 PDB
Residue 26: an α-helix; the 'disordered' region

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.Pro26Leu Uncertain significance ★ ⚠ same residue
RRAS c.454-10dup Benign ★ same condition
RRAS p.Ala109Thr Uncertain significance ★★ ⚠ same condition
RRAS p.Ala162Thr Uncertain significance ★★ ⚠ same condition
RRAS p.Ala205Val Uncertain significance ★★ ⚠ same condition
RRAS p.Ala5Thr Uncertain significance ★★ same condition
RRAS p.Ala85Val Uncertain significance ★★ ⚠ same condition
RRAS p.Arg113Gln 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-pro26fs (accessed [today's date]).

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