SOS1

SOS Ras/Rac guanine nucleotide exchange factor 1, the group of Pleckstrin homology domain containing|Dbl family Rho GEFs

Basic information

Region (hg38): 2:38962206-39124345

Previous symbols: [ "GINGF" ]

Links

ENSG00000115904 ∙ NCBI:6654 ∙ OMIM:182530 ∙ HGNC:11187 ∙ Uniprot:Q07889 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• Noonan syndrome 4 (Strong), mode of inheritance: AD
• Noonan syndrome 4 (Definitive), mode of inheritance: AD
• Noonan syndrome 4 (Strong), mode of inheritance: AD
• Noonan syndrome (Supportive), mode of inheritance: AD
• hereditary gingival fibromatosis (Supportive), mode of inheritance: AD
• fibromatosis, gingival, 1 (Strong), mode of inheritance: AD
• Noonan syndrome 4 (Strong), mode of inheritance: AD
• Noonan syndrome (Definitive), mode of inheritance: AD
• Costello syndrome (Disputed Evidence), mode of inheritance: AD
• cardiofaciocutaneous syndrome (Disputed Evidence), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Noonan syndrome 4	AD	Cardiovascular; Hematologic	Surveillance and treatment related to manifestations such as cardiac anomalies (which include pulmonic stenosis and hypertrophic cardiomyopathy) 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	11868160; 17143285; 17143282; 17586837; 18678287; 18925667; 19047498; 18456719; 19438935; 19077116; 20602484; 20876176; 20301303

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the SOS1 gene.

• RASopathy (25 variants)
• not provided (22 variants)
• Noonan syndrome (20 variants)
• Noonan syndrome 4 (18 variants)
• Noonan syndrome and Noonan-related syndrome (9 variants)
• Noonan syndrome 1 (9 variants)
• Cardiovascular phenotype (7 variants)
• Fibromatosis, gingival, 1;Noonan syndrome 4 (4 variants)
• SOS1-related disorder (4 variants)
• Noonan syndrome 4;Fibromatosis, gingival, 1 (3 variants)
• Fibromatosis, gingival, 1 (2 variants)
• not specified (2 variants)
• Noonan syndrome 3 (1 variants)
• Inborn genetic diseases (1 variants)
• See cases (1 variants)
• Abnormal aortic valve morphology (1 variants)
• Neonatal hypotonia (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the SOS1 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			6	295	15	316
missense	26	37	650	37	10	760
nonsense			9			9
start loss						0
frameshift		1	15	1		17
inframe indel		1	14			15
splice donor/acceptor (+/-2bp)			3			3
splice region			33	37	6	76
non coding			85	180	69	334
Total	26	39	782	513	94

Variants in SOS1

This is a list of pathogenic ClinVar variants found in the SOS1 region.

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

Position	Type	Phenotype	Significance	ClinVar
2-38962804-G-A			Likely benign (Jul 01, 2024)
2-38962849-C-A			Likely benign (Aug 01, 2024)
2-38966091-G-C		not specified	Uncertain significance (May 07, 2024)
2-38973731-A-C		not specified	Uncertain significance (May 24, 2023)
2-38973767-C-G		not specified	Uncertain significance (May 24, 2023)
2-38973802-C-G		not specified	Uncertain significance (May 26, 2022)
2-38981559-T-C		Noonan syndrome 4 • Fibromatosis, gingival, 1	Uncertain significance (Jan 12, 2018)
2-38981603-G-A		Fibromatosis, gingival, 1 • Noonan syndrome 4	Benign/Likely benign (Jan 12, 2018)
2-38981714-G-T		Noonan syndrome 4 • Fibromatosis, gingival, 1	Uncertain significance (Jan 12, 2018)
2-38981747-C-A		Fibromatosis, gingival, 1 • Noonan syndrome 4 • Fibromatosis, gingival, 1;Noonan syndrome 4	Uncertain significance (Sep 09, 2021)
2-38981748-G-A		Noonan syndrome 4 • Fibromatosis, gingival, 1	Uncertain significance (Jan 12, 2018)
2-38981801-A-G		Noonan syndrome 4 • Fibromatosis, gingival, 1 • Noonan syndrome 4;Fibromatosis, gingival, 1	Conflicting classifications of pathogenicity (Jul 01, 2023)
2-38981810-A-G		Noonan syndrome 4 • Fibromatosis, gingival, 1 • Fibromatosis, gingival, 1;Noonan syndrome 4	Uncertain significance (Oct 27, 2021)
2-38981835-C-G		Noonan syndrome 4 • Fibromatosis, gingival, 1 • Fibromatosis, gingival, 1;Noonan syndrome 4	Uncertain significance (Feb 11, 2022)
2-38981906-A-G		Fibromatosis, gingival, 1 • Noonan syndrome 4	Benign (Jan 13, 2018)
2-38982013-A-G		Noonan syndrome 4 • Fibromatosis, gingival, 1	Uncertain significance (Jan 13, 2018)
2-38982074-A-G		Fibromatosis, gingival, 1 • Noonan syndrome 4	Uncertain significance (Jan 13, 2018)
2-38982097-C-G		Noonan syndrome 4 • Fibromatosis, gingival, 1	Uncertain significance (Jan 13, 2018)
2-38982099-A-G		Noonan syndrome 4 • Fibromatosis, gingival, 1	Uncertain significance (Jan 13, 2018)
2-38982100-A-G		Fibromatosis, gingival, 1 • Noonan syndrome 4	Benign (Jan 13, 2018)
2-38982105-AC-A			Benign (Feb 01, 2023)
2-38982232-G-A		Noonan syndrome 4 • Fibromatosis, gingival, 1	Benign/Likely benign (Jan 12, 2018)
2-38982255-A-G		Fibromatosis, gingival, 1 • Noonan syndrome 4	Benign/Likely benign (Aug 26, 2021)
2-38982255-AAAC-A		Noonan syndrome • Gingival fibromatosis	Uncertain significance (Jun 14, 2016)
2-38982285-A-G		Fibromatosis, gingival, 1 • Noonan syndrome 4	Benign (May 15, 2021)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
SOS1	protein_coding	protein_coding	ENST00000426016	23	142950

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.00	4.59e-9	125697	0	43	125740	0.000171

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	3.05	473	700	0.676	0.0000355	8767
Missense in Polyphen		118	285.7	0.41302		3583
Synonymous	0.0977	235	237	0.992	0.0000117	2523
Loss of Function	7.49	5	74.9	0.0667	0.00000487	840

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000239	0.000239
Ashkenazi Jewish	0.000199	0.000198
East Asian	0.000109	0.000109
Finnish	0.0000924	0.0000924
European (Non-Finnish)	0.000248	0.000246
Middle Eastern	0.000109	0.000109
South Asian	0.0000327	0.0000327
Other	0.000328	0.000326

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Promotes the exchange of Ras-bound GDP by GTP (PubMed:8493579). Probably by promoting Ras activation, regulates phosphorylation of MAP kinase MAPK3 in response to EGF (PubMed:17339331). Catalytic component of a trimeric complex that participates in transduction of signals from Ras to Rac by promoting the Rac-specific guanine nucleotide exchange factor (GEF) activity (By similarity). {ECO:0000250|UniProtKB:Q62245, ECO:0000269|PubMed:17339331, ECO:0000269|PubMed:8493579}.
• Disease: DISEASE: Fibromatosis, gingival, 1 (GINGF1) [MIM:135300]: A form of hereditary gingival fibromatosis, a rare condition characterized by a slow, progressive overgrowth of the gingiva. The excess gingival tissue can cover part of or the entire crown, and can result in diastemas, teeth displacement, or retention of primary or impacted teeth. GINGF1 is usually transmitted as an autosomal dominant trait, although sporadic cases are common. {ECO:0000269|PubMed:11868160}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Noonan syndrome 4 (NS4) [MIM:610733]: 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. Some patients with NS4 have polyarticular villonodular synovitis. {ECO:0000269|PubMed:17143282, ECO:0000269|PubMed:17143285, ECO:0000269|PubMed:19020799, ECO:0000269|PubMed:19438935, ECO:0000269|PubMed:19953625, ECO:0000269|PubMed:20673819, ECO:0000269|PubMed:20683980, ECO:0000269|PubMed:21387466}. 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);EGFR Inhibitor Pathway, Pharmacodynamics;Human papillomavirus infection - Homo sapiens (human);Fc Epsilon Receptor I Signaling in Mast Cells;Insulin Signalling;EGF-Core;IL-5 Signaling Pathway;Angiogenesis overview;Integrin-mediated Cell Adhesion;Leptin signaling pathway;Prolactin Signaling Pathway;Pilocytic astrocytoma;Androgen Receptor Network in Prostate Cancer;B Cell Receptor Signaling Pathway;TNF alpha Signaling Pathway;Oncostatin M Signaling Pathway;Alpha 6 Beta 4 signaling pathway;JAK-STAT;IL-3 Signaling Pathway;nerve growth factor pathway (ngf);Kit receptor signaling pathway;Focal Adhesion;Signaling of Hepatocyte Growth Factor Receptor;Rac1-Pak1-p38-MMP-2 pathway;IL-6 signaling pathway;Hepatitis C and Hepatocellular Carcinoma;TGF-beta Signaling Pathway;BDNF-TrkB Signaling;Association Between Physico-Chemical Features and Toxicity Associated Pathways;MAPK Signaling Pathway;T-Cell antigen Receptor (TCR) pathway during Staphylococcus aureus infection;IL-4 Signaling Pathway;Angiopoietin Like Protein 8 Regulatory Pathway;Chemokine signaling pathway;ESC Pluripotency Pathways;Focal Adhesion-PI3K-Akt-mTOR-signaling pathway;PDGFR-beta pathway;miRNA regulation of prostate cancer signaling pathways;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;IL-2 Signaling Pathway;Regulation of Actin Cytoskeleton;EPO Receptor Signaling;ErbB Signaling Pathway;T-Cell antigen Receptor (TCR) Signaling Pathway;DNA Damage Response (only ATM dependent);SHC1 events in ERBB2 signaling;Developmental Biology;Signaling by GPCR;FRS-mediated FGFR2 signaling;Signaling by FGFR2;Regulation of Ras family activation;SHC-mediated cascade:FGFR2;FRS-mediated FGFR3 signaling;Downstream signaling of activated FGFR2;SHC-mediated cascade:FGFR3;Antigen activates B Cell Receptor (BCR) leading to generation of second messengers;Downstream signaling of activated FGFR3;Disease;Signaling by FGFR3;Signal Transduction;FRS-mediated FGFR4 signaling;SHC-mediated cascade:FGFR4;Downstream signaling of activated FGFR4;Signaling by Interleukins;DAP12 signaling;DAP12 interactions;Signaling by FGFR4;Signaling by FGFR;inhibition of cellular proliferation by gleevec;bioactive peptide induced signaling pathway;role of erk5 in neuronal survival pathway;links between pyk2 and map kinases;role of egf receptor transactivation by gpcrs in cardiac hypertrophy;egf signaling pathway;il 2 signaling pathway;trefoil factors initiate mucosal healing;transcription factor creb and its extracellular signals;angiotensin ii mediated activation of jnk pathway via pyk2 dependent signaling;integrin signaling pathway;il-2 receptor beta chain in t cell activation;ras signaling pathway;phospholipids as signalling intermediaries;multiple antiapoptotic pathways from igf-1r signaling lead to bad phosphorylation;pten dependent cell cycle arrest and apoptosis;vegf hypoxia and angiogenesis;mcalpain and friends in cell motility;nfat and hypertrophy of the heart ;il 6 signaling pathway;sprouty regulation of tyrosine kinase signals;phosphorylation of mek1 by cdk5/p35 down regulates the map kinase pathway;trka receptor signaling pathway;insulin signaling pathway;t cell receptor signaling pathway;bcr signaling pathway;calcium signaling by hbx of hepatitis b virus;erk1/erk2 mapk signaling pathway;role of erbb2 in signal transduction and oncology;keratinocyte differentiation;Cytokine Signaling in Immune system;map kinase inactivation of smrt corepressor;B cell receptor signaling;Signal attenuation;SOS-mediated signalling;IRS-mediated signalling;Insulin receptor signalling cascade;Signaling by Insulin receptor;Signaling by the B Cell Receptor (BCR);SHC1 events in EGFR signaling;Signaling by PDGF;CD4 T cell receptor signaling-ERK cascade;igf-1 signaling pathway;GRB2:SOS provides linkage to MAPK signaling for Integrins ;Integrin alphaIIb beta3 signaling;il 3 signaling pathway;HGF;FCERI mediated MAPK activation;FCERI mediated Ca+2 mobilization;Fc epsilon receptor (FCERI) signaling;TCR;Oncostatin_M;IGF signaling;Innate Immune System;Immune System;FGF;Interleukin receptor SHC signaling;Interleukin-2 family signaling;Signaling by FGFR2 in disease;Adaptive Immune System;KitReceptor;Fibroblast growth factor-1;insulin Mam;Activation of RAC1;Rho GTPase cycle;BCR;pdgf signaling pathway;Signaling by EGFR;epo signaling pathway;Platelet Aggregation (Plug Formation);Signalling to RAS;Platelet activation, signaling and aggregation;Regulation of KIT signaling;Signaling by Rho GTPases;tpo signaling pathway;Signalling to ERKs;Signaling by NTRK1 (TRKA);Integrin;fc epsilon receptor i signaling in mast cells;Activated NTRK2 signals through RAS;Signaling by NTRK2 (TRKB);Signaling by NTRKs;EGFR1;SHP2 signaling;Regulation of RAC1 activity;Tie2 Signaling;Integrin signaling;growth hormone signaling pathway;ErbB1 downstream signaling;Cell surface interactions at the vascular wall;Hemostasis;NRAGE signals death through JNK;the igf-1 receptor and longevity;RAF/MAP kinase cascade;MAPK1/MAPK3 signaling;MAPK family signaling cascades;BCR signaling pathway;Signaling events mediated by TCPTP;JAK STAT pathway and regulation;PDGF;IL2;GRB2 events in ERBB2 signaling;EGFR Transactivation by Gastrin;NCAM signaling for neurite out-growth;VEGFR3 signaling in lymphatic endothelium;NGF;Death Receptor Signalling;Signaling events regulated by Ret tyrosine kinase;p75 NTR receptor-mediated signalling;IL2-mediated signaling events;Downstream signal transduction;Signaling by ROBO receptors;Signaling by EGFRvIII in Cancer;Signaling by EGFR in Cancer;EGFR-dependent Endothelin signaling events;GRB2 events in EGFR signaling;EPO signaling pathway;Signaling by FGFR3 point mutants in cancer;Signaling by FGFR4 in disease;RET signaling;Axon guidance;Signaling by FGFR3 fusions in cancer;Signaling by FGFR3 in disease;G alpha (12/13) signalling events;Signaling by SCF-KIT;Signaling by FGFR in disease;IL5;Signaling by ERBB2;SHC1 events in ERBB4 signaling;Signaling by ERBB4;IL6;SHC-related events triggered by IGF1R;IRS-related events triggered by IGF1R;IGF1R signaling cascade;TNFalpha;MET activates RAS signaling;Signaling by FGFR1 in disease;Signaling by MET;Constitutive Signaling by EGFRvIII;Signaling by Receptor Tyrosine Kinases;Gastrin-CREB signalling pathway via PKC and MAPK;G alpha (q) signalling events;GPCR downstream signalling;Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants;Signaling by Ligand-Responsive EGFR Variants in Cancer;EGF;ErbB2/ErbB3 signaling events;GMCSF-mediated signaling events;IL2 signaling events mediated by STAT5;Insulin Pathway;Neurotrophic factor-mediated Trk receptor signaling;Diseases of signal transduction;Signaling events mediated by Hepatocyte Growth Factor Receptor (c-Met);Fc-epsilon receptor I signaling in mast cells;Internalization of ErbB1;Signaling events mediated by focal adhesion kinase;IL2 signaling events mediated by PI3K;TCR signaling in naïve CD8+ T cells;Cell death signalling via NRAGE, NRIF and NADE;IGF1 pathway;Signaling events mediated by Stem cell factor receptor (c-Kit);Plasma membrane estrogen receptor signaling;Trk receptor signaling mediated by PI3K and PLC-gamma;PDGFR-beta signaling pathway;Downstream signaling of activated FGFR1;Signaling by Type 1 Insulin-like Growth Factor 1 Receptor (IGF1R);IL6-mediated signaling events;FGF signaling pathway;TCR signaling in naïve CD4+ T cells;PDGFR-alpha signaling pathway;TGF-beta receptor signaling;FRS-mediated FGFR1 signaling;Role of LAT2/NTAL/LAB on calcium mobilization;SHC-mediated cascade:FGFR1;insulin;Signaling by FGFR1;CD4 T cell receptor signaling;Interleukin-3, 5 and GM-CSF signaling (Consensus)

Recessive Scores

• pRec: 0.384

Intolerance Scores

• loftool: 0.0249
• rvis_EVS: -1
• rvis_percentile_EVS: 8.54

Haploinsufficiency Scores

• pHI: 0.721
• hipred: Y
• hipred_score: 0.825
• ghis: 0.623

Essentials

• essential_gene_CRISPR: E
• essential_gene_CRISPR2: E
• gene_indispensability_pred: E
• gene_indispensability_score: 0.955

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Sos1
• Phenotype: embryo phenotype; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); hematopoietic system phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); digestive/alimentary phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); vision/eye phenotype; immune system phenotype; skeleton phenotype; growth/size/body region phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); endocrine/exocrine gland phenotype; muscle phenotype; craniofacial phenotype; homeostasis/metabolism phenotype; cellular phenotype

Gene ontology

• Biological process: MAPK cascade;B cell homeostasis;hair follicle development;cardiac atrium morphogenesis;pericardium morphogenesis;signal transduction;epidermal growth factor receptor signaling pathway;G protein-coupled receptor signaling pathway;Ras protein signal transduction;vitellogenesis;axon guidance;insulin receptor signaling pathway;cytokine-mediated signaling pathway;regulation of T cell differentiation in thymus;regulation of Rho protein signal transduction;multicellular organism growth;Fc-epsilon receptor signaling pathway;ERBB2 signaling pathway;regulation of T cell proliferation;positive regulation of apoptotic process;positive regulation of GTPase activity;positive regulation of epidermal growth factor receptor signaling pathway;neurotrophin TRK receptor signaling pathway;blood vessel morphogenesis;leukocyte migration;regulation of small GTPase mediated signal transduction;positive regulation of small GTPase mediated signal transduction;roof of mouth development;eyelid development in camera-type eye;heart trabecula morphogenesis;midbrain morphogenesis;regulation of pro-B cell differentiation
• Cellular component: nucleosome;cytoplasm;cytosol;plasma membrane;postsynaptic density;neuronal cell body
• Molecular function: DNA binding;guanyl-nucleotide exchange factor activity;Ras guanyl-nucleotide exchange factor activity;Rho guanyl-nucleotide exchange factor activity;GTPase activator activity;protein binding;SH3 domain binding;protein heterodimerization activity