Noonan syndrome 9

Summary

Noonan syndrome 9 (MONDO:0014691) is a disease caused by SOS2 (GenCC Definitive), with 3 cohort genes.

At a glance

• Causal gene: SOS2 (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 1,534

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Noonan syndrome 9
Mondo ID	MONDO:0014691
OMIM	616559
DOID	DOID:0060587
NCIT	C176937
UMLS	C4225282
MedGen	896352
GARD	0016137
Is cancer (heuristic)	no

Also known as: Noonan syndrome 9 · Noonan syndrome caused by mutation in SOS2 · Noonan syndrome type 9 · NS9 · SOS2 Noonan syndrome

Data availability: 1,534 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 9

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 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

600 retrieved; paginated sample, class counts are floors:

257 likely benign, 256 uncertain significance, 56 conflicting classifications of pathogenicity, 16 benign/likely benign, 12 benign, 2 pathogenic, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
2039738	NM_006939.4(SOS2):c.1291G>A (p.Glu431Lys)	SOS2	Pathogenic	criteria provided, single submitter
209091	NM_006939.4(SOS2):c.1127C>G (p.Thr376Ser)	SOS2	Pathogenic	criteria provided, multiple submitters, no conflicts
209092	NM_006939.4(SOS2):c.800T>A (p.Met267Lys)	SOS2	Likely pathogenic	reviewed by expert panel
1008208	NM_006939.4(SOS2):c.1264G>A (p.Glu422Lys)	SOS2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1009041	NM_006939.4(SOS2):c.3868C>G (p.Pro1290Ala)	SOS2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1009920	NM_006939.4(SOS2):c.364G>A (p.Val122Met)	SOS2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1022197	NM_006939.4(SOS2):c.3944C>T (p.Ser1315Leu)	SOS2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1022639	NM_006939.4(SOS2):c.3902A>G (p.His1301Arg)	SOS2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1044427	NM_006939.4(SOS2):c.3644C>G (p.Thr1215Ser)	SOS2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1058281	NM_006939.4(SOS2):c.2068G>A (p.Val690Ile)	SOS2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1062417	NM_006939.4(SOS2):c.1567A>G (p.Ile523Val)	SOS2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1112815	NM_006939.4(SOS2):c.1989A>G (p.Lys663=)	SOS2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1172861	NM_006939.4(SOS2):c.3026A>G (p.Asn1009Ser)	SOS2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1355420	NM_006939.4(SOS2):c.3673G>C (p.Glu1225Gln)	SOS2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1361688	NM_006939.4(SOS2):c.2217G>T (p.Lys739Asn)	SOS2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1362777	NM_006939.4(SOS2):c.3772T>G (p.Ser1258Ala)	SOS2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1367776	NM_006939.4(SOS2):c.3735T>G (p.Asp1245Glu)	SOS2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1370463	NM_006939.4(SOS2):c.374A>T (p.His125Leu)	SOS2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1370968	NM_006939.4(SOS2):c.532C>G (p.Gln178Glu)	SOS2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1382582	NM_006939.4(SOS2):c.2275A>G (p.Ile759Val)	SOS2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1392321	NM_006939.4(SOS2):c.2166A>T (p.Lys722Asn)	SOS2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1396080	NM_006939.4(SOS2):c.3641A>T (p.Asp1214Val)	SOS2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1404777	NM_006939.4(SOS2):c.3547C>T (p.Pro1183Ser)	SOS2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1410946	NM_006939.4(SOS2):c.2191A>G (p.Ile731Val)	SOS2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1412201	NM_006939.4(SOS2):c.1732A>G (p.Lys578Glu)	SOS2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1420396	NM_006939.4(SOS2):c.1714G>A (p.Val572Ile)	SOS2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1422493	NM_006939.4(SOS2):c.3523A>G (p.Ile1175Val)	SOS2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1431205	NM_006939.4(SOS2):c.121A>G (p.Asn41Asp)	SOS2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1443246	NM_006939.4(SOS2):c.3814C>T (p.Arg1272Cys)	SOS2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1466234	NM_006939.4(SOS2):c.1615C>T (p.Leu539Phe)	SOS2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 4 · 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
SOS2	Definitive	Autosomal dominant	Noonan syndrome 9	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SOS2	Orphanet:648	Noonan syndrome
ATL1	Orphanet:100984	Autosomal dominant spastic paraplegia type 3
ATL1	Orphanet:36386	Hereditary sensory and autonomic neuropathy type 1
L2HGDH	Orphanet:79314	L-2-hydroxyglutaric aciduria

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SOS2	HGNC:11188	ENSG00000100485	Q07890	Son of sevenless homolog 2	gencc,clinvar
ATL1	HGNC:11231	ENSG00000198513	Q8WXF7	Atlastin-1	clinvar
L2HGDH	HGNC:20499	ENSG00000087299	Q9H9P8	L-2-hydroxyglutarate dehydrogenase, mitochondrial	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SOS2	Son of sevenless homolog 2	Acts as guanine nucleotide exchange factor (GEF) for RAS proteins.
ATL1	Atlastin-1	Atlastin-1 (ATL1) is a membrane-anchored GTPase that mediates the GTP-dependent fusion of endoplasmic reticulum (ER) membranes, maintaining the continuous ER network.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 1 · Druggable fraction: 0.33

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
Scaffold/PPI	1	5.8×	0.345
Enzyme (other)	1	4.0×	0.345
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SOS2	Scaffold/PPI	no		DH_dom, Ras-like_Gua-exchang_fac_N, PH_domain
ATL1	Other/Unknown	no		Guanylate-bd_N, P-loop_NTPase, G_GB1_RHD3_dom
L2HGDH	Enzyme (other)	yes	1.1.99.2	FAD-dep_OxRdtase, FAD/NAD-bd_sf

Expression context

Cohort genes with no expression data: 0.

3 cohort genes 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
biceps brachii	1
buccal mucosa cell	1
vastus lateralis	1
Brodmann (1909) area 23	1
endothelial cell	1
middle temporal gyrus	1
gastrocnemius	1
muscle of leg	1
primordial germ cell in gonad	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SOS2	298	ubiquitous	marker	vastus lateralis, biceps brachii, buccal mucosa cell
ATL1	241	ubiquitous	marker	middle temporal gyrus, Brodmann (1909) area 23, endothelial cell
L2HGDH	209	ubiquitous	marker	primordial germ cell in gonad, muscle of leg, gastrocnemius

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SOS2	2,473
L2HGDH	1,778
ATL1	1,206

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ATL1	Q8WXF7	14
SOS2	Q07890	11

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
L2HGDH	Q9H9P8	88.26

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 25. Enrichment computed across 3 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Interconversion of 2-oxoglutarate and 2-hydroxyglutarate	1	1903.3×	0.013	L2HGDH
Activation of RAC1	1	407.9×	0.020	SOS2
Interleukin-15 signaling	1	380.7×	0.020	SOS2
Interleukin-2 family signaling	1	317.2×	0.020	SOS2
Cell death signalling via NRAGE, NRIF and NADE	1	109.8×	0.039	SOS2
p75 NTR receptor-mediated signalling	1	93.6×	0.039	SOS2
NRAGE signals death through JNK	1	92.1×	0.039	SOS2
Death Receptor Signaling	1	69.6×	0.040	SOS2
G alpha (12/13) signalling events	1	68.8×	0.040	SOS2
Signaling by ROBO receptors	1	62.1×	0.040	SOS2
Aerobic respiration and respiratory electron transport	1	44.3×	0.051	L2HGDH
Signaling by Interleukins	1	32.1×	0.059	SOS2
RAC1 GTPase cycle	1	30.5×	0.059	SOS2
RHO GTPase cycle	1	30.1×	0.059	SOS2
Axon guidance	1	22.6×	0.065	SOS2
GPCR downstream signalling	1	21.7×	0.065	SOS2
Nervous system development	1	21.5×	0.065	SOS2
Cytokine Signaling in Immune system	1	20.4×	0.065	SOS2
Signaling by GPCR	1	20.0×	0.065	SOS2
Signaling by Rho GTPases	1	17.1×	0.070	SOS2
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1	16.7×	0.070	SOS2
Developmental Biology	1	7.2×	0.152	SOS2
Immune System	1	6.5×	0.161	SOS2
Metabolism	1	5.8×	0.172	L2HGDH
Signal Transduction	1	5.1×	0.187	SOS2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
small molecule metabolic process	1	5617.3×	0.002	L2HGDH
endoplasmic reticulum membrane fusion	1	1123.5×	0.004	ATL1
regulation of pro-B cell differentiation	1	1123.5×	0.004	SOS2
regulation of T cell differentiation in thymus	1	802.5×	0.004	SOS2
endoplasmic reticulum tubular network membrane organization	1	702.2×	0.004	ATL1
regulation of T cell proliferation	1	351.1×	0.006	SOS2
2-oxoglutarate metabolic process	1	312.1×	0.006	L2HGDH
B cell homeostasis	1	187.2×	0.009	SOS2
endoplasmic reticulum organization	1	140.4×	0.010	ATL1
insulin receptor signaling pathway	1	73.9×	0.017	SOS2
Ras protein signal transduction	1	68.5×	0.017	SOS2
axonogenesis	1	53.5×	0.020	ATL1
protein homooligomerization	1	40.7×	0.024	ATL1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 3 evidence-associated genes (33%) 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
SOS2	TACRINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SOS2	1	4
ATL1	0	0
L2HGDH	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
TACRINE	4	SOS2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
SOS2	10	Binding:10

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
L2HGDH	1.1.99.2	L-2-hydroxyglutarate dehydrogenase

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; 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)
TACRINE	4	SOS2

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	SOS2
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	L2HGDH
E	Difficult family or no structure, no drug	1	ATL1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
ATL1	0	—
L2HGDH	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.