Noonan syndrome 4

Summary

Noonan syndrome 4 (MONDO:0012547) is a disease caused by SOS1 (GenCC Definitive), with 2 cohort genes.

At a glance

• Causal gene: SOS1 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 467

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Noonan syndrome 4
Mondo ID	MONDO:0012547
MeSH	C548082
OMIM	610733
DOID	DOID:0060582
NCIT	C176932
UMLS	C1853120
MedGen	339908
GARD	0010699
Is cancer (heuristic)	no

Also known as: Noonan syndrome 4 · Noonan syndrome caused by mutation in SOS1 · Noonan syndrome type 4 · NS4 · SOS1 gene related Noonan syndrome · SOS1 Noonan syndrome

Data availability: 467 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 4

Related subtypes (13): Noonan syndrome 1, Noonan syndrome 2, Noonan syndrome 3, 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 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

467 retrieved; paginated sample, class counts are floors:

195 uncertain significance, 94 conflicting classifications of pathogenicity, 64 likely benign, 39 benign/likely benign, 34 benign, 19 pathogenic, 11 likely pathogenic, 11 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
12869	NM_005633.4(SOS1):c.797C>A (p.Thr266Lys)	SOS1	Pathogenic	criteria provided, multiple submitters, no conflicts
12870	NM_005633.4(SOS1):c.806T>G (p.Met269Arg)	SOS1	Pathogenic	criteria provided, multiple submitters, no conflicts
12871	NM_005633.4(SOS1):c.1654A>G (p.Arg552Gly)	SOS1	Pathogenic	reviewed by expert panel
12872	NM_005633.4(SOS1):c.1656G>C (p.Arg552Ser)	SOS1	Pathogenic	reviewed by expert panel
12873	NM_005633.4(SOS1):c.1294T>C (p.Trp432Arg)	SOS1	Pathogenic	criteria provided, multiple submitters, no conflicts
181551	NM_005633.4(SOS1):c.1310T>G (p.Ile437Ser)	SOS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
181552	NM_005633.4(SOS1):c.1430A>G (p.Gln477Arg)	SOS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
40648	NM_005633.4(SOS1):c.253T>C (p.Trp85Arg)	SOS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
40649	NM_005633.4(SOS1):c.322G>A (p.Glu108Lys)	SOS1	Pathogenic	reviewed by expert panel
40651	NM_005633.4(SOS1):c.508A>G (p.Lys170Glu)	SOS1	Pathogenic	reviewed by expert panel
40662	NM_005633.4(SOS1):c.806T>C (p.Met269Thr)	SOS1	Pathogenic	reviewed by expert panel
40669	NM_005633.4(SOS1):c.1297G>A (p.Glu433Lys)	SOS1	Pathogenic	criteria provided, multiple submitters, no conflicts
40670	NM_005633.4(SOS1):c.1300G>C (p.Gly434Arg)	SOS1	Pathogenic	criteria provided, multiple submitters, no conflicts
40672	NM_005633.4(SOS1):c.1300G>A (p.Gly434Arg)	SOS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
40673	NM_005633.4(SOS1):c.1322G>A (p.Cys441Tyr)	SOS1	Pathogenic	criteria provided, multiple submitters, no conflicts
40678	NM_005633.4(SOS1):c.1642A>C (p.Ser548Arg)	SOS1	Pathogenic	reviewed by expert panel
40679	NM_005633.4(SOS1):c.1644T>A (p.Ser548Arg)	SOS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
40680	NM_005633.4(SOS1):c.1649T>C (p.Leu550Pro)	SOS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
40682	NM_005633.4(SOS1):c.1655G>C (p.Arg552Thr)	SOS1	Pathogenic	reviewed by expert panel
40683	NM_005633.4(SOS1):c.1655G>A (p.Arg552Lys)	SOS1	Pathogenic	reviewed by expert panel
40684	NM_005633.4(SOS1):c.1656G>T (p.Arg552Ser)	SOS1	Pathogenic	reviewed by expert panel
40696	NM_005633.4(SOS1):c.2104T>C (p.Tyr702His)	SOS1	Pathogenic	criteria provided, multiple submitters, no conflicts
40699	NM_005633.4(SOS1):c.2183A>T (p.Lys728Ile)	SOS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
40701	NM_005633.4(SOS1):c.2197A>T (p.Ile733Phe)	SOS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
40706	NM_005633.4(SOS1):c.2536G>A (p.Glu846Lys)	SOS1	Pathogenic	reviewed by expert panel
45344	NM_005633.4(SOS1):c.1132A>G (p.Thr378Ala)	SOS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
45345	NM_005633.4(SOS1):c.1310T>C (p.Ile437Thr)	SOS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
45379	NM_005633.4(SOS1):c.925G>T (p.Asp309Tyr)	SOS1	Pathogenic	criteria provided, multiple submitters, no conflicts
477721	NM_005633.4(SOS1):c.305C>G (p.Pro102Arg)	SOS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
932923	NM_005633.4(SOS1):c.3134C>G (p.Pro1045Arg)	SOS1	Pathogenic	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 10 · Orphanet: 2 · 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
SOS1	Definitive	Autosomal dominant	Noonan syndrome	10

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SOS1	Orphanet:2024	Hereditary gingival fibromatosis
SOS1	Orphanet:648	Noonan syndrome

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SOS1	HGNC:11187	ENSG00000115904	Q07889	Son of sevenless homolog 1	gencc,clinvar
CDKL4	HGNC:19287	ENSG00000205111	Q5MAI5	Cyclin-dependent kinase-like 4	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SOS1	Son of sevenless homolog 1	Promotes the exchange of Ras-bound GDP by GTP.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 0 · Druggable fraction: 0.5

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
Kinase	1	13.9×	0.112
Scaffold/PPI	1	8.6×	0.112

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SOS1	Scaffold/PPI	no		DH_dom, Ras-like_Gua-exchang_fac_N, PH_domain
CDKL4	Kinase	yes		Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf

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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
colonic epithelium	1
jejunal mucosa	1
tendon of biceps brachii	1
adrenal tissue	1
male germ line stem cell (sensu Vertebrata) in testis	1
testis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SOS1	289	ubiquitous	marker	colonic epithelium, jejunal mucosa, tendon of biceps brachii
CDKL4	119		yes	male germ line stem cell (sensu Vertebrata) in testis, adrenal tissue, testis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SOS1	3,625
CDKL4	373

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SOS1	Q07889	91

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CDKL4	Q5MAI5	79.67

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 133. Enrichment computed across 2 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
Downstream signaling of activated FGFR2	1	5710.0×	0.004	SOS1
Downstream signaling of activated FGFR3	1	5710.0×	0.004	SOS1
Downstream signaling of activated FGFR4	1	3806.7×	0.004	SOS1
Signaling by ERBB2 in Cancer	1	2284.0×	0.004	SOS1
Signaling by EGFRvIII in Cancer	1	2284.0×	0.004	SOS1
Signaling by Ligand-Responsive EGFR Variants in Cancer	1	1903.3×	0.004	SOS1
Signaling by NTRK2 (TRKB)	1	1631.4×	0.004	SOS1
Signaling by PDGFR in disease	1	1631.4×	0.004	SOS1
SOS-mediated signalling	1	1427.5×	0.004	SOS1
IGF1R signaling cascade	1	1427.5×	0.004	SOS1
Activated NTRK3 signals through RAS	1	1268.9×	0.004	SOS1
Signaling by EGFR in Cancer	1	1142.0×	0.004	SOS1
EGFR Transactivation by Gastrin	1	1142.0×	0.004	SOS1
SHC-related events triggered by IGF1R	1	1142.0×	0.004	SOS1
Signaling by FGFR3	1	1142.0×	0.004	SOS1
Activated NTRK2 signals through RAS	1	1142.0×	0.004	SOS1
Signaling by NTRK3 (TRKC)	1	1142.0×	0.004	SOS1
Signaling by KIT in disease	1	1142.0×	0.004	SOS1
FLT3 signaling in disease	1	1142.0×	0.004	SOS1
IRS-mediated signalling	1	1038.2×	0.004	SOS1
IRS-related events triggered by IGF1R	1	1038.2×	0.004	SOS1
Signaling by FGFR4	1	1038.2×	0.004	SOS1
Signal attenuation	1	1038.2×	0.004	SOS1
MET activates RAS signaling	1	1038.2×	0.004	SOS1
Signaling by Erythropoietin	1	1038.2×	0.004	SOS1
Signaling by Type 1 Insulin-like Growth Factor 1 Receptor (IGF1R)	1	951.7×	0.004	SOS1
Signaling by FGFR4 in disease	1	951.7×	0.004	SOS1
Activated NTRK2 signals through FRS2 and FRS3	1	951.7×	0.004	SOS1
Constitutive Signaling by Overexpressed ERBB2	1	951.7×	0.004	SOS1
Signaling by Insulin receptor	1	878.5×	0.004	SOS1

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
midbrain morphogenesis	1	4213.0×	0.003	SOS1
vitellogenesis	1	3370.4×	0.003	SOS1
regulation of pro-B cell differentiation	1	3370.4×	0.003	SOS1
cardiac atrium morphogenesis	1	2808.7×	0.003	SOS1
regulation of T cell differentiation in thymus	1	2407.4×	0.003	SOS1
pericardium morphogenesis	1	2106.5×	0.003	SOS1
heart trabecula morphogenesis	1	1872.4×	0.003	SOS1
Schwann cell development	1	1053.2×	0.003	SOS1
regulation of T cell proliferation	1	1053.2×	0.003	SOS1
neurotrophin TRK receptor signaling pathway	1	1053.2×	0.003	SOS1
eyelid development in camera-type eye	1	1053.2×	0.003	SOS1
blood vessel morphogenesis	1	802.5×	0.004	SOS1
Fc-epsilon receptor signaling pathway	1	732.7×	0.004	SOS1
positive regulation of Rac protein signal transduction	1	648.1×	0.004	SOS1
leukocyte migration	1	624.1×	0.004	SOS1
B cell homeostasis	1	561.7×	0.004	SOS1
positive regulation of epidermal growth factor receptor signaling pathway	1	495.6×	0.004	SOS1
insulin-like growth factor receptor signaling pathway	1	495.6×	0.004	SOS1
B cell receptor signaling pathway	1	401.2×	0.004	SOS1
hair follicle development	1	383.0×	0.004	SOS1
fibroblast growth factor receptor signaling pathway	1	285.6×	0.005	SOS1
T cell activation	1	259.3×	0.005	SOS1
response to ischemia	1	251.5×	0.005	SOS1
myelination	1	251.5×	0.005	SOS1
epidermal growth factor receptor signaling pathway	1	247.8×	0.005	SOS1
roof of mouth development	1	247.8×	0.005	SOS1
insulin receptor signaling pathway	1	221.7×	0.006	SOS1
Ras protein signal transduction	1	205.5×	0.006	SOS1
multicellular organism growth	1	137.0×	0.009	SOS1
cytokine-mediated signaling pathway	1	130.6×	0.009	SOS1

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 2 · Undrugged: 0

Druggability breadth: 2 of 2 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
SOS1	IDARUBICIN

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SOS1	5	4
CDKL4	1	1

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
IDARUBICIN	4	SOS1
DOXORUBICIN	4	SOS1
SOTORASIB	4	SOS1
ADAGRASIB	4	SOS1
MRTX-0902	1	SOS1
5-(6-BENZOTHIAZOLYLMETHYLENE)-3,5-DIHYDRO-2-(((1S)-1-(METHOXYMETHYL)-3-METHYLBUTYL)AMINO)-4H-IMIDAZOL-4-ONE, (5Z)-	1	CDKL4

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
SOS1	421	Binding:409, Functional:12
CDKL4	20	Binding:20

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
SOS1	421

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

6 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)
IDARUBICIN	4	SOS1
DOXORUBICIN	4	SOS1
SOTORASIB	4	SOS1
ADAGRASIB	4	SOS1
MRTX-0902	1	SOS1
5-(6-BENZOTHIAZOLYLMETHYLENE)-3,5-DIHYDRO-2-(((1S)-1-(METHOXYMETHYL)-3-METHYLBUTYL)AMINO)-4H-IMIDAZOL-4-ONE, (5Z)-	1	CDKL4

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	SOS1
B	Phased (≥1) drug, not yet approved	1	CDKL4
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.