SH3GL2

Summary

SH3GL2 (SH3 domain containing GRB2 like 2, endophilin A1, HGNC:10831) is a protein-coding gene on chromosome 9p22.2, encoding Endophilin-A1 (Q99962). Implicated in synaptic vesicle endocytosis.

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.

Source: NCBI Gene 6456 — RefSeq curated summary.

At a glance

• GWAS associations: 24
• Clinical variants (ClinVar): 45 total — 1 pathogenic
• MANE Select transcript: NM_003026

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10831
Approved symbol	SH3GL2
Name	SH3 domain containing GRB2 like 2, endophilin A1
Location	9p22.2
Locus type	gene with protein product
Status	Approved
Aliases	SH3P4, SH3D2A, CNSA2, EEN-B1
Ensembl gene	ENSG00000107295
Ensembl biotype	protein_coding
OMIM	604465
Entrez	6456

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 5 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000380607, ENST00000467085, ENST00000885051, ENST00000917907, ENST00000955338, ENST00000955339

RefSeq mRNA: 1 — MANE Select: NM_003026 NM_003026

CCDS: CCDS6483

Canonical transcript exons

ENST00000380607 — 9 exons

Exon	Start	End
ENSE00000691743	17786381	17786524
ENSE00000691749	17787380	17787513
ENSE00000691752	17789392	17789550
ENSE00000691755	17791231	17791334
ENSE00001676590	17795544	17797124
ENSE00001868540	17579066	17579287
ENSE00002717502	17793367	17793497
ENSE00003592009	17761437	17761509
ENSE00003608968	17747066	17747134

Expression profiles

Bgee: expression breadth ubiquitous, 193 present calls, max score 99.49.

FANTOM5 (CAGE): breadth broad, TPM avg 6.8554 / max 732.0343, expressed in 343 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
96214	4.1829	294
96213	2.4213	252
96215	0.2512	71

Top tissues by expression

284 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
Brodmann (1909) area 23	UBERON:0013554	99.49	gold quality
middle temporal gyrus	UBERON:0002771	99.40	gold quality
endothelial cell	CL:0000115	99.20	gold quality
cerebellar cortex	UBERON:0002129	98.90	gold quality
cerebellar hemisphere	UBERON:0002245	98.90	gold quality
cerebellum	UBERON:0002037	98.78	gold quality
right hemisphere of cerebellum	UBERON:0014890	98.72	gold quality
cortical plate	UBERON:0005343	98.68	gold quality
cerebellar vermis	UBERON:0004720	98.46	gold quality
primary visual cortex	UBERON:0002436	98.41	gold quality
lateral nuclear group of thalamus	UBERON:0002736	98.28	gold quality
orbitofrontal cortex	UBERON:0004167	97.87	gold quality
superior frontal gyrus	UBERON:0002661	97.56	gold quality
Brodmann (1909) area 9	UBERON:0013540	97.51	gold quality
prefrontal cortex	UBERON:0000451	97.34	gold quality
occipital lobe	UBERON:0002021	97.32	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	97.14	gold quality
frontal cortex	UBERON:0001870	97.09	gold quality
Brodmann (1909) area 46	UBERON:0006483	97.05	gold quality
right frontal lobe	UBERON:0002810	96.84	gold quality
postcentral gyrus	UBERON:0002581	96.72	gold quality
paraflocculus	UBERON:0005351	96.71	gold quality
parietal lobe	UBERON:0001872	96.64	gold quality
neocortex	UBERON:0001950	96.50	gold quality
entorhinal cortex	UBERON:0002728	96.40	gold quality
cerebral cortex	UBERON:0000956	96.08	gold quality
frontal pole	UBERON:0002795	96.05	gold quality
pons	UBERON:0000988	95.18	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	94.84	gold quality
cingulate cortex	UBERON:0003027	94.80	gold quality

Single-cell (SCXA)

Detected in 6 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-HCAD-25	yes	90.59
E-HCAD-35	yes	65.45
E-HCAD-5	yes	51.21
E-MTAB-5061	yes	14.66
E-MTAB-6058	no	827.42
E-ANND-3	no	3.54

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

3 targets.

Target	Regulation
EGFR	Repression
OCLN	Repression
TJP1	Repression

miRNA regulators (miRDB)

142 targeting SH3GL2, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-3662	99.99	73.82	5684
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-545-3P	99.95	70.74	2783
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-6768-5P	99.92	67.36	1942
HSA-MIR-329-3P	99.91	66.56	1234
HSA-MIR-362-3P	99.91	66.38	1267
HSA-MIR-498-3P	99.91	71.27	1114
HSA-MIR-15A-5P	99.90	72.80	2787
HSA-MIR-15B-5P	99.90	72.78	2798
HSA-MIR-16-5P	99.90	72.80	2780
HSA-MIR-195-5P	99.90	72.81	2805
HSA-MIR-627-3P	99.90	71.42	3316
HSA-MIR-424-5P	99.89	71.90	2641
HSA-MIR-6838-5P	99.89	71.94	2690

Literature-anchored findings (GeneRIF, showing 26)

• Alterations of SH3GL2 and CDKN2A loci have a synergistic role in the development of early-onset breast cancer. (PMID:18239974)
• These data implicate ataxin-2 to play a role in endocytic receptor cycling. (PMID:18602463)
• Using shotgun mass spectrometry, we found this protein differentially expressed in the dorsolateral prefrontal cortex from patients with schizophrenia. (PMID:19165527)
• SH3GL2 participates in the regulation of apoptosis through the MEK-ERK signal pathway by adjusting EGFR in the laryngeal carcinoma cell line Hep2 (PMID:20512084)
• simulations constitute a multi-dimensional exploration of how EGF-dependent EGFR endocytosis and ERK activation are dynamically affected by scaffolds KSR and MP1, co-regulated by Cbl-CIN85 and Endophilin A1 (PMID:21829671)
• Our results indicate that SH3GL2 is frequently deleted in NSCLC and regulates cellular growth and invasion by modulating EGFR function. (PMID:22968441)
• Data suggest that expression of endothelin-1 and vWF (von Willebrand factor) is up-regulated and eNOS (endothelial nitric oxide synthase) activity is increased in radial artery in diabetic patients with coronary artery disease. (PMID:22972845)
• Overexpression of EGFR in head and neck squamous cell carcinoma is associated with inactivation of SH3GL2 and CDC25A genes. (PMID:23675485)
• these findings identify loss of Sh3gl2 as a frequent event in Urothelial carcinoma (UC) development that promotes disease progression. (PMID:23814487)
• this study suggests a novel mechanism in which Lpd mediates EGFR endocytosis via Mena downstream of endophilin. (PMID:24076656)
• miR-330 negatively regulated the expression of SH3GL2 in GSCs, which promoted the oncogenic progression of GSCs through activating ERK and PI3K/AKT signaling pathways. (PMID:24736727)
• study described that endophilin-1 is expressed in hCMEC/D3 cells where it regulates the permeability of blood-brain barrier by altering the expression of ZO-1 and occludin via the EGFR-ERK1/2 pathway (PMID:24854121)
• Endophilin-1 positively regulated blood-brain barrier permeability via the EGFR-JNK signaling pathway in hCMEC/D3 cells, which would provide an experimental basis for further research on endophilin-1 mediated the opening of blood-brain barrier . (PMID:25721793)
• Data indicate that the presence of the susceptible G allele in SNP rs1049430 is associated with the inactivation of SH3-domain GRB2-like 2 protein (SH3GL2) and could be used as a prognostic marker of head and neck squamous cell carcinoma (HNSCC). (PMID:25728707)
• these results reveal a novel function of postsynaptic endophilin A1 in spine morphogenesis, stabilization and synaptic function through the regulation of p140Cap (PMID:25771685)
• Methylation status of SH3GL2 gene was associated with the TNM staging and HPV infection status of vulvar squamous cell carcinoma. (PMID:26823912)
• This study identified a new mitochondria reprogramming pathway influencing breast cancer progression through SH3GL2 and MFN2. These proteins were frequently lost in breast cancer, which was traceable in the circulating exosomes. (PMID:26888829)
• Endophilin-1 was a direct and functional downstream target of miR-107. (PMID:27038654)
• Alix acts in concert with endophilin A to promote clathrin-independent endocytosis of cholera toxin and to regulate cell migration. (PMID:27244115)
• The results suggest that SH3GL2 suppresses migration and invasion behaviors of glioma cells through negatively regulating STAT3/MMP2 signaling. (PMID:28470949)
• endophilin A1 plays a critical role in epilepsy (PMID:29481784)
• miR-424-5p could affect the expression of tight junction proteins, ZO-1 and occludin, via Endophilin-1, and thereby regulate blood brain barrier (BBB) permeability in an BBB model in vitro with Amyloid-beta incubated endothelial cells. (PMID:31375213)
• Cancer Testis Antigen Promotes Triple Negative Breast Cancer Metastasis and is Traceable in the Circulating Extracellular Vesicles. (PMID:31406142)
• In mammals, VGLUT1 gained a proline-rich sequence that recruits endophilinA1 and turns the transporter into a regulator of synaptic vesicles organization and spontaneous release. (PMID:31663854)
• A family of fuchs endothelial corneal dystrophy and anterior polar cataract with an analysis of whole exome sequencing. (PMID:32367751)
• EndophilinA-dependent coupling between activity-induced calcium influx and synaptic autophagy is disrupted by a Parkinson-risk mutation. (PMID:36827984)

Cross-species orthologs

9 orthologs

Organism	Symbol	Gene ID
danio_rerio	sh3gl2a	ENSDARG00000023600
danio_rerio	sh3gl2b	ENSDARG00000039901
mus_musculus	Sh3gl2	ENSMUSG00000028488
rattus_norvegicus	Sh3gl2	ENSRNOG00000006761
drosophila_melanogaster	Dlish	FBGN0034264
drosophila_melanogaster	EndoB	FBGN0034433
caenorhabditis_elegans		WBGENE00001335
caenorhabditis_elegans		WBGENE00012891
caenorhabditis_elegans		WBGENE00015128

Paralogs (12): SORBS1 (ENSG00000095637), SH3GLB1 (ENSG00000097033), NCF4 (ENSG00000100365), SH3D19 (ENSG00000109686), SORBS3 (ENSG00000120896), SH3GL3 (ENSG00000140600), SH3GL1 (ENSG00000141985), SH3GLB2 (ENSG00000148341), SH3RF1 (ENSG00000154447), SORBS2 (ENSG00000154556), SH3RF2 (ENSG00000156463), SH3RF3 (ENSG00000172985)

Protein

Protein identifiers

Endophilin-A1 — Q99962 (reviewed: Q99962)

Alternative names: EEN-B1, Endophilin-1, SH3 domain protein 2A, SH3 domain-containing GRB2-like protein 2

All UniProt accessions (1): Q99962

UniProt curated annotations — full annotation on UniProt →

Function. Implicated in synaptic vesicle endocytosis. May recruit other proteins to membranes with high curvature. Required for BDNF-dependent dendrite outgrowth. Cooperates with SH3GL2 to mediate BDNF-NTRK2 early endocytic trafficking and signaling from early endosomes.

Subunit / interactions. Monomer; in cytoplasm. Homodimer; when associated with membranes. Interacts with OPHN1. Interacts with SYNJ1. Interacts with DNM1. Interacts with MAP4K3; the interaction appears to regulate MAP4K3-mediated JNK activation. Interacts with PDCD6IP. Interacts with ATXN2. Interacts with ADAM9 and ADAM15 cytoplasmic tails. Interacts with BIN2. Interacts with TMEM108. Interacts with ADGRB2.

Subcellular location. Cytoplasm. Membrane. Early endosome. Presynapse.

Tissue specificity. Brain, mostly in frontal cortex. Expressed at high level in fetal cerebellum.

Domain organisation. An N-terminal amphipathic helix, the BAR domain and a second amphipathic helix inserted into helix 1 of the BAR domain (N-BAR domain) induce membrane curvature and bind curved membranes. The BAR domain dimer forms a rigid crescent shaped bundle of helices with the pair of second amphipathic helices protruding towards the membrane-binding surface.

Miscellaneous. HeLa cells expressing the N-BAR domain of SH3GL2 show tubulation of the plasma membrane. The N-BAR domain binds liposomes and induces formation of tubules from liposomes. The N-terminal amphipathic helix is required for liposome binding. The second amphipathic helix enhances liposome tubulation.

Similarity. Belongs to the endophilin family.

RefSeq proteins (1): NP_003017* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001452	SH3_domain	Domain
IPR004148	BAR_dom	Domain
IPR027267	AH/BAR_dom_sf	Homologous_superfamily
IPR035824	Endophilin_A_SH3	Domain
IPR036028	SH3-like_dom_sf	Homologous_superfamily
IPR050384	Endophilin_SH3RF	Family

Pfam: PF03114, PF07653

UniProt features (33 total): helix 9, mutagenesis site 6, strand 5, region of interest 5, domain 2, compositionally biased region 2, modified residue 2, chain 1, coiled-coil region 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
2D4C	X-RAY DIFFRACTION	2.4
1X04	X-RAY DIFFRACTION	2.9
1X03	X-RAY DIFFRACTION	3.1
2DBM	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q99962-F1	86.61	0.66

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (2): 262, 299

Mutagenesis-validated functional residues (6):

Position	Phenotype
63	reduced tubulation of liposomes, 3-fold increase in tubule diameter, no effect on liposome binding; when associated with
66	loss of tubulation of liposomes, no effect on liposome binding.
66	reduced tubulation of liposomes, 3-fold increase in tubule diameter, no effect on liposome binding; when associated with
66	vesiculation of liposomes, no effect on liposome binding, indol ring located in hydrophobic core of the membrane.
70	reduced tubulation of liposomes, 3-fold increase in tubule diameter, no effect on liposome binding; when associated with
202	no effect. indol ring not associated with the membrane.

Function

Pathways and Gene Ontology

Reactome pathways

29 pathways

ID	Pathway
R-HSA-177504	Retrograde neurotrophin signalling
R-HSA-182971	EGFR downregulation
R-HSA-2132295	MHC class II antigen presentation
R-HSA-432720	Lysosome Vesicle Biogenesis
R-HSA-432722	Golgi Associated Vesicle Biogenesis
R-HSA-437239	Recycling pathway of L1
R-HSA-6807004	Negative regulation of MET activity
R-HSA-8856825	Cargo recognition for clathrin-mediated endocytosis
R-HSA-8856828	Clathrin-mediated endocytosis
R-HSA-8875360	InlB-mediated entry of Listeria monocytogenes into host cell
R-HSA-1266738	Developmental Biology
R-HSA-1280218	Adaptive Immune System
R-HSA-162582	Signal Transduction
R-HSA-1643685	Disease
R-HSA-166520	Signaling by NTRKs
R-HSA-168256	Immune System
R-HSA-177929	Signaling by EGFR
R-HSA-187037	Signaling by NTRK1 (TRKA)
R-HSA-199991	Membrane Trafficking
R-HSA-199992	trans-Golgi Network Vesicle Budding
R-HSA-373760	L1CAM interactions
R-HSA-422475	Axon guidance
R-HSA-5653656	Vesicle-mediated transport
R-HSA-5663205	Infectious disease
R-HSA-6806834	Signaling by MET
R-HSA-8876384	Listeria monocytogenes entry into host cells
R-HSA-9006934	Signaling by Receptor Tyrosine Kinases
R-HSA-9675108	Nervous system development
R-HSA-9824439	Bacterial Infection Pathways

MSigDB gene sets: 227 (showing top): REACTOME_RETROGRADE_NEUROTROPHIN_SIGNALLING, MODY_HIPPOCAMPUS_POSTNATAL, BENPORATH_ES_WITH_H3K27ME3, YAGI_AML_WITH_INV_16_TRANSLOCATION, GOBP_REGULATION_OF_ERBB_SIGNALING_PATHWAY, GOBP_NEURON_PROJECTION_EXTENSION, GOBP_CIRCULATORY_SYSTEM_PROCESS, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, GOBP_NEGATIVE_REGULATION_OF_ERBB_SIGNALING_PATHWAY, GOBP_GROWTH, GOBP_NEUROGENESIS, TGACCTY_ERR1_Q2, TAKADA_GASTRIC_CANCER_COPY_NUMBER_DN, GOBP_VESICLE_MEDIATED_TRANSPORT

GO Biological Process (13): regulation of receptor internalization (GO:0002090), signal transduction (GO:0007165), central nervous system development (GO:0007417), negative regulation of gene expression (GO:0010629), neuron projection development (GO:0031175), negative regulation of epidermal growth factor receptor signaling pathway (GO:0042059), negative regulation of MAPK cascade (GO:0043409), synaptic vesicle endocytosis (GO:0048488), dendrite extension (GO:0097484), postsynaptic actin cytoskeleton organization (GO:0098974), negative regulation of blood-brain barrier permeability (GO:1905604), cellular response to brain-derived neurotrophic factor stimulus (GO:1990416), endocytosis (GO:0006897)

GO Molecular Function (3): lipid binding (GO:0008289), identical protein binding (GO:0042802), protein binding (GO:0005515)

GO Cellular Component (16): Golgi membrane (GO:0000139), cytoplasm (GO:0005737), early endosome (GO:0005769), cytosol (GO:0005829), plasma membrane (GO:0005886), clathrin-coated endocytic vesicle membrane (GO:0030669), perinuclear region of cytoplasm (GO:0048471), photoreceptor ribbon synapse (GO:0098684), presynapse (GO:0098793), postsynapse (GO:0098794), glutamatergic synapse (GO:0098978), presynaptic cytosol (GO:0099523), endosome (GO:0005768), membrane (GO:0016020), cell projection (GO:0042995), synapse (GO:0045202)

Reactome top-level categories

Rollup of top-13 pathways:

Category	Pathways
trans-Golgi Network Vesicle Budding	2
Membrane Trafficking	2
Signaling by Receptor Tyrosine Kinases	2
Signaling by NTRK1 (TRKA)	1
Signaling by EGFR	1
Adaptive Immune System	1
L1CAM interactions	1
Signaling by MET	1
Clathrin-mediated endocytosis	1
Listeria monocytogenes entry into host cells	1
Immune System	1
Signaling by NTRKs	1
Vesicle-mediated transport	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	7
synapse	3
binding	2
cytoplasm	2
receptor internalization	1
regulation of receptor-mediated endocytosis	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
nervous system development	1
system development	1
gene expression	1
regulation of gene expression	1
negative regulation of macromolecule biosynthetic process	1
neuron development	1
plasma membrane bounded cell projection organization	1
epidermal growth factor receptor signaling pathway	1
regulation of epidermal growth factor receptor signaling pathway	1
negative regulation of ERBB signaling pathway	1
MAPK cascade	1
regulation of MAPK cascade	1
negative regulation of intracellular signal transduction	1
synaptic vesicle recycling	1
presynaptic endocytosis	1
neuron projection extension	1
actin cytoskeleton organization	1
postsynaptic cytoskeleton organization	1
negative regulation of vascular permeability	1
regulation of blood-brain barrier permeability	1
cellular response to nerve growth factor stimulus	1
vesicle budding from membrane	1
membrane invagination	1
vesicle-mediated transport	1
import into cell	1
protein binding	1
Golgi apparatus	1
bounding membrane of organelle	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

2018 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SH3GL2	SYNJ1	O43426	993
SH3GL2	SYNJ2	O15056	971
SH3GL2	AMPH	P49418	884
SH3GL2	SNX9	Q9Y5X1	869
SH3GL2	BIN1	O00499	843
SH3GL2	ATXN2	Q99700	816
SH3GL2	SLC17A7	Q9P2U7	792
SH3GL2	TMEM108	Q6UXF1	792
SH3GL2	LRRK2	Q5S007	773
SH3GL2	EPS15	P42566	759
SH3GL2	PRKN	O60260	757
SH3GL2	ADAM15	Q13444	748
SH3GL2	SNAP91	O60641	731
SH3GL2	PDCD6IP	Q8WUM4	702
SH3GL2	ADAM9	Q13443	678

IntAct

141 interactions, top by confidence:

A	B	Type	Score
CBL	SH3KBP1	psi-mi:“MI:0914”(association)	0.980
SH3KBP1	CBL	psi-mi:“MI:0914”(association)	0.980
SH3GL2	SH3GL1	psi-mi:“MI:0914”(association)	0.800
SH3GL1	SH3GL2	psi-mi:“MI:0915”(physical association)	0.800
SH3GL2	SH3KBP1	psi-mi:“MI:0915”(physical association)	0.790
ATXN2	SH3GL2	psi-mi:“MI:0915”(physical association)	0.780
SH3GL2	ATXN2	psi-mi:“MI:0915”(physical association)	0.780
SH3GL2	SH3GL2	psi-mi:“MI:0407”(direct interaction)	0.740
SH3GL2	SH3GL2	psi-mi:“MI:0915”(physical association)	0.740
SH3GL2	RAPH1	psi-mi:“MI:0915”(physical association)	0.720
SH3GL2	SH3GL3	psi-mi:“MI:0915”(physical association)	0.720
SH3GL3	SH3GL2	psi-mi:“MI:0915”(physical association)	0.720
DNM2	SH3GL2	psi-mi:“MI:0915”(physical association)	0.720

BioGRID (145): SH3GL2 (Two-hybrid), SH3GL2 (Affinity Capture-MS), SH3GL2 (Two-hybrid), SH3GL2 (Affinity Capture-MS), SH3GL1 (Affinity Capture-MS), SH3GL3 (Affinity Capture-MS), SH3GL2 (Affinity Capture-MS), SH3GL2 (Affinity Capture-MS), SH3GL2 (PCA), SH3GL2 (Affinity Capture-Luminescence), SH3GL2 (FRET), ITCH (Affinity Capture-Western), SH3GL2 (Affinity Capture-Western), SH3GL2 (Far Western), SH3GL2 (Reconstituted Complex)

ESM2 similar proteins: B1V8A0, F1M3L7, O35179, O35180, O35964, O74352, P25343, P34552, P39743, P40531, Q08509, Q08DK5, Q12929, Q19253, Q1LU86, Q2KJA1, Q2VR06, Q32LM0, Q4VAA7, Q59LF3, Q5AFE4, Q5PPJ9, Q5PPZ5, Q5R8P5, Q5ZIR1, Q5ZJ81, Q62419, Q62420, Q62421, Q68FW8, Q6AYE2, Q6GN09, Q6NRL2, Q8AXU9, Q8AXV0, Q8AXV1, Q8I190, Q8I1A6, Q8I1C0, Q8I1I3

Diamond homologs: A0A8I3PDQ1, A1CEK6, A1DFN5, A2QW93, A4FU49, A4RF61, A7A261, O13736, O35177, O35179, O35964, O42287, O43281, P29355, P34109, P38753, P43603, P56945, Q08012, Q0CJU8, Q0P5B1, Q0U6X7, Q14511, Q15811, Q16584, Q1E878, Q2GT05, Q4R729, Q4WHP5, Q557J6, Q5BBL4, Q5I1X5, Q61140, Q62419, Q62420, Q63767, Q64355, Q66HA1, Q6BNP6, Q6C2N2

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
ROCK2	down-regulates	SH3GL2	phosphorylation
LRRK2	down-regulates	SH3GL2	phosphorylation
SH3GL2	up-regulates	Endocytosis

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 90 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
EGFR downregulation	5	27.5×	9e-05
Amine ligand-binding receptors	5	27.5×	9e-05
Signaling by EGFR	5	25.9×	9e-05
Signaling by MET	5	25.2×	9e-05
Clathrin-mediated endocytosis	11	14.9×	6e-08
Cargo recognition for clathrin-mediated endocytosis	7	11.6×	1e-04
Signaling by Receptor Tyrosine Kinases	7	5.7×	4e-03
GPCR downstream signalling	7	4.8×	1e-02

GO biological processes:

GO term	Partners	Fold	FDR
G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger	5	20.0×	1e-03
positive regulation of MAPK cascade	8	8.3×	1e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

45 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	38
Likely benign	1
Benign	1

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
1527509	GRCh37/hg19 9p24.1-22.1(chr9:6788084-19213960)x1	Pathogenic

SpliceAI

3029 predictions. Top by Δscore:

Variant	Effect	Δscore
9:17579285:CAGG:C	donor_loss	1.0000
9:17579286:AGG:A	donor_loss	1.0000
9:17579287:GG:G	donor_loss	1.0000
9:17579289:T:G	donor_loss	1.0000
9:17747050:T:TA	acceptor_gain	1.0000
9:17747056:T:G	acceptor_gain	1.0000
9:17747061:TACA:T	acceptor_loss	1.0000
9:17747062:A:AG	acceptor_gain	1.0000
9:17747063:C:G	acceptor_gain	1.0000
9:17747063:CA:C	acceptor_loss	1.0000
9:17747064:A:AG	acceptor_gain	1.0000
9:17747064:AGA:A	acceptor_loss	1.0000
9:17747065:G:GG	acceptor_gain	1.0000
9:17747065:GA:G	acceptor_gain	1.0000
9:17747065:GAAA:G	acceptor_gain	1.0000
9:17747133:GG:G	donor_gain	1.0000
9:17747133:GGGT:G	donor_loss	1.0000
9:17747134:GG:G	donor_gain	1.0000
9:17747134:GGTAA:G	donor_loss	1.0000
9:17747135:G:C	donor_loss	1.0000
9:17747135:G:GG	donor_gain	1.0000
9:17747136:T:A	donor_loss	1.0000
9:17787375:CCTA:C	acceptor_loss	1.0000
9:17787376:CTA:C	acceptor_loss	1.0000
9:17787377:TA:T	acceptor_loss	1.0000
9:17787378:A:AG	acceptor_gain	1.0000
9:17787378:AGGCC:A	acceptor_gain	1.0000
9:17787379:G:GA	acceptor_gain	1.0000
9:17787513:AG:A	donor_loss	1.0000
9:17787514:G:GG	donor_gain	1.0000

AlphaMissense

2337 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
9:17789419:C:A	R165S	1.000
9:17789420:G:C	R165P	1.000
9:17789423:T:C	L166P	1.000
9:17795569:C:G	C295W	1.000
9:17795574:C:A	A297D	1.000
9:17795585:T:C	F301L	1.000
9:17795586:T:C	F301S	1.000
9:17795586:T:G	F301C	1.000
9:17795587:T:A	F301L	1.000
9:17795587:T:G	F301L	1.000
9:17795610:T:C	L309S	1.000
9:17795616:T:C	F311S	1.000
9:17795634:T:A	I317N	1.000
9:17795634:T:G	I317S	1.000
9:17795640:T:A	L319H	1.000
9:17795655:A:T	D324V	1.000
9:17795663:T:A	W327R	1.000
9:17795663:T:C	W327R	1.000
9:17795664:G:C	W327S	1.000
9:17795665:G:C	W327C	1.000
9:17795665:G:T	W327C	1.000
9:17795672:G:A	G330R	1.000
9:17795672:G:C	G330R	1.000
9:17795672:G:T	G330W	1.000
9:17795673:G:A	G330E	1.000
9:17795694:G:A	G337D	1.000
9:17795700:T:C	F339S	1.000
9:17795702:C:A	P340T	1.000
9:17795702:C:T	P340S	1.000
9:17795703:C:A	P340H	1.000

dbSNP variants (sampled 300 via entrez): RS1000017729 (9:17666877 A>C), RS1000029517 (9:17717205 G>T), RS1000031648 (9:17682698 G>A), RS1000035030 (9:17722004 G>A), RS1000043754 (9:17792440 C>T), RS1000055696 (9:17676525 G>A), RS1000071677 (9:17758080 A>G), RS1000076865 (9:17601903 A>G), RS1000084823 (9:17657165 T>C), RS1000091542 (9:17780056 A>G), RS1000094153 (9:17713028 C>G,T), RS1000124267 (9:17610922 A>T), RS1000125959 (9:17664272 G>A,C,T), RS1000133023 (9:17778823 AAG>A), RS1000142787 (9:17622059 T>G)

Disease associations

OMIM: gene MIM:604465 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

24 associations (top):

Study	Trait	p-value
GCST000269_6	Multiple sclerosis	3.000000e-06
GCST000477_12	Cognitive performance	4.000000e-06
GCST000675_3	Heart failure	7.000000e-07
GCST001430_11	Parkinson’s disease	5.000000e-07
GCST001762_273	Obesity-related traits	2.000000e-06
GCST003984_24	Parkinson’s disease	8.000000e-09
GCST003997_2	Myopia	2.000000e-14
GCST004285_4	Midgestational circulating levels of PBDEs	3.000000e-08
GCST004746_19	Small cell lung carcinoma	9.000000e-07
GCST004902_51	Parkinson’s disease	5.000000e-13
GCST005024_1	Pursuit maintenance gain	3.000000e-08
GCST005024_77	Pursuit maintenance gain	2.000000e-07
GCST006223_3	Cerebral cortical growth	5.000000e-06
GCST006291_28	Spherical equivalent or myopia (age of diagnosis)	2.000000e-13
GCST007429_50	Lung function (FVC)	2.000000e-09
GCST007432_86	FEV1	3.000000e-12
GCST009325_49	Parkinson’s disease or first degree relation to individual with Parkinson’s disease	9.000000e-18
GCST009325_50	Parkinson’s disease or first degree relation to individual with Parkinson’s disease	5.000000e-17
GCST009723_41	Vertical cup-disc ratio (adjusted for vertical disc diameter)	8.000000e-10
GCST009724_15	Vertical cup-disc ratio (multi-trait analysis)	2.000000e-11
GCST010991_32	Parkinson’s disease	3.000000e-10
GCST011155_8	Nontraumatic osteonecrosis of the femoral head	9.000000e-07
GCST011743_80	HDL cholesterol levels in HIV infection	1.000000e-07
GCST012194_8	Obsessive-compulsive traits	2.000000e-07

EFO canonical traits (12, from GWAS)

EFO ID	Trait name
EFO:0003926	neuropsychological test
EFO:0003940	physical activity
EFO:0007961	polybrominated biphenyl measurement
EFO:0007962	polybrominated diphenyl ether measurement
EFO:0007964	gestational serum measurement
EFO:0008433	pursuit maintenance gain measurement
EFO:0004847	age at onset
EFO:0004312	vital capacity
EFO:0004314	forced expiratory volume
EFO:0006939	cup-to-disc ratio measurement
EFO:1001930	idiopathic osteonecrosis of the femoral head
EFO:0004612	high density lipoprotein cholesterol measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

30 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, increases expression, increases methylation	5
Arsenic Trioxide	affects binding, decreases reaction, increases expression	2
Benzo(a)pyrene	affects methylation, decreases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
methylmercuric chloride	decreases expression	1
methyleugenol	decreases expression	1
terbufos	increases methylation	1
trichostatin A	decreases expression, increases expression	1
sodium arsenite	affects splicing, increases expression	1
4-aminophenylarsenoxide	affects binding, decreases reaction	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
abrine	increases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
Air Pollutants	affects methylation, increases abundance, affects expression	1
Arbutin	decreases expression	1
Doxorubicin	decreases expression	1
Fonofos	increases methylation	1
Ivermectin	decreases expression	1
Lead	affects expression	1
Lipopolysaccharides	increases expression, affects response to substance	1
Parathion	increases methylation	1
Tetrachlorodibenzodioxin	decreases expression	1
Urethane	increases expression	1
Aflatoxin B1	affects expression	1
Cadmium Chloride	increases expression	1
Okadaic Acid	increases expression	1
Acrylamide	decreases expression	1
Particulate Matter	affects methylation, increases abundance, affects expression	1

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.