SHOC2

Chr 10AD

SHOC2 leucine rich repeat scaffold protein

Also known as: NSLH1, SIAA0862, SOC2, SUR8

NCBI Gene: 8036ENSG00000108061UniProt: Q9UQ13

This gene encodes a protein that consists almost entirely of leucine-rich repeats, a domain implicated in protein-protein interactions. The protein may function as a scaffold linking RAS to downstream signal transducers in the RAS/ERK MAP kinase signaling cascade. Mutations in this gene have been associated with Noonan-like syndrome with loose anagen hair. [provided by RefSeq, May 2010]

Primary Disease Associations & Inheritance

Noonan syndrome-like with loose anagen hair 1MIM #607721
AD
594
ClinVar variants
18
Pathogenic / LP
1.00
pLI score· haploinsufficient
1
Active trials
Clinical Summary— SHOC2
🧬
Gene-Disease Validity (ClinGen)
Noonan syndrome-like disorder with loose anagen hair · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

4 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
18 Pathogenic / Likely Pathogenic· 286 VUS of 594 total submissions
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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 0.999
Z-score 4.31
OE 0.00 (0.00–0.14)
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.
2.97Z-score
OE missense 0.52 (0.45–0.59)
153 obs / 296.8 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.0.00 (0.00–0.14)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.52 (0.45–0.59)
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.0.90
0≤1.21.6
LoF obs/exp: 0 / 21.7Missense obs/exp: 153 / 296.8Syn Z: 0.80

ClinVar Variant Classifications

594 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic17
Likely Pathogenic1
VUS286
Likely Benign261
Benign18
Conflicting11
17
Pathogenic
1
Likely Pathogenic
286
VUS
261
Likely Benign
18
Benign
11
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
1
16
0
17
Likely Pathogenic
0
0
1
0
1
VUS
4
259
21
2
286
Likely Benign
0
3
77
181
261
Benign
0
0
16
2
18
Conflicting
—11
Total4263131185594

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

View in ClinVar →

Protein Context — Lollipop Plot

SHOC2 · protein map & ClinVar variants

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

Gene2Phenotype Curations

SHOC2-related Noonan-like syndrome with loose anagen hair

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

Noonan syndrome-like with loose anagen hair 1

MIM #607721

Molecular basis of disorder known

Autosomal dominant
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Targeting the SHOC2-RAS interaction in RAS-mutant cancers.
Hauseman ZJ et al.·Nature
2025
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
Small-molecule targeting BCAT1-mediated BCAA metabolism inhibits the activation of SHOC2-RAS-ERK to induce apoptosis of Triple-negative breast cancer cells.
Huang L et al.·J Adv Res
2025
Ras-MAPK pathway in patients with lupus nephritis.
Zhang C et al.·Lupus Sci Med
2025Cohort
Expanding the molecular spectrum of pathogenic SHOC2 variants underlying Mazzanti syndrome.
Motta M et al.·Hum Mol Genet
2022
M-Ras/Shoc2 signaling modulates E-cadherin turnover and cell-cell adhesion during collective cell migration.
Kota P et al.·Proc Natl Acad Sci U S A
2019
Noonan syndrome and clinically related disorders.
Tartaglia M et al.·Best Pract Res Clin Endocrinol Metab
2011Review
Clinical and molecular analysis of seventy-one fetal cases with RASopathies.
Yu QX et al.·Eur J Obstet Gynecol Reprod Biol
2025Cohort
SHOC2 is associated with the survival of breast cancer cells and has prognostic value for patients with breast cancer.
Geng W et al.·Mol Med Rep
2020Cohort
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