Is RRAS p.Ala77= (c.231C>A) pathogenic?

RRAS p.Ala77= (c.231C>A) is classified Benign/Likely benign in RRAS (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-03-13). Rare (popmax 0.22%, sas); Associated with Noonan syndrome.

What condition is associated with RRAS p.Ala77= (c.231C>A)?

RRAS p.Ala77= (c.231C>A) is associated with Noonan syndrome (ClinVar).

How common is RRAS p.Ala77= (c.231C>A) in the general population?

RRAS p.Ala77= (c.231C>A) is rare (popmax 0.22%, sas) (gnomAD).

RRAS p.Ala77=

c.231C>A · rs557964716 · VCV527796

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

rare (popmax 0.22%, sas)

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 -0.52	GERP -3.4, phastCons 0.004
Overall
CADD	5.365	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.22% South Asian · 200/91,050 alleles

Filtering AF 0.195% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.185%

Overall 0.0132% 213/1,613,676 alleles · rare exomes 203/1,461,422 · genomes 10/152,254 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.22%	455
Middle Eastern	0.033%	3,031
Remaining individualsnot grpmax-eligible	0.0096%	10,418
European (non-Finnish)	0.000424%	235,988

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.Ala77=
Coding: c.231C>A
MANE Select: NM_006270
dbSNP: rs557964716
Type: single nucleotide variant
Location: chr19:49637053 (GRCh38)
Gene constraint: LOEUF 1.175 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.79 · 2 PDB
Residue 77: 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.Ala77Thr Conflicting classifications of pathogenicity ★ ⚠ 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-ala77 (accessed [today's date]).

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