GRB2

Chr 17

growth factor receptor bound protein 2

Also known as: ASH, EGFRBP-GRB2, Grb3-3, MST084, MSTP084, NCKAP2

NCBI Gene: 2885ENSG00000177885UniProt: P62993

The protein encoded by this gene binds the epidermal growth factor receptor and contains one SH2 domain and two SH3 domains. Its two SH3 domains direct complex formation with proline-rich regions of other proteins, and its SH2 domain binds tyrosine phosphorylated sequences. This gene is similar to the Sem5 gene of C.elegans, which is involved in the signal transduction pathway. Two alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

0
Active trials
12
Pathogenic / LP
32
ClinVar variants
10
Pubs (1 yr)
2.9
Missense Z
0.36
LOEUF
Clinical Summary— GRB2
⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.94). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
12 Pathogenic / Likely Pathogenic· 19 VUS of 32 total submissions

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.
0.36LOEUF
pLI 0.939
Z-score 3.12
OE 0.08 (0.03–0.36)
Highly constrained

More LoF-intolerant than ~75% of genes

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.
2.85Z-score
OE missense 0.31 (0.24–0.40)
41 obs / 133.8 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.0.08 (0.03–0.36)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.31 (0.24–0.40)
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.0.76
0≤1.21.6
LoF obs/exp: 1 / 13.3Missense obs/exp: 41 / 133.8Syn Z: 1.34

ClinVar Variant Classifications

32 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic11
Likely Pathogenic1
VUS19
Benign1
11
Pathogenic
1
Likely Pathogenic
19
VUS
1
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
11
0
11
Likely Pathogenic
0
0
1
0
1
VUS
0
7
12
0
19
Likely Benign
0
0
0
0
0
Benign
0
0
0
1
1
Total0724132

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

View in ClinVar →

Protein Context — Lollipop Plot

GRB2 · protein map & ClinVar variants

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Kinase-mediated RAS signaling via membraneless cytoplasmic protein granules.
Tulpule A et al.·Cell
2021
An autoimmune disease variant of IgG1 modulates B cell activation and differentiation.
Chen X et al.·Science
2018
miR-3606-3p alleviates skin fibrosis by integratively suppressing the integrin/FAK, p-AKT/p-ERK, and TGF-β signaling cascades.
Chen Y et al.·J Adv Res
2025
RNF173 suppresses RAF/MEK/ERK signaling to regulate invasion and metastasis via GRB2 ubiquitination in Hepatocellular Carcinoma.
Zhou J et al.·Cell Commun Signal
2023
RASH3D19 mediates RAS activation through a positive feedback loop in KRAS-mutant cancer.
Treekitkarnmongkol W et al.·Nat Cell Biol
2026
Bufalin inhibits hepatocellular carcinoma progression by blocking EGFR-mediated RAS-RAF-MEK-ERK pathway activation.
Liu J et al.·J Exp Clin Cancer Res
2025
Identification of Novel Genetic Risk Factors for Focal Segmental Glomerulosclerosis in Children: Results From the Chronic Kidney Disease in Children (CKiD) Cohort.
Durand A et al.·Am J Kidney Dis
2023Cohort
Wiskott-Aldrich syndrome protein, WASP.
O'Sullivan E et al.·Int J Biochem Cell Biol
1999Review
DUS4L suppresses invasion and metastasis in LUAD via modulation of PI3K/AKT and ERK/MAPK signaling through GRB2.
Li Z et al.·Int Immunopharmacol
2024
Targeting SNORA38B attenuates tumorigenesis and sensitizes immune checkpoint blockade in non-small cell lung cancer by remodeling the tumor microenvironment via regulation of GAB2/AKT/mTOR signaling pathway.
Zhuo Y et al.·J Immunother Cancer
2022Functional
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Physalin A Suppresses Human Oral Squamous Carcinoma Cell Migration and Invasion Through Inhibiting Grb2/Ras and MMP/uPA Signaling Pathways.
Ma YS et al.·In Vivo
2026Open Access
Targeting GRB2 with Polyphyllin H overcomes PIKFYVE inhibitor resistance in bladder cancer by blocking Akt-SREBP1-SCD1 pathway.
Song YS et al.·Phytomedicine
2026
pH-Dependent Conformational Changes in Grb2 Monomer Reveal Different Binding Sites for Coumarin: An Insight for Small Molecule Drug Discovery.
Casteluci G et al.·ACS Omega
2026Open Access
FOXK1 drives colorectal cancer progression by transcriptionally activating GRB2.
Wang Y et al.·Eur J Med Res
2025Open Access
Characterization of the CD28 signaling pathway related genes (CD28, Grb2 and SLP-76) of golden pompano (Trachinotus ovatus).
Qi Z et al.·Dev Comp Immunol
2025
Top 5 resultsSearch Europe PMC ↗
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
The Configuration of GRB2 in Protein Interaction and Signal Transduction
Wang D et al.·Biomolecules
2024
The possible correlation between serum GRB2 levels and carotid atherosclerosis in patients with type 2 diabetes mellitus
Dong Y et al.·Front Endocrinol (Lausanne)
2022Cohort
Conformational Flexibility of GRB2 as a Key Factor in the Stability and Regulation of Its Interaction with SOS1
Pedro RP et al.·ACS Omega
2025
Screening and Verification of Key Ubiquitination Genes Related to Immune Infiltration in Stage III/IV Hepatocellular Carcinoma
Tang Y et al.·J Hepatocell Carcinoma
2023
Identification of Grb2 protein as a potential mediator of macrophage activation in acute pancreatitis based on bioinformatics and experimental verification
Shen Q et al.·Front Immunol
2025
Integrated identification of key immune related genes and patterns of immune infiltration in calcified aortic valvular disease: A network based meta-analysis
Wu LD et al.·Front Genet
2022
Regulation of microRNA expression by the adaptor protein GRB2
Stainthorp AK et al.·Sci Rep
2023
Allosteric regulation of GRB2 modulates RAS activation.
Kazemein Jasemi NS et al.·Small GTPases
2022
The structural basis of BCR-ABL recruitment of GRB2 in chronic myelogenous leukemia
Liu Y et al.·Biophys J
2022
VEGF-B, VEGF-A, FLT-1, KDR, ERBB2, EGFR, GRB2, RAC1, CDH1 and HYAL-1 Genes Expression Analysis in Canine Mammary Gland Tumors and the Association with Tumor ClinicoPathological Parameters and Dog Breed Assessment
Sakalauskaitė S et al.·Vet Sci
2021
Top 10 full-text resultsSearch PubTator3 ↗

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