Noonan syndrome 6

Summary

Noonan syndrome 6 (MONDO:0013186) is a disease caused by NRAS (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: NRAS (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 94

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Noonan syndrome 6
Mondo ID	MONDO:0013186
MeSH	C548084
OMIM	613224
DOID	DOID:0060584
NCIT	C176934
UMLS	C2750732
MedGen	413028
GARD	0010701
Is cancer (heuristic)	no

Also known as: Noonan syndrome 6 · Noonan syndrome caused by mutation in NRAS · Noonan syndrome type 6 · NRAS gene related Noonan syndrome · NRAS Noonan syndrome · NS6

Data availability: 94 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › Noonan syndrome › Noonan syndrome 6

Related subtypes (13): Noonan syndrome 1, Noonan syndrome 2, Noonan syndrome 3, Noonan syndrome 4, Noonan syndrome 5, Noonan syndrome 7, Noonan syndrome 8, Noonan syndrome 9, Noonan syndrome 10, Noonan syndrome 14, Noonan syndrome 11, noonan syndrome 12, 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

94 retrieved; paginated sample, class counts are floors:

50 uncertain significance, 14 likely benign, 8 benign, 7 conflicting classifications of pathogenicity, 6 pathogenic, 4 pathogenic/likely pathogenic, 3 likely pathogenic, 2 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
13900	NM_002524.5(NRAS):c.182A>G (p.Gln61Arg)	NRAS	Pathogenic	criteria provided, multiple submitters, no conflicts
13901	NM_002524.5(NRAS):c.38G>A (p.Gly13Asp)	NRAS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
13902	NM_002524.5(NRAS):c.149C>T (p.Thr50Ile)	NRAS	Pathogenic	reviewed by expert panel
13903	NM_002524.5(NRAS):c.179G>A (p.Gly60Glu)	NRAS	Pathogenic	reviewed by expert panel
177778	NM_002524.5(NRAS):c.34G>A (p.Gly12Ser)	NRAS	Pathogenic	reviewed by expert panel
219097	NM_002524.5(NRAS):c.35G>C (p.Gly12Ala)	NRAS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
280409	NM_002524.5(NRAS):c.182A>C (p.Gln61Pro)	NRAS	Pathogenic	criteria provided, single submitter
39648	NM_002524.5(NRAS):c.35G>A (p.Gly12Asp)	NRAS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
40469	NM_002524.5(NRAS):c.34G>C (p.Gly12Arg)	NRAS	Pathogenic	criteria provided, multiple submitters, no conflicts
40473	NM_002524.5(NRAS):c.175G>A (p.Ala59Thr)	NRAS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1320232	NM_002524.5(NRAS):c.449A>G (p.Gln150Arg)	NRAS	Likely pathogenic	criteria provided, single submitter
1335888	NM_002524.5(NRAS):c.108A>G (p.Ile36Met)	NRAS	Likely pathogenic	criteria provided, single submitter
13899	NM_002524.5(NRAS):c.37G>C (p.Gly13Arg)	NRAS	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1334247	NM_002524.5(NRAS):c.179G>T (p.Gly60Val)	NRAS	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
291949	NM_002524.5(NRAS):c.*2805T>C	NRAS	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
291958	NM_002524.5(NRAS):c.*2513T>A	NRAS	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
291975	NM_002524.5(NRAS):c.*111A>G	NRAS	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3338000	NM_002524.5(NRAS):c.203G>T (p.Arg68Ile)	NRAS	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
875227	NM_002524.5(NRAS):c.*2618A>G	NRAS	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
876240	NM_002524.5(NRAS):c.112-6C>G	NRAS	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
291977	NM_002524.5(NRAS):c.-106G>T	LOC129931249	Uncertain significance	criteria provided, single submitter
164809	NM_002524.5(NRAS):c.368G>A (p.Arg123Lys)	NRAS	Uncertain significance	reviewed by expert panel
179025	NM_002524.5(NRAS):c.553C>T (p.Pro185Ser)	NRAS	Uncertain significance	reviewed by expert panel
211686	NM_002524.5(NRAS):c.317C>T (p.Ser106Leu)	NRAS	Uncertain significance	criteria provided, multiple submitters, no conflicts
291940	NM_002524.5(NRAS):c.*3404T>C	NRAS	Uncertain significance	criteria provided, single submitter
291941	NM_002524.5(NRAS):c.*3392T>C	NRAS	Uncertain significance	criteria provided, single submitter
291945	NM_002524.5(NRAS):c.*3062C>T	NRAS	Uncertain significance	criteria provided, single submitter
291947	NM_002524.5(NRAS):c.*2860G>A	NRAS	Uncertain significance	criteria provided, single submitter
291948	NM_002524.5(NRAS):c.*2844T>A	NRAS	Uncertain significance	criteria provided, single submitter
291951	NM_002524.5(NRAS):c.*2714G>T	NRAS	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 10 · Orphanet: 7 · 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
NRAS	Definitive	Autosomal dominant	Noonan syndrome	10

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NRAS	Orphanet:146	Differentiated thyroid carcinoma
NRAS	Orphanet:2612	Linear nevus sebaceus syndrome
NRAS	Orphanet:268114	RAS-associated autoimmune leukoproliferative disease
NRAS	Orphanet:389	Langerhans cell histiocytosis
NRAS	Orphanet:626	Large/giant congenital melanocytic nevus
NRAS	Orphanet:648	Noonan syndrome
NRAS	Orphanet:86834	Juvenile myelomonocytic leukemia

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
NRAS	HGNC:7989	ENSG00000213281	P01111	GTPase NRas	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NRAS	GTPase NRas	Ras proteins bind GDP/GTP and possess intrinsic GTPase activity.

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)
NRAS	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
epithelium of nasopharynx	1
gingival epithelium	1
secondary oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NRAS	278	ubiquitous	marker	gingival epithelium, epithelium of nasopharynx, secondary oocyte

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NRAS	7,598

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NRAS	P01111	35

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 68. 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
Signaling by RAS GAP mutants	1	3806.7×	0.003	NRAS
Signaling by RAS GTPase mutants	1	3806.7×	0.003	NRAS
Activation of RAS in B cells	1	2284.0×	0.003	NRAS
RAS signaling downstream of NF1 loss-of-function variants	1	1631.4×	0.003	NRAS
Estrogen-stimulated signaling through PRKCZ	1	1631.4×	0.003	NRAS
SOS-mediated signalling	1	1427.5×	0.003	NRAS
Activated NTRK3 signals through RAS	1	1268.9×	0.003	NRAS
EGFR Transactivation by Gastrin	1	1142.0×	0.003	NRAS
SHC-related events triggered by IGF1R	1	1142.0×	0.003	NRAS
Activated NTRK2 signals through RAS	1	1142.0×	0.003	NRAS
MET activates RAS signaling	1	1038.2×	0.003	NRAS
Signaling by FGFR4 in disease	1	951.7×	0.003	NRAS
Activated NTRK2 signals through FRS2 and FRS3	1	951.7×	0.003	NRAS
Constitutive Signaling by Overexpressed ERBB2	1	951.7×	0.003	NRAS
p38MAPK events	1	878.5×	0.003	NRAS
Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants	1	878.5×	0.003	NRAS
Signaling by PDGFRA extracellular domain mutants	1	878.5×	0.003	NRAS
PTK6 Regulates RHO GTPases, RAS GTPase and MAP kinases	1	815.7×	0.003	NRAS
GRB2 events in EGFR signaling	1	761.3×	0.003	NRAS
Erythropoietin activates RAS	1	761.3×	0.003	NRAS
Signaling by FLT3 ITD and TKD mutants	1	761.3×	0.003	NRAS
SHC1 events in ERBB4 signaling	1	713.8×	0.003	NRAS
SHC1 events in EGFR signaling	1	713.8×	0.003	NRAS
Constitutive Signaling by EGFRvIII	1	713.8×	0.003	NRAS
Signalling to RAS	1	671.8×	0.003	NRAS
Insulin receptor signalling cascade	1	671.8×	0.003	NRAS
Signaling by ERBB2 ECD mutants	1	671.8×	0.003	NRAS
GRB2 events in ERBB2 signaling	1	634.4×	0.003	NRAS
Tie2 Signaling	1	601.0×	0.003	NRAS
SHC-mediated cascade:FGFR3	1	601.0×	0.003	NRAS

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 endothelial cell proliferation	1	230.8×	0.007	NRAS
Ras protein signal transduction	1	205.5×	0.007	NRAS
MAPK cascade	1	153.2×	0.007	NRAS

Therapeutics

Drug target analysis

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

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
NRAS	1	1

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
L-778123 FREE BASE	1	NRAS

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
NRAS	18	Binding:18

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

1 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.

Compound	Max phase	Cohort target (bioactivity)
L-778123 FREE BASE	1	NRAS

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	1	NRAS
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.