SOS2

Summary

SOS2 (SOS Ras/Rho guanine nucleotide exchange factor 2, HGNC:11188) is a protein-coding gene on chromosome 14q21.3, encoding Son of sevenless homolog 2 (Q07890). Acts as guanine nucleotide exchange factor (GEF) for RAS proteins.

This gene encodes a regulatory protein that is involved in the positive regulation of ras proteins. Mutations in this gene are associated with Noonan Syndrome-9.

Source: NCBI Gene 6655 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Noonan syndrome (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 14
• Clinical variants (ClinVar): 2,008 total — 5 pathogenic, 4 likely-pathogenic
• Phenotypes (HPO): 81
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_006939

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11188
Approved symbol	SOS2
Name	SOS Ras/Rho guanine nucleotide exchange factor 2
Location	14q21.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000100485
Ensembl biotype	protein_coding
OMIM	601247
Entrez	6655

Gene structure

Transcript identifiers

Ensembl transcripts: 13 — 10 protein_coding, 2 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000216373, ENST00000543680, ENST00000555666, ENST00000555794, ENST00000556452, ENST00000556469, ENST00000934708, ENST00000934709, ENST00000953731, ENST00000953732, ENST00000953733, ENST00000953734, ENST00000953735

RefSeq mRNA: 2 — MANE Select: NM_006939 NM_001411020, NM_006939

CCDS: CCDS91874, CCDS9697

Canonical transcript exons

ENST00000216373 — 23 exons

Exon	Start	End
ENSE00000656810	50120275	50120384
ENSE00000656814	50134123	50134239
ENSE00000656815	50138612	50138784
ENSE00000656816	50139942	50140059
ENSE00000656817	50145170	50145332
ENSE00000656818	50145477	50145596
ENSE00000656819	50150008	50150230
ENSE00000656821	50153070	50153173
ENSE00000656822	50156999	50157121
ENSE00000656827	50180572	50180682
ENSE00000656829	50182463	50182606
ENSE00000656830	50188497	50188700
ENSE00000854636	50129961	50130002
ENSE00000854637	50130501	50130762
ENSE00001174956	50117130	50118853
ENSE00002525812	50231197	50231578
ENSE00003482357	50199691	50199855
ENSE00003493295	50204284	50204409
ENSE00003591887	50200953	50201084
ENSE00003741626	50158565	50158646
ENSE00003743313	50159431	50160086
ENSE00003744640	50174454	50174552
ENSE00003751699	50161482	50161609

Expression profiles

Bgee: expression breadth ubiquitous, 298 present calls, max score 97.15.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 16.5551 / max 1368.4825, expressed in 1794 samples.

FANTOM5 promoters (12 alternative TSS)

Promoter ID	TPM avg	Samples expressed
143137	9.1988	1715
143142	2.6390	1031
143138	1.4751	808
143141	0.7738	315
143144	0.7268	409
143140	0.6739	349
143139	0.5240	272
143143	0.2493	96
207211	0.2071	76
143134	0.0561	15

Top tissues by expression

299 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
vastus lateralis	UBERON:0001379	97.15	gold quality
biceps brachii	UBERON:0001507	96.94	gold quality
buccal mucosa cell	CL:0002336	96.69	gold quality
quadriceps femoris	UBERON:0001377	96.68	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	96.59	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	96.13	gold quality
jejunal mucosa	UBERON:0000399	95.75	gold quality
jejunum	UBERON:0002115	95.49	gold quality
skeletal muscle tissue	UBERON:0001134	95.36	gold quality
diaphragm	UBERON:0001103	95.25	gold quality
germinal epithelium of ovary	UBERON:0001304	95.03	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	94.99	gold quality
body of tongue	UBERON:0011876	94.30	gold quality
corpus callosum	UBERON:0002336	94.25	gold quality
subthalamic nucleus	UBERON:0001906	93.85	gold quality
muscle tissue	UBERON:0002385	93.82	gold quality
inferior vagus X ganglion	UBERON:0005363	93.66	gold quality
deltoid	UBERON:0001476	93.63	gold quality
corpus epididymis	UBERON:0004359	93.52	gold quality
inferior olivary complex	UBERON:0002127	93.45	gold quality
mammary duct	UBERON:0001765	93.44	gold quality
parietal pleura	UBERON:0002400	93.36	gold quality
epithelium of mammary gland	UBERON:0003244	93.22	gold quality
heart right ventricle	UBERON:0002080	93.03	gold quality
skeletal muscle organ	UBERON:0014892	92.93	gold quality
muscle organ	UBERON:0001630	92.92	gold quality
pleura	UBERON:0000977	92.89	gold quality
superficial temporal artery	UBERON:0001614	92.82	gold quality
medulla oblongata	UBERON:0001896	92.81	gold quality
bone marrow	UBERON:0002371	92.76	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.19

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 10)

• Significant association of single nucleotide polymorphism within three genes–PPARgamma, SOS2, and PCK1–with Alzheimer’s disease, was confirmed. (PMID:17440948)
• Loss of MADD expression resulted in reduced Grb2 and Sos1/2 recruitment to the TNFR1 complex and decreased Ras and MEKK1/2 activation (PMID:19289468)
• intracellular Francisella tularensis novicida triggers temporal and early activation of Ras through the SOS2/GrB2/PKCalpha/PKCbetaI quaternary complex; Ras signalling by intracellular F. tularensis is essential for intracellular proliferation in the cytosol (PMID:20618341)
• multicenter pharmacogenetic study in children (ages 6-11): Data suggest that SNP in SOS2 (rs13379306) in children with growth hormone deficiency is associated with drug resistance to hormone replacement therapy with recombinant human growth hormone. (PMID:23761422)
• We identified two novel genes, SOS2 and LZTR1, associated with Noonan syndrome, thereby expanding the molecular spectrum of RASopathies. (PMID:25795793)
• Activating Mutations Affecting the Dbl Homology Domain of SOS2 Cause Noonan Syndrome (PMID:26173643)
• miR-148a-3p inhibits NSCLC cells proliferation and epithelial-mesenchymal transition by reducing the expression of SOS2 (PMID:30536836)
• Variants of SOS2 are a rare cause of Noonan syndrome with particular predisposition for lymphatic complications. (PMID:32788663)
• First prenatal case of Noonan syndrome with SOS2 mutation: Implications of early diagnosis for genetic counseling. (PMID:33750022)
• Genetic variants of SOS2, MAP2K1 and RASGRF2 in the RAS pathway genes predict survival of HBV-related hepatocellular carcinoma patients. (PMID:37029817)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	sos2	ENSDARG00000060506
mus_musculus	Sos2	ENSMUSG00000034801
rattus_norvegicus	Sos2	ENSRNOG00000004826

Paralogs (24): RASGRF1 (ENSG00000058335), RASGRP2 (ENSG00000068831), RAPGEF3 (ENSG00000079337), RAPGEF4 (ENSG00000091428), RAPGEF1 (ENSG00000107263), RAPGEFL1 (ENSG00000108352), RAPGEF2 (ENSG00000109756), RASGRF2 (ENSG00000113319), SOS1 (ENSG00000115904), RALGPS2 (ENSG00000116191), RAPGEF5 (ENSG00000136237), RALGPS1 (ENSG00000136828), RASGEF1B (ENSG00000138670), RGL1 (ENSG00000143344), RASGEF1C (ENSG00000146090), RASGRP3 (ENSG00000152689), RAPGEF6 (ENSG00000158987), RGL4 (ENSG00000159496), RALGDS (ENSG00000160271), RASGRP4 (ENSG00000171777), RASGRP1 (ENSG00000172575), RASGEF1A (ENSG00000198915), RGL3 (ENSG00000205517), RGL2 (ENSG00000237441)

Protein

Protein identifiers

Son of sevenless homolog 2 — Q07890 (reviewed: Q07890)

All UniProt accessions (3): Q07890, A0A087X277, G3V5W3

UniProt curated annotations — full annotation on UniProt →

Function. Acts as guanine nucleotide exchange factor (GEF) for RAS proteins. Catalyzes the GDP-to-GTP exchange, resulting in an increase of the active GTP-bound form of HRAS. Acts as a key modulator of PI3K-AKT signaling.

Subunit / interactions. Interacts with TTC1. Interacts with GNA15.

Disease relevance. Noonan syndrome 9 (NS9) [MIM:616559] A form of Noonan syndrome, a disease characterized by short stature, facial dysmorphic features such as hypertelorism, a downward eyeslant and low-set posteriorly rotated ears, and a high incidence of congenital heart defects and hypertrophic cardiomyopathy. Other features can include a short neck with webbing or redundancy of skin, deafness, motor delay, variable intellectual deficits, multiple skeletal defects, cryptorchidism, and bleeding diathesis. Individuals with Noonan syndrome are at risk of juvenile myelomonocytic leukemia, a myeloproliferative disorder characterized by excessive production of myelomonocytic cells. The disease is caused by variants affecting the gene represented in this entry.

Isoforms (2)

UniProt ID	Names	Canonical?
Q07890-1	1	yes
Q07890-2	2

RefSeq proteins (2): NP_001397949, NP_008870* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000219	DH_dom	Domain
IPR000651	Ras-like_Gua-exchang_fac_N	Domain
IPR001849	PH_domain	Domain
IPR001895	RASGEF_cat_dom	Domain
IPR008937	Ras-like_GEF	Family
IPR009072	Histone-fold	Homologous_superfamily
IPR011993	PH-like_dom_sf	Homologous_superfamily
IPR019804	Ras_G-nucl-exch_fac_CS	Conserved_site
IPR023578	Ras_GEF_dom_sf	Homologous_superfamily
IPR035899	DBL_dom_sf	Homologous_superfamily
IPR036964	RASGEF_cat_dom_sf	Homologous_superfamily
IPR055251	SOS1_NGEF_PH	Domain

Pfam: PF00617, PF00618, PF00621, PF22697

UniProt features (87 total): helix 29, sequence conflict 17, sequence variant 10, strand 10, turn 6, compositionally biased region 5, domain 4, region of interest 3, chain 1, modified residue 1, splice variant 1

Structure

Experimental structures (PDB)

11 structures.

PDB	Method	Resolution (Å)
8UF2	X-RAY DIFFRACTION	1.6
9BVI	X-RAY DIFFRACTION	1.79
8T5M	X-RAY DIFFRACTION	1.79
9BVF	X-RAY DIFFRACTION	1.82
8T5G	X-RAY DIFFRACTION	1.92
9GIN	X-RAY DIFFRACTION	2.06
8T5R	X-RAY DIFFRACTION	2.12
9BVE	X-RAY DIFFRACTION	2.4
8UC9	X-RAY DIFFRACTION	2.44
6EIE	X-RAY DIFFRACTION	2.72
8UH0	X-RAY DIFFRACTION	2.73

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q07890-F1	74.67	0.37

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (1): 1321

Function

Pathways and Gene Ontology

Reactome pathways

22 pathways

ID	Pathway
R-HSA-193648	NRAGE signals death through JNK
R-HSA-416482	G alpha (12/13) signalling events
R-HSA-428540	Activation of RAC1
R-HSA-8983432	Interleukin-15 signaling
R-HSA-9013149	RAC1 GTPase cycle
R-HSA-1266738	Developmental Biology
R-HSA-1280215	Cytokine Signaling in Immune system
R-HSA-162582	Signal Transduction
R-HSA-168256	Immune System
R-HSA-193704	p75 NTR receptor-mediated signalling
R-HSA-194315	Signaling by Rho GTPases
R-HSA-204998	Cell death signalling via NRAGE, NRIF and NADE
R-HSA-372790	Signaling by GPCR
R-HSA-376176	Signaling by ROBO receptors
R-HSA-388396	GPCR downstream signalling
R-HSA-422475	Axon guidance
R-HSA-449147	Signaling by Interleukins
R-HSA-451927	Interleukin-2 family signaling
R-HSA-73887	Death Receptor Signaling
R-HSA-9012999	RHO GTPase cycle
R-HSA-9675108	Nervous system development
R-HSA-9716542	Signaling by Rho GTPases, Miro GTPases and RHOBTB3

MSigDB gene sets: 552 (showing top): GOBP_REGULATION_OF_CELL_ACTIVATION, REACTOME_INTERLEUKIN_2_FAMILY_SIGNALING, GOBP_HEMATOPOIETIC_PROGENITOR_CELL_DIFFERENTIATION, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_REGULATION_OF_LEUKOCYTE_PROLIFERATION, GOBP_B_CELL_HOMEOSTASIS, DACOSTA_UV_RESPONSE_VIA_ERCC3_XPCS_DN, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, KEGG_MAPK_SIGNALING_PATHWAY, GOLDRATH_IMMUNE_MEMORY, GOBP_LYMPHOCYTE_HOMEOSTASIS, KEGG_DORSO_VENTRAL_AXIS_FORMATION, REACTOME_NRAGE_SIGNALS_DEATH_THROUGH_JNK, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, BEIER_GLIOMA_STEM_CELL_DN

GO Biological Process (8): B cell homeostasis (GO:0001782), Ras protein signal transduction (GO:0007265), insulin receptor signaling pathway (GO:0008286), regulation of T cell differentiation in thymus (GO:0033081), regulation of T cell proliferation (GO:0042129), regulation of pro-B cell differentiation (GO:2000973), lymphocyte homeostasis (GO:0002260), small GTPase-mediated signal transduction (GO:0007264)

GO Molecular Function (3): guanyl-nucleotide exchange factor activity (GO:0005085), protein heterodimerization activity (GO:0046982), protein binding (GO:0005515)

GO Cellular Component (2): cytosol (GO:0005829), plasma membrane (GO:0005886)

Reactome top-level categories

Rollup of top-16 pathways:

Category	Pathways
Signal Transduction	2
Cell death signalling via NRAGE, NRIF and NADE	1
GPCR downstream signalling	1
Signaling by ROBO receptors	1
Interleukin-2 family signaling	1
RHO GTPase cycle	1
Immune System	1
Death Receptor Signaling	1
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1
p75 NTR receptor-mediated signalling	1
Axon guidance	1
Signaling by GPCR	1
Nervous system development	1
Cytokine Signaling in Immune system	1
Signaling by Interleukins	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
lymphocyte homeostasis	1
small GTPase-mediated signal transduction	1
cell surface receptor protein tyrosine kinase signaling pathway	1
cellular response to insulin stimulus	1
T cell differentiation in thymus	1
regulation of T cell differentiation	1
T cell proliferation	1
regulation of lymphocyte proliferation	1
regulation of T cell activation	1
pro-B cell differentiation	1
regulation of lymphoid progenitor cell differentiation	1
leukocyte homeostasis	1
intracellular signaling cassette	1
GTP binding	1
GDP binding	1
GTPase regulator activity	1
protein dimerization activity	1
binding	1
cytoplasm	1
cellular anatomical structure	1
membrane	1
cell periphery	1

Protein interactions and networks

STRING

2352 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SOS2	GRB2	P29354	999
SOS2	SHC1	P29353	995
SOS2	RABIF	P47224	965
SOS2	PTPN11	Q06124	945
SOS2	GAB2	Q9UQC2	915
SOS2	EGFR	P00533	903
SOS2	FRS2	Q8WU20	902
SOS2	IRS1	P35568	871
SOS2	GRAP2	O75791	847
SOS2	HRAS	P01112	798
SOS2	KRAS	P01116	794
SOS2	GAB1	Q13480	782
SOS2	SRC	P12931	737
SOS2	GRAP	Q13588	725
SOS2	LCK	P06239	709

IntAct

53 interactions, top by confidence:

A	B	Type	Score
GRB2	SOS2	psi-mi:“MI:0915”(physical association)	0.940
SOS2	GRB2	psi-mi:“MI:0915”(physical association)	0.940
GRB2	WIPF3	psi-mi:“MI:0914”(association)	0.730
CRK	SOS2	psi-mi:“MI:0915”(physical association)	0.670
NCK1	SOS2	psi-mi:“MI:0915”(physical association)	0.670
NCK2	SH3PXD2B	psi-mi:“MI:0914”(association)	0.640
SOS2	PLCG1	psi-mi:“MI:0915”(physical association)	0.600
SOS2	PLCG1	psi-mi:“MI:0407”(direct interaction)	0.600
EGFR	SOS2	psi-mi:“MI:0915”(physical association)	0.550
GRB2	ARHGEF35	psi-mi:“MI:0914”(association)	0.530
GRB2	SH3PXD2B	psi-mi:“MI:0914”(association)	0.530
NCK1	SH3PXD2B	psi-mi:“MI:0914”(association)	0.530
CRK	ARHGAP42	psi-mi:“MI:0914”(association)	0.530
PACSIN3	SOS2	psi-mi:“MI:0915”(physical association)	0.520
SNX9	SOS2	psi-mi:“MI:0915”(physical association)	0.520

BioGRID (68): SOS2 (Two-hybrid), SOS2 (Affinity Capture-MS), SOS2 (PCA), SOS2 (Affinity Capture-MS), SOS2 (Affinity Capture-RNA), SOS2 (Reconstituted Complex), SOS2 (Affinity Capture-MS), SHC1 (Affinity Capture-Western), EGFR (Affinity Capture-Western), SOS2 (Affinity Capture-MS), CKB (Affinity Capture-MS), DUT (Affinity Capture-MS), EVI5L (Affinity Capture-MS), FUBP3 (Affinity Capture-MS), GLO1 (Affinity Capture-MS)

ESM2 similar proteins: A0JM95, A1A4S6, A2A2Y4, A4II46, A4IJ06, A6NI28, B2RQE8, B5DFQ4, F1LVW7, O60879, O60890, O70566, O95267, P0C7A6, P0CAX5, Q02384, Q07889, Q07890, Q08DP6, Q0P4Q4, Q28EC1, Q4V7P7, Q566W7, Q5R6F6, Q5R803, Q5U4T3, Q62245, Q69ZK0, Q6DBW1, Q6DHR3, Q6NTL4, Q6PCS4, Q6Y5D8, Q6ZM89, Q7YQL5, Q7YQL6, Q8AVG0, Q8BHD4, Q8IV61, Q8N9B8

Diamond homologs: A2AR50, A2CEA7, B0M0P8, B0UXH6, F1M386, F1MSG6, F1PBJ0, O14827, P27671, P28818, P70392, Q03385, Q03386, Q07889, Q07890, Q12967, Q13905, Q13972, Q3MIN7, Q3UYI5, Q4R7W3, Q54FF3, Q54PQ4, Q54TK8, Q552M5, Q55GH9, Q5JS13, Q5ZJK0, Q60695, Q86G47, Q86X27, Q8CHG7, Q8IS14, Q8IS15, Q8IS16, Q8IS18, Q8IS20, Q8IS21, Q8SSQ0, Q8SSW7

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
GRB2	up-regulates	SOS2	binding
SOS2	up-regulates	HRAS	“guanine nucleotide exchange factor”
SOS2	up-regulates	KRAS	“guanine nucleotide exchange factor”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 31 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Downstream signal transduction	10	146.4×	5e-18
Constitutive Signaling by EGFRvIII	5	137.3×	2e-08
Signaling by ERBB2 ECD mutants	5	129.2×	2e-08
Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants	5	109.8×	4e-08
Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants	5	99.8×	5e-08
Regulation of signaling by CBL	5	95.5×	6e-08
Nephrin family interactions	5	91.5×	7e-08
Signaling by ERBB2 KD Mutants	5	81.3×	1e-07

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of Rac protein signal transduction	5	120.0×	9e-08
ephrin receptor signaling pathway	6	76.4×	4e-08
epidermal growth factor receptor signaling pathway	7	64.2×	6e-09
T cell receptor signaling pathway	5	28.1×	1e-04
cell migration	6	13.7×	2e-04
intracellular signal transduction	5	7.1×	6e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

2008 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	5
Likely pathogenic	4
Uncertain significance	933
Likely benign	745
Benign	133

Top pathogenic / likely-pathogenic (9)

Variant ID	HGVS	Classification
2039738	NM_006939.4(SOS2):c.1291G>A (p.Glu431Lys)	Pathogenic
209091	NM_006939.4(SOS2):c.1127C>G (p.Thr376Ser)	Pathogenic
373114	NM_006939.4(SOS2):c.800T>C (p.Met267Thr)	Pathogenic
684625	NM_006939.4(SOS2):c.1126A>T (p.Thr376Ser)	Pathogenic
974590	NM_006939.4(SOS2):c.791C>G (p.Thr264Arg)	Pathogenic
209092	NM_006939.4(SOS2):c.800T>A (p.Met267Lys)	Likely pathogenic
2821826	NM_006939.4(SOS2):c.1127C>T (p.Thr376Ile)	Likely pathogenic
4796475	NM_006939.4(SOS2):c.530A>T (p.Asp177Val)	Likely pathogenic
974591	NM_006939.4(SOS2):c.798_800delinsCAA (p.Glu266_Met267delinsAspLys)	Likely pathogenic

SpliceAI

4114 predictions. Top by Δscore:

Variant	Effect	Δscore
14:50130758:CTAGG:C	acceptor_gain	1.0000
14:50134116:GACTT:G	donor_loss	1.0000
14:50134117:ACTT:A	donor_loss	1.0000
14:50134118:CTTA:C	donor_loss	1.0000
14:50134119:TTA:T	donor_loss	1.0000
14:50134120:TA:T	donor_loss	1.0000
14:50134121:A:AC	donor_gain	1.0000
14:50134121:AC:A	donor_loss	1.0000
14:50134122:C:CA	donor_gain	1.0000
14:50134122:CA:C	donor_gain	1.0000
14:50134122:CAA:C	donor_gain	1.0000
14:50134122:CAAA:C	donor_gain	1.0000
14:50134122:CAAAT:C	donor_gain	1.0000
14:50134235:AATCT:A	acceptor_gain	1.0000
14:50134236:ATCT:A	acceptor_gain	1.0000
14:50134238:CT:C	acceptor_gain	1.0000
14:50134239:TC:T	acceptor_loss	1.0000
14:50134240:C:CA	acceptor_loss	1.0000
14:50134240:C:CC	acceptor_gain	1.0000
14:50134241:T:A	acceptor_loss	1.0000
14:50134245:A:AC	acceptor_gain	1.0000
14:50134246:T:C	acceptor_gain	1.0000
14:50134246:T:TC	acceptor_gain	1.0000
14:50134251:C:CT	acceptor_gain	1.0000
14:50134252:A:T	acceptor_gain	1.0000
14:50138610:AC:A	donor_gain	1.0000
14:50138611:CC:C	donor_gain	1.0000
14:50145163:AACTT:A	donor_loss	1.0000
14:50145164:ACTTA:A	donor_loss	1.0000
14:50145165:CTT:C	donor_loss	1.0000

AlphaMissense

8819 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
14:50138651:C:A	Q973H	1.000
14:50138651:C:G	Q973H	1.000
14:50138683:C:G	A963P	1.000
14:50138696:C:A	K958N	1.000
14:50138696:C:G	K958N	1.000
14:50138702:G:C	F956L	1.000
14:50138702:G:T	F956L	1.000
14:50138703:A:G	F956S	1.000
14:50138704:A:G	F956L	1.000
14:50138705:A:C	N955K	1.000
14:50138705:A:T	N955K	1.000
14:50138763:A:G	L936P	1.000
14:50138784:C:T	G929E	1.000
14:50139946:A:C	F927L	1.000
14:50139946:A:T	F927L	1.000
14:50139948:A:G	F927L	1.000
14:50139950:G:T	P926H	1.000
14:50139955:A:C	C924W	1.000
14:50139956:C:T	C924Y	1.000
14:50139959:G:T	P923H	1.000
14:50139977:A:G	L917P	1.000
14:50145186:A:G	L884P	1.000
14:50145188:T:A	R883S	1.000
14:50145188:T:G	R883S	1.000
14:50145189:C:G	R883T	1.000
14:50145242:A:C	N865K	1.000
14:50145242:A:T	N865K	1.000
14:50145525:A:G	L819S	1.000
14:50145560:C:A	W807C	1.000
14:50145560:C:G	W807C	1.000

dbSNP variants (sampled 300 via entrez): RS1000030353 (14:50139749 A>C), RS1000040596 (14:50160446 G>A), RS1000060750 (14:50179614 C>A), RS1000061391 (14:50139416 G>A), RS1000099696 (14:50136223 T>C,G), RS1000118108 (14:50214427 C>G), RS1000127523 (14:50217739 G>A), RS1000250380 (14:50132693 C>A), RS1000264432 (14:50120060 G>A), RS1000278177 (14:50163169 A>G,T), RS1000311067 (14:50162896 G>C,T), RS1000337473 (14:50208253 C>T), RS1000340134 (14:50151642 CTTAAT>C), RS1000367410 (14:50219798 G>A), RS1000372971 (14:50126391 A>C,G)

Disease associations

OMIM: gene MIM:601247 | disease phenotypes: MIM:616559, MIM:163950

GenCC curated gene-disease

Disease	Classification	Inheritance
Noonan syndrome 9	Definitive	Autosomal dominant
Noonan syndrome	Definitive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
Noonan syndrome	Definitive	AD

Mondo (6): Noonan syndrome 9 (MONDO:0014691), Noonan syndrome and Noonan-related syndrome (MONDO:0020297), congenital heart disease (MONDO:0005453), Noonan syndrome 1 (MONDO:0008104), Noonan syndrome (MONDO:0018997), RASopathy (MONDO:0021060)

Orphanet (3): Noonan syndrome (Orphanet:648), Noonan syndrome and Noonan-related syndrome (Orphanet:98733), RASopathy (Orphanet:536391)

HPO phenotypes

81 total (30 of 81 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000028	Cryptorchidism
HP:0000044	Hypogonadotropic hypogonadism
HP:0000072	Hydroureter
HP:0000078	Abnormality of the genital system
HP:0000179	Thick lower lip vermilion
HP:0000218	High palate
HP:0000316	Hypertelorism
HP:0000325	Triangular face
HP:0000347	Micrognathia
HP:0000348	High forehead
HP:0000358	Posteriorly rotated ears
HP:0000391	Thickened helices
HP:0000407	Sensorineural hearing impairment
HP:0000465	Webbed neck
HP:0000470	Short neck
HP:0000474	Thickened nuchal skin fold
HP:0000476	Cystic hygroma
HP:0000486	Strabismus
HP:0000494	Downslanted palpebral fissures
HP:0000508	Ptosis
HP:0000520	Proptosis
HP:0000635	Blue irides
HP:0000639	Nystagmus
HP:0000767	Pectus excavatum
HP:0000768	Pectus carinatum
HP:0000938	Osteopenia
HP:0000978	Bruising susceptibility
HP:0000995	Melanocytic nevus
HP:0001004	Lymphedema

GWAS associations

14 associations (top):

Study	Trait	p-value
GCST002312_10	Periodontal disease-related phenotype (Socransky)	8.000000e-06
GCST002380_4	Erythema nodosum in inflammatory bowel disease	7.000000e-06
GCST005580_117	Intraocular pressure	6.000000e-11
GCST006394_95	Intraocular pressure	2.000000e-10
GCST006412_86	Intraocular pressure	4.000000e-11
GCST007269_57	Pulse pressure	1.000000e-10
GCST007876_97	Estimated glomerular filtration rate	3.000000e-08
GCST007928_9	Medication use (diuretics)	1.000000e-10
GCST007929_98	Medication use (calcium channel blockers)	3.000000e-08
GCST007930_112	Medication use (agents acting on the renin-angiotensin system)	2.000000e-14
GCST008362_76	Birth weight	6.000000e-10
GCST009725_52	Intraocular pressure	2.000000e-10
GCST90002384_337	Hemoglobin	8.000000e-10
GCST90002403_505	Red blood cell count	6.000000e-09

EFO canonical traits (8, from GWAS)

EFO ID	Trait name
EFO:0004695	intraocular pressure measurement
EFO:0005763	pulse pressure measurement
EFO:0009928	Diuretic use measurement
EFO:0009930	Calcium channel blocker use measurement
EFO:0009931	Agents acting on the renin-angiotensin system use measurement
EFO:0004344	birth weight
EFO:0004509	hemoglobin measurement
EFO:0004305	erythrocyte count

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D006330	Heart Defects, Congenital	C14.240.400; C14.280.400; C16.131.240.400
D009634	Noonan Syndrome	C05.660.207.690; C14.240.400.787; C14.280.400.787; C16.131.240.400.784; C16.131.621.207.690; C17.300.690
C537846	Noonan like syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL4524041 (SINGLE PROTEIN), CHEMBL5169071 (PROTEIN-PROTEIN INTERACTION)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 35,360 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL95	TACRINE	4	35,360

PharmGKB: 1 entry (VIP=true, CPIC=false)

ChEMBL bioactivities

6 potent at pChembl≥5 of 16 total, top 6 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.89	Kd	1300	nM	CHEMBL6159919
5.85	Kd	1400	nM	CHEMBL6163045
5.80	Kd	1600	nM	CHEMBL6167330
5.47	Kd	3400	nM	CHEMBL6164095
5.34	Kd	4600	nM	CHEMBL1198612
5.28	Kd	5300	nM	CHEMBL6134434

CTD chemical–gene interactions

50 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases abundance, increases expression	4
Valproic Acid	affects expression, decreases expression, decreases methylation	4
potassium chromate(VI)	affects cotreatment, decreases expression	2
perfluorooctane sulfonic acid	affects expression, affects cotreatment, decreases expression	2
Arsenic	increases methylation, increases abundance, increases expression	2
ammonium 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)-propanoate	affects cotreatment, affects expression	1
moringin	affects cotreatment, decreases expression	1
geldanamycin	increases expression	1
testosterone enanthate	affects expression	1
bisphenol A	affects cotreatment, increases methylation	1
trichostatin A	decreases expression	1
arsenite	affects binding, decreases reaction	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
butyraldehyde	decreases expression	1
perfluorooctanoic acid	affects cotreatment, affects expression	1
ochratoxin A	decreases expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
di-n-butylphosphoric acid	affects expression	1
chromium hexavalent ion	decreases expression	1
entinostat	decreases expression	1
ON 01910	increases expression	1
perfluorobutanesulfonic acid	decreases expression, affects cotreatment, affects expression	1
asparanin A	decreases expression	1
jinfukang	decreases expression	1
Sunitinib	increases expression	1
Zoledronic Acid	affects cotreatment, increases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Vorinostat	decreases expression	1
Leflunomide	decreases expression	1
Fluvastatin	affects cotreatment, increases expression	1

ChEMBL screening assays

10 unique, capped per target: 10 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4881445	Binding	KRAS(G12C)–SOS2(cat) activation assay	Data for DCP probe BAY-293

Cellosaurus cell lines

4 cell lines: 3 cancer cell line, 1 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_D8BA	Ubigene A-549 SOS2 KO	Cancer cell line	Male
CVCL_D8W1	Ubigene HCT 116 SOS2 KO	Cancer cell line	Male
CVCL_D9SR	Ubigene HEK293 SOS2 KO	Transformed cell line	Female
CVCL_E0PQ	Ubigene HeLa SOS2 KO	Cancer cell line	Female

Clinical trials (associated diseases)

327 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00668824	PHASE4	UNKNOWN	Improved Diagnosis of Congenital Heart Disease by Magnetic Resonance Imaging Using Vasovist
NCT01368705	PHASE4	COMPLETED	Nitrogen Balance in Infants After Post Cardiothoracic Surgery
NCT01619982	PHASE4	COMPLETED	Pre-operative Prophylaxis With Vancomycin and Cefazolin in Pediatric Cardiovascular Surgery Patients
NCT02122679	PHASE4	WITHDRAWN	Tranexamic Acid Effect on Platelet Aggregation Following Infant Cardiopulmonary Bypass
NCT02527811	PHASE4	UNKNOWN	Ulinastatin Injection in in Pediatric Patients Undergoing Open Heart Surgery
NCT03014700	PHASE4	COMPLETED	Fibrinogen Concentrate vs Cryoprecipitate
NCT03408340	PHASE4	TERMINATED	Paravertebral Nerve Blocks in Neonates
NCT03630796	PHASE4	UNKNOWN	Effect of Sevoflurane in Postoperative Troponin I Levels in Children Undergoing Congenital Heart Defects Surgery
NCT03667703	PHASE4	COMPLETED	Stress Ulcer Prophylaxis Versus Placebo in Critically Ill Infants With Congenital Heart Disease
NCT04453761	PHASE4	UNKNOWN	Thiamine Influenced on Substrate Energy Effectiveness in Indonesian Children Undergoing Cardiopulmonary Bypass
NCT06668389	PHASE4	RECRUITING	Sodium-Glucose Cotransporter 2 Inhibitors for Repaired Tetralogy of Fallot Patients for Enhancement of Cardio-Pulmonary Status Trial
NCT07499154	PHASE4	NOT_YET_RECRUITING	Perioperative Lidocaine for Lung Protection in Infants Undergoing Cardiac Surgery
NCT00452725	PHASE3	COMPLETED	Effect of MAXOMAT ® on the Growth of Small Children to NOONAN’s Syndrome
NCT01529840	PHASE3	COMPLETED	Somatropin Effect on Linear Growth and Final Height in Subjects With Noonan Syndrome
NCT01529944	PHASE3	COMPLETED	Genetic Testing of Noonan Subjects Previously Treated With Norditropin®. An Extension to Trial GHNOO-1658
NCT01927861	PHASE3	COMPLETED	Investigating the Long-term Efficacy and Safety of Two Doses of NN-220 (Somatropin) in Short Stature Due to Noonan Syndrome
NCT02713945	PHASE3	COMPLETED	Treatment With HMG-COA Reductase Inhibitor of Growth and Bone Abnormalities in Children With Noonan Syndrome
NCT05723835	PHASE3	ACTIVE_NOT_RECRUITING	A Research Study Looking at How Safe Somapacitan is and How Well it Works in Children Who Need Help to Grow - REAL 9
NCT00000470	PHASE3	COMPLETED	Infant Heart Surgery: Central Nervous System Sequelae of Circulatory Arrest
NCT00000494	PHASE3	COMPLETED	Management of Patent Ductus in Premature Infants
NCT01134302	PHASE3	UNKNOWN	Hybrid Versus Norwood Management Strategies in Infants Undergoing Single Ventricle Palliation
NCT01607983	PHASE3	WITHDRAWN	Effects of Pulmonary Vasodilation Upon VA Coupling in Fontan Patients
NCT01662011	PHASE3	UNKNOWN	Application of Neurally Adjusted Ventilatory Assist to Children After Congenital Cardiac Surgery
NCT02320669	PHASE3	COMPLETED	Phase 3 Triiodothyronine Supplementation for Infants After Cardiopulmonary Bypass
NCT02615262	PHASE3	COMPLETED	Intraoperative Dexamethasone in Pediatric Cardiac Surgery
NCT03153137	PHASE3	COMPLETED	Clinical Study Assessing the Efficacy and Safety of Macitentan in Fontan-palliated Subjects
NCT03154476	PHASE3	COMPLETED	Role of Sildenafil for Fontan Associated Liver Disease (SiFALD) Study
NCT04536194	PHASE3	COMPLETED	Dopamine Versus Norepinephrine Under General Anesthesia
NCT04702373	PHASE3	ACTIVE_NOT_RECRUITING	Training in Exercise Activities and Motion for Growth (TEAM 4 Growth) RCT
NCT05049590	PHASE3	COMPLETED	Acute Normovolemic Hemodilution in Complex Cardiac Surgery
NCT06406517	PHASE3	UNKNOWN	Comparative Effectiveness of Gadopiclenol for Evaluation of Adult Congenital Heart Anatomy and Hemodynamics
NCT06693674	PHASE3	RECRUITING	Effect of Sacubitril-Valsartan on Cardiac Structure and Function
NCT06955260	PHASE3	NOT_YET_RECRUITING	SGLT2 Inhibition With Empagliflozin in Fontan Circulatory Failure
NCT00351221	PHASE2	TERMINATED	Research Study Using Recombinant Human Insulin-Like Growth Factor-1/Recombinant Human Insulin-Like Growth Factor Binding Protein-3 for Children With Noonan Syndrome
NCT06555237	PHASE2	RECRUITING	MEK Inhibitors for the Treatment of Hypertrophic Cardiomyopathy in Patients With RASopathies
NCT06668805	PHASE2	RECRUITING	A Study of Vosoritide in Children With Noonan Syndrome With Inadequate Growth During or After Human Growth Hormone Treatment
NCT00115375	PHASE2	COMPLETED	Platelet Aggregation Inhibition in Children on Clopidogrel (PICOLO)
NCT00350220	PHASE2	COMPLETED	Transfusion Strategies in Pediatric Cardiothoracic Surgery
NCT00374088	PHASE2	COMPLETED	N-Acetylcysteine in Neonatal Congenital Heart Surgery (INACT Study)
NCT00538785	PHASE2	COMPLETED	A Study to Evaluate MEDI-524 In Children With Hemodynamically Significant Congenital Heart Disease