SH3GL2

Chr 9

SH3 domain containing GRB2 like 2, endophilin A1

Also known as: CNSA2, EEN-B1, SH3D2A, SH3P4

NCBI Gene: 6456ENSG00000107295UniProt: Q99962

Enables identical protein binding activity. Involved in negative regulation of blood-brain barrier permeability; negative regulation of gene expression; and negative regulation of signal transduction. Located in perinuclear region of cytoplasm. [provided by Alliance of Genome Resources, Jul 2025]

141
ClinVar variants
50
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— SH3GL2
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
50 Pathogenic / Likely Pathogenic· 42 VUS of 141 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
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.
0.79LOEUF
pLI 0.000
Z-score 2.30
OE 0.47 (0.29–0.79)
Tolerant

Typical tolerance to LoF variation

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.
0.96Z-score
OE missense 0.80 (0.70–0.92)
153 obs / 190.4 exp
Tolerant

Mild missense constraint

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.0.47 (0.29–0.79)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.80 (0.70–0.92)
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.1.32
0≤1.21.6
LoF obs/exp: 10 / 21.5Missense obs/exp: 153 / 190.4Syn Z: -2.04

ClinVar Variant Classifications

141 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic45
Likely Pathogenic5
VUS42
Likely Benign2
Benign1
45
Pathogenic
5
Likely Pathogenic
42
VUS
2
Likely Benign
1
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
45
0
45
Likely Pathogenic
0
0
5
0
5
VUS
0
37
5
0
42
Likely Benign
0
0
2
0
2
Benign
0
0
0
1
1
Total03757195

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

View in ClinVar →

Protein Context — Lollipop Plot

SH3GL2 · 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 Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Oxidative Stress and Dopaminergic Metabolism: A Major PD Pathogenic Mechanism and Basis of Potential Antioxidant Therapies.
Rasool A et al.·CNS Neurol Disord Drug Targets
2024Review
Reduction of nuclear Y654-p-β-catenin expression through SH3GL2-meditated downregulation of EGFR in chemotolerance TNBC: Clinical and prognostic importance.
Islam MS et al.·J Cell Physiol
2020
A candidate loss-of-function variant in SGIP1 causes synaptic dysfunction and recessive parkinsonism.
Decet M et al.·Cell Rep Med
2024
Clinicopathological characteristics of pheochromocytoma/paraganglioma and screening of prognostic markers.
Lei J et al.·J Surg Oncol
2023
SNP rs1049430 in the 3'-UTR of SH3GL2 regulates its expression: Clinical and prognostic implications in head and neck squamous cell carcinoma.
Maiti GP et al.·Biochim Biophys Acta
2015
Endophilin-A/SH3GL2 calcium switch for synaptic autophagy induction is impaired by a Parkinson's risk variant.
Decet M et al.·Autophagy
2024
Identification of Immune Subtypes and Candidate mRNA Vaccine Antigens in Small Cell Lung Cancer.
Wei Y et al.·Oncologist
2023
Elucidate biomarkers and the molecular pathways associated with genetic variants that contribute to the etiology of Parkinson's disease.
Nguyen HD·Acta Neurol Belg
2025
Targeting of insulin receptor endocytosis as a treatment to insulin resistance.
Tim B et al.·J Diabetes Complications
2023
Germline Genetic Biomarkers of Sunitinib Efficacy in Advanced Renal Cell Carcinoma: Results From the RENAL EFFECT Trial.
Motzer RJ et al.·Clin Genitourin Cancer
2017Clinical trial
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

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools