SOS2

Chr 14AD

SOS Ras/Rho guanine nucleotide exchange factor 2

Also known as: NS9, SOS-2

NCBI Gene: 6655ENSG00000100485UniProt: Q07890

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. [provided by RefSeq, Jul 2016]

Primary Disease Associations & Inheritance

Noonan syndrome 9MIM #616559
AD
1
Active trials
1
Pathogenic / LP
380
ClinVar variants
42
Pubs (1 yr)
2.5
Missense Z
0.26
LOEUF· LoF intolerant
Clinical Summary— SOS2
🧬
Gene-Disease Validity (ClinGen)
Noonan syndrome · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
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
1 Pathogenic / Likely Pathogenic· 222 VUS of 380 total submissions
💊
Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available
📖
GeneReview available — SOS2
Authoritative clinical overview · Recommended first read
Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
LoF Constraint
0.26LOEUF
pLI 1.000
Z-score 6.40
OE 0.15 (0.09–0.26)
Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint
2.53Z-score
OE missense 0.73 (0.68–0.79)
506 obs / 693.3 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios
LoF OE0.15 (0.09–0.26)
0≤0.351.4
Missense OE0.73 (0.68–0.79)
0≤0.61.4
Synonymous OE0.96
0≤1.21.6
LoF obs/exp: 10 / 66.2Missense obs/exp: 506 / 693.3Syn Z: 0.44
LOFGOF
DN
0.3892th %ile
GOF
0.4776th %ile
LOF
0.64top 25%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFprediction above median · LOEUF 0.26
GOF1 literature citation

Literature Evidence

GOFActivating Mutations Affecting the Dbl Homology Domain of SOS2 Cause Noonan Syndrome.PMID:26173643

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

380 submitted variants in ClinVar

ClinVar

Classification Summary

Likely Pathogenic1
VUS222
Likely Benign149
Benign6
Conflicting2
1
Likely Pathogenic
222
VUS
149
Likely Benign
6
Benign
2
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
0
0
0
Likely Pathogenic
0
1
0
0
1
VUS
14
191
17
0
222
Likely Benign
0
14
56
79
149
Benign
0
2
3
1
6
Conflicting
—2
Total142087680380

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

View in ClinVar →

SOS2 · protein map & ClinVar variants

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

Gene2Phenotype Curations

SOS2-related Noonan syndrome

definitive
ADUndeterminedAltered Gene Product Structure
Dev. DisordersSkin
G2P ↗
missense variantinframe deletioninframe insertion

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

Clinical Literature
Landmark / reviewRecent case evidence
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
In-silico identification, characterization and expression analysis of salt overly sensitive-2 (SOS2) gene family in Gossypium hirsutum L. against abiotic stresses.
Iqra L et al.·Sci Rep
2025Open Access
SOS2-FREE1 regulates SOS1 tonoplast sorting to promote Na+ compartmentalization in vacuole during salt stress response.
Liu G et al.·J Integr Plant Biol
2025
The ESCRT component FYVE4 modulates salt-stress response by strengthening the SOS1-SOS2 interaction in Arabidopsis.
Liu C et al.·Plant Commun
2025Open Access
Screening Enamine Fragments Library in the Quest for Novel SOS2 Inhibitors: Pharmacophore Modelling, Molecular Docking, MMGBSA Calculations, and MD Simulation.
Alzain AA et al.·J Pharm Bioallied Sci
2025Open AccessFunctional
Severe Nerve Enlargement in SOS2-Related Noonan Syndrome.
Leenders E et al.·Am J Med Genet A
2025
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients