Is RASA2 p.Arg404Gln (c.1211G>A) pathogenic?

RASA2 p.Arg404Gln (c.1211G>A) is classified Uncertain significance in RASA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-14). Very rare (popmax 0.00373%, nfe); Associated with Noonan syndrome.

What condition is associated with RASA2 p.Arg404Gln (c.1211G>A)?

RASA2 p.Arg404Gln (c.1211G>A) is associated with Noonan syndrome (ClinVar).

How common is RASA2 p.Arg404Gln (c.1211G>A) in the general population?

RASA2 p.Arg404Gln (c.1211G>A) is very rare (popmax 0.00373%, nfe) (gnomAD).

RASA2 p.Arg404Gln

c.1211G>A · VCV4279901

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00373%, nfe)

Conditions

Noonan syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.087	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 121 kb · p 0.039 · regional, not allelic
Overall
CADD	25.5	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00373% European (non-Finnish) · 44/1,179,688 alleles

Filtering AF 0.00283% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00252%

Overall 0.00291% 47/1,613,372 alleles · very rare exomes 46/1,461,258 · genomes 1/152,114 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00373%	26,811
Remaining individualsnot grpmax-eligible	0.0032%	31,226
East Asian	0.00223%	44,782

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: RASA2
Protein: p.Arg404Gln
Coding: c.1211G>A
MANE Select: NM_006506
Type: single nucleotide variant
Location: chr3:141572650 (GRCh38)
Gene constraint: LOEUF 1.484 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.63
Residue 404: the ras-gap domain

Full RASA2 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

RASA2 p.Arg404Pro Uncertain significance ★★ same residue
RASA2 p.Arg404Ter Uncertain significance ★ same residue
RASA2 p.His605Gln Uncertain significance ★ same condition
RASA2 c.612-3C>T Uncertain significance ★★ same type
RASA2 p.Ala360Gly Uncertain significance ★★ same type
RASA2 p.Ala489Thr Uncertain significance ★★ same type
RASA2 p.Ala503Ser Uncertain significance ★★ same type
RASA2 p.Ala742Val Uncertain significance ★★ same type

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/rasa2-p-arg404gln (accessed [today's date]).

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