Is RRAS p.Val140= (c.420C>T) pathogenic?

RRAS p.Val140= (c.420C>T) is classified Likely benign in RRAS (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-08-14). Very rare (popmax 0.00446%, eas); Associated with Noonan syndrome.

What condition is associated with RRAS p.Val140= (c.420C>T)?

RRAS p.Val140= (c.420C>T) is associated with Noonan syndrome (ClinVar).

How common is RRAS p.Val140= (c.420C>T) in the general population?

RRAS p.Val140= (c.420C>T) is very rare (popmax 0.00446%, eas) (gnomAD).

RRAS p.Val140=

c.420C>T · rs576507390 · VCV1738729

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Conditions

Noonan syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.78 · evaluated, not missing
Constraint at this position
Conservation	phyloP -1.1	GERP -3.7
Overall
CADD	1.683	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00446% East Asian · 2/44,884 alleles

Filtering AF 0.00291% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0026%

Overall 0.00328% 53/1,614,038 alleles · very rare exomes 52/1,461,756 · genomes 1/152,282 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00446%	22,442
European (non-Finnish)	0.00381%	26,221
South Asian	0.00329%	30,356
Admixed American	0.00167%	60,032
Remaining individualsnot grpmax-eligible	0.0016%	62,494
African / African-American	0.00133%	75,032

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.Val140=
Coding: c.420C>T
MANE Select: NM_006270
dbSNP: rs576507390
Type: single nucleotide variant
Location: chr19:49636652 (GRCh38)
Gene constraint: LOEUF 1.175 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.79 · 2 PDB
Residue 140: a β-strand

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.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
RRAS p.Arg132His 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-val140 (accessed [today's date]).

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