SOS2

SOS Ras/Rho guanine nucleotide exchange factor 2, the group of Dbl family Rho GEFs|Pleckstrin homology domain containing

Basic information

Region (hg38): 14:50117130-50231578

Links

ENSG00000100485 ∙ NCBI:6655 ∙ OMIM:601247 ∙ HGNC:11188 ∙ Uniprot:Q07890 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• Noonan syndrome 9 (Strong), mode of inheritance: AD
• Noonan syndrome 9 (Strong), mode of inheritance: AD
• Noonan syndrome 9 (Strong), mode of inheritance: AD
• Noonan syndrome (Supportive), mode of inheritance: AD
• Noonan syndrome (Definitive), mode of inheritance: AD
• Noonan syndrome 9 (Definitive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Noonan syndrome 9	AD	Cardiovascular; Hematologic	Surveillance and treatment related to manifestations such as cardiac anomalies (which include pulmonic stenosis) can be beneficial; The condition can include bleeding diathesis, and recognition and preventive measures (eg, in surgical situations) can be beneficial	Cardiovascular; Craniofacial; Dermatologic; Hematologic; Musculoskeletal; Neurologic	25795793

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the SOS2 gene.

• Noonan syndrome 9 (5 variants)
• Noonan syndrome (3 variants)
• not provided (2 variants)
• Noonan syndrome 1 (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the SOS2 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			5	334	8	347
missense	5	6	633	70	11	725
nonsense			15	1		16
start loss			1			1
frameshift			20	2	4	26
inframe indel			9	2	1	12
splice donor/acceptor (+/-2bp)			9			9
splice region			37	38	11	86
non coding			8	205	96	309
Total	5	6	700	614	120

Variants in SOS2

This is a list of pathogenic ClinVar variants found in the SOS2 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
14-50118110-C-T		Noonan syndrome 9	Uncertain significance (Jul 16, 2021)
14-50118294-A-T			Likely benign (Jul 17, 2018)
14-50118346-A-G		Noonan syndrome 9 • not specified • Noonan syndrome	Uncertain significance (Jan 17, 2025)
14-50118347-T-C		Noonan syndrome 9	Likely benign (Dec 11, 2023)
14-50118356-T-G		Noonan syndrome 9	Conflicting classifications of pathogenicity (Apr 17, 2024)
14-50118359-T-C		Noonan syndrome 9 • Cardiovascular phenotype	Likely benign (Nov 08, 2022)
14-50118362-A-G		Noonan syndrome 9 • Cardiovascular phenotype	Likely benign (Dec 16, 2021)
14-50118362-AT-A		Noonan syndrome 9	Uncertain significance (Nov 24, 2023)
14-50118368-T-C		Cardiovascular phenotype • Noonan syndrome 9	Likely benign (Jul 19, 2023)
14-50118370-G-A		Cardiovascular phenotype	Likely benign (Oct 28, 2024)
14-50118375-G-A		Noonan syndrome 9 • Cardiovascular phenotype	Uncertain significance (Apr 13, 2024)
14-50118378-A-G		Noonan syndrome 9	Uncertain significance (Jul 12, 2022)
14-50118382-T-G			Uncertain significance (Nov 01, 2024)
14-50118383-G-A		Noonan syndrome 9 • Cardiovascular phenotype	Likely benign (Oct 28, 2024)
14-50118385-A-G		Noonan syndrome 9 • Cardiovascular phenotype	Uncertain significance (Jan 11, 2024)
14-50118386-C-A		Noonan syndrome 9	Uncertain significance (Apr 17, 2023)
14-50118387-A-G		Cardiovascular phenotype	Uncertain significance (Jul 14, 2024)
14-50118388-A-C		Cardiovascular phenotype	Uncertain significance (Oct 28, 2024)
14-50118389-T-C		Noonan syndrome 9 • Cardiovascular phenotype • not specified	Likely benign (Jan 09, 2024)
14-50118390-G-T		Noonan syndrome 9	Uncertain significance (Mar 23, 2023)
14-50118391-G-A		Noonan syndrome 9 • SOS2-related disorder • Cardiovascular phenotype • not specified	Benign/Likely benign (Jan 22, 2025)
14-50118391-G-C		Noonan syndrome 9	Benign (Dec 03, 2023)
14-50118391-G-T		Noonan syndrome 9	Uncertain significance (Nov 12, 2023)
14-50118392-G-A		Noonan syndrome 9 • Cardiovascular phenotype	Likely benign (Apr 06, 2024)
14-50118392-G-C		Noonan syndrome 9	Likely benign (Jan 22, 2024)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
SOS2	protein_coding	protein_coding	ENST00000216373	23	114430

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.00	0.000452	125730	0	18	125748	0.0000716

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	2.53	506	693	0.730	0.0000356	8778
Missense in Polyphen		130	238.64	0.54475		3048
Synonymous	0.444	229	238	0.963	0.0000117	2488
Loss of Function	6.40	10	66.2	0.151	0.00000384	828

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000304	0.0000304
Ashkenazi Jewish	0.000100	0.0000992
East Asian	0.0000571	0.0000544
Finnish	0.0000926	0.0000924
European (Non-Finnish)	0.0000893	0.0000879
Middle Eastern	0.0000571	0.0000544
South Asian	0.000106	0.0000980
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Promotes the exchange of Ras-bound GDP by GTP. {ECO:0000250|UniProtKB:Q62245}.
• Disease: DISEASE: 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. {ECO:0000269|PubMed:25795793}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: PI3K-Akt signaling pathway - Homo sapiens (human);Non-small cell lung cancer - Homo sapiens (human);Chronic myeloid leukemia - Homo sapiens (human);Gastric cancer - Homo sapiens (human);Focal adhesion - Homo sapiens (human);mTOR signaling pathway - Homo sapiens (human);Relaxin signaling pathway - Homo sapiens (human);T cell receptor signaling pathway - Homo sapiens (human);B cell receptor signaling pathway - Homo sapiens (human);Fc epsilon RI signaling pathway - Homo sapiens (human);Renal cell carcinoma - Homo sapiens (human);Neurotrophin signaling pathway - Homo sapiens (human);Choline metabolism in cancer - Homo sapiens (human);Jak-STAT signaling pathway - Homo sapiens (human);Acute myeloid leukemia - Homo sapiens (human);GnRH signaling pathway - Homo sapiens (human);Breast cancer - Homo sapiens (human);ErbB signaling pathway - Homo sapiens (human);Gap junction - Homo sapiens (human);FoxO signaling pathway - Homo sapiens (human);Chemokine signaling pathway - Homo sapiens (human);Regulation of actin cytoskeleton - Homo sapiens (human);Thermogenesis - Homo sapiens (human);Hepatocellular carcinoma - Homo sapiens (human);Glioma - Homo sapiens (human);Prostate cancer - Homo sapiens (human);Estrogen signaling pathway - Homo sapiens (human);Ras signaling pathway - Homo sapiens (human);MAPK signaling pathway - Homo sapiens (human);Natural killer cell mediated cytotoxicity - Homo sapiens (human);Phospholipase D signaling pathway - Homo sapiens (human);Proteoglycans in cancer - Homo sapiens (human);Prolactin signaling pathway - Homo sapiens (human);MicroRNAs in cancer - Homo sapiens (human);Pathways in cancer - Homo sapiens (human);Hepatitis C - Homo sapiens (human);Endometrial cancer - Homo sapiens (human);Colorectal cancer - Homo sapiens (human);Alcoholism - Homo sapiens (human);Insulin signaling pathway - Homo sapiens (human);Human papillomavirus infection - Homo sapiens (human);MAPK Signaling Pathway;Angiopoietin Like Protein 8 Regulatory Pathway;Chemokine signaling pathway;Endometrial cancer;PI3K-Akt Signaling Pathway;MET in type 1 papillary renal cell carcinoma;Ras Signaling;EMT transition in Colorectal Cancer;EGF-EGFR Signaling Pathway;Insulin Signaling;Regulation of Actin Cytoskeleton;DNA Damage Response (only ATM dependent);Developmental Biology;Signaling by GPCR;Regulation of Ras family activation;Signal Transduction;B cell receptor signaling;CD4 T cell receptor signaling-ERK cascade;HGF;TCR;IGF signaling;FGF;insulin Mam;Activation of RAC1;Rho GTPase cycle;BCR;Signaling by Rho GTPases;Integrin;EGFR1;NRAGE signals death through JNK;JAK STAT pathway and regulation;PDGF;NGF;Death Receptor Signalling;p75 NTR receptor-mediated signalling;Signaling by ROBO receptors;Axon guidance;G alpha (12/13) signalling events;TNFalpha;GPCR downstream signalling;EGF;Cell death signalling via NRAGE, NRIF and NADE;insulin;CD4 T cell receptor signaling (Consensus)

Recessive Scores

• pRec: 0.115

Intolerance Scores

• loftool: 0.227
• rvis_EVS: -0.93
• rvis_percentile_EVS: 9.72

Haploinsufficiency Scores

• pHI: 0.941
• hipred: Y
• hipred_score: 0.726
• ghis: 0.580

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.757

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium

Mouse Genome Informatics

• Gene name: Sos2
• Phenotype: normal phenotype

Zebrafish Information Network

• Gene name: sos2
• Affected structure: pronephric proximal convoluted tubule
• Phenotype tag: abnormal
• Phenotype quality: decreased size

Gene ontology

• Biological process: G protein-coupled receptor signaling pathway;small GTPase mediated signal transduction;regulation of Rho protein signal transduction;positive regulation of apoptotic process;regulation of small GTPase mediated signal transduction;positive regulation of small GTPase mediated signal transduction
• Cellular component: nucleosome;cytosol
• Molecular function: DNA binding;guanyl-nucleotide exchange factor activity;Rho guanyl-nucleotide exchange factor activity;protein binding;protein heterodimerization activity