SOS1

Chr 2AD

SOS Ras/Rac guanine nucleotide exchange factor 1

Also known as: GF1, GGF1, GINGF, HGF, NS4, SOS-1

NCBI Gene: 6654ENSG00000115904UniProt: Q07889

This gene encodes a protein that is a guanine nucleotide exchange factor for RAS proteins, membrane proteins that bind guanine nucleotides and participate in signal transduction pathways. GTP binding activates and GTP hydrolysis inactivates RAS proteins. The product of this gene may regulate RAS proteins by facilitating the exchange of GTP for GDP. Mutations in this gene are associated with gingival fibromatosis 1 and Noonan syndrome type 4. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

Fibromatosis, gingival, 1MIM #135300
AD
Noonan syndrome 4MIM #610733
AD
600
ClinVar variants
22
Pathogenic / LP
1.00
pLI score· haploinsufficient
1
Active trials
Clinical Summary— SOS1
🧬
Gene-Disease Validity (ClinGen)
Noonan syndrome · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

3 total gene-disease associations curated

⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
22 Pathogenic / Likely Pathogenic· 310 VUS of 600 total submissions
💊
Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.14LOEUF
pLI 1.000
Z-score 7.49
OE 0.07 (0.03–0.14)
Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
3.05Z-score
OE missense 0.68 (0.63–0.73)
473 obs / 700.0 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.07 (0.03–0.14)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.68 (0.63–0.73)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.99
0≤1.21.6
LoF obs/exp: 5 / 74.9Missense obs/exp: 473 / 700.0Syn Z: 0.10

ClinVar Variant Classifications

600 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic12
Likely Pathogenic10
VUS310
Likely Benign169
Benign51
Conflicting48
12
Pathogenic
10
Likely Pathogenic
310
VUS
169
Likely Benign
51
Benign
48
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
3
9
0
12
Likely Pathogenic
0
10
0
0
10
VUS
6
259
42
3
310
Likely Benign
0
15
69
85
169
Benign
0
2
43
6
51
Conflicting
—48
Total628916394600

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

SOS1 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

SOS1-related Noonan syndrome

definitive
ADGain Of FunctionAltered Gene Product Structure
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Fibromatosis, gingival, 1

MIM #135300

Molecular basis of disorder known

Autosomal dominant

Noonan syndrome 4

MIM #610733

Molecular basis of disorder known

Autosomal dominant
📖
GeneReview available — SOS1
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Targeting KRAS in pancreatic cancer.
Stickler S et al.·Oncol Res
2024Review
Targeted protein relocalization via protein transport coupling.
Ng CSC et al.·Nature
2024
Kinase-mediated RAS signaling via membraneless cytoplasmic protein granules.
Tulpule A et al.·Cell
2021
SOS1 mutations in Noonan syndrome: molecular spectrum, structural insights on pathogenic effects, and genotype-phenotype correlations.
Lepri F et al.·Hum Mutat
2011
Comparative assessment of gene-specific variant distribution in prenatal and postnatal cohorts tested for Noonan syndrome and related conditions.
Leach NT et al.·Genet Med
2019Cohort
Co-targeting SOS1 enhances the antitumor effects of KRAS(G12C) inhibitors by addressing intrinsic and acquired resistance.
Thatikonda V et al.·Nat Cancer
2024
Clinical features and molecular genetics of patients with RASopathies: expanding the phenotype with rare genes and novel variants.
Yılmaz Uzman C et al.·Eur J Pediatr
2024Cohort
Mapping variant effects on anti-tumor hallmarks of primary human T cells with base-editing screens.
Walsh ZH et al.·Nat Biotechnol
2025
Rare variants in SOS2 and LZTR1 are associated with Noonan syndrome.
Yamamoto GL et al.·J Med Genet
2015
Drugging the 'undruggable' KRAS: breakthroughs, challenges, and opportunities in pancreatic cancer.
Khan N et al.·Cancer Biol Med
2025Review
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
RASopathy

Study of the Thyroid Function and Echostructural Morphology in Patients Affected With Rasopathies (ECORAS2023)

RECRUITING
NCT06489067University of Bari Aldo MoroStarted 2024-01-15

External Resources

Links to major genomics databases and tools