Noonan syndrome 12

Summary

Noonan syndrome 12 (MONDO:0032839) is a disease caused by RRAS2 (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: RRAS2 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 11

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	noonan syndrome 12
Mondo ID	MONDO:0032839
OMIM	618624
DOID	DOID:0112170
NCIT	C177120
UMLS	C5231432
MedGen	1684730
GARD	0016369
Is cancer (heuristic)	no

Also known as: NS12

Data availability: 11 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › Noonan syndrome › noonan syndrome 12

Related subtypes (13): Noonan syndrome 1, Noonan syndrome 2, Noonan syndrome 3, Noonan syndrome 4, Noonan syndrome 5, Noonan syndrome 6, Noonan syndrome 7, Noonan syndrome 8, Noonan syndrome 9, Noonan syndrome 10, Noonan syndrome 14, Noonan syndrome 11, Noonan syndrome 13

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

11 retrieved; paginated sample, class counts are floors:

4 uncertain significance, 3 pathogenic, 1 benign, 1 conflicting classifications of pathogenicity, 1 pathogenic/likely pathogenic, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1699117	NM_012250.6(RRAS2):c.68G>A (p.Gly23Asp)	LOC130005368	Pathogenic	criteria provided, multiple submitters, no conflicts
2446526	NM_012250.6(RRAS2):c.71G>A (p.Gly24Asp)	LOC130005368	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
626913	NM_012250.6(RRAS2):c.70_78dup (p.Gly24_Gly26dup)	LOC130005368	Pathogenic	criteria provided, multiple submitters, no conflicts
9447	NM_012250.6(RRAS2):c.215A>T (p.Gln72Leu)	RRAS2	Pathogenic	reviewed by expert panel
626912	NM_012250.6(RRAS2):c.208G>A (p.Ala70Thr)	RRAS2	Likely pathogenic	reviewed by expert panel
2444166	NM_012250.6(RRAS2):c.67G>A (p.Gly23Ser)	LOC130005368	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
4759314	NM_012250.6(RRAS2):c.70G>T (p.Gly24Cys)	LOC130005368	Uncertain significance	criteria provided, single submitter
2445986	NM_012250.6(RRAS2):c.439C>T (p.Arg147Trp)	RRAS2	Uncertain significance	criteria provided, single submitter
2576594	NM_012250.6(RRAS2):c.560C>G (p.Pro187Arg)	RRAS2	Uncertain significance	criteria provided, single submitter
3377589	NM_012250.6(RRAS2):c.139A>G (p.Ile47Val)	RRAS2	Uncertain significance	criteria provided, single submitter
1270813	NM_012250.6(RRAS2):c.409-16A>T	RRAS2	Benign	reviewed by expert panel

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · Orphanet: 1 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
RRAS2	Definitive	Autosomal dominant	Noonan syndrome	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
RRAS2	Orphanet:648	Noonan syndrome

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
RRAS2	HGNC:17271	ENSG00000133818	P62070	Ras-related protein R-Ras2	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
RRAS2	Ras-related protein R-Ras2	GTP-binding protein with GTPase activity, involved in the regulation of MAPK signaling pathway and thereby controlling multiple cellular processes.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
RRAS2	Other/Unknown	no		Small_GTPase, Small_GTP-bd, Small_GTPase_Ras-type

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
oocyte	1
secondary oocyte	1
skeletal muscle tissue of rectus abdominis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RRAS2	287	ubiquitous	marker	secondary oocyte, oocyte, skeletal muscle tissue of rectus abdominis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
RRAS2	237

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
RRAS2	P62070	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 5. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
RND1 GTPase cycle	1	265.6×	0.019	RRAS2
RHO GTPase cycle	1	60.1×	0.037	RRAS2
Signaling by Rho GTPases	1	34.2×	0.037	RRAS2
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1	33.5×	0.037	RRAS2
Signal Transduction	1	10.2×	0.098	RRAS2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
positive regulation of Schwann cell migration	1	16852.0×	2e-04	RRAS2
Schwann cell migration	1	5617.3×	4e-04	RRAS2
Ras protein signal transduction	1	205.5×	0.006	RRAS2
osteoblast differentiation	1	121.2×	0.008	RRAS2

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 1

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
RRAS2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
RRAS2	3	Binding:3

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	RRAS2

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
RRAS2	3	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.