SORBS2

Summary

SORBS2 (sorbin and SH3 domain containing 2, HGNC:24098) is a protein-coding gene on chromosome 4q35.1, encoding Sorbin and SH3 domain-containing protein 2 (O94875). Adapter protein that plays a role in the assembling of signaling complexes, being a link between ABL kinases and actin cytoskeleton.

Arg and c-Abl represent the mammalian members of the Abelson family of non-receptor protein-tyrosine kinases. They interact with the Arg/Abl binding proteins via the SH3 domains present in the carboxy end of the latter group of proteins. This gene encodes the sorbin and SH3 domain containing 2 protein. It has three C-terminal SH3 domains and an N-terminal sorbin homology (SoHo) domain that interacts with lipid raft proteins. The subcellular localization of this protein in epithelial and cardiac muscle cells suggests that it functions as an adapter protein to assemble signaling complexes in stress fibers, and that it is a potential link between Abl family kinases and the actin cytoskeleton. Alternative splicing results in multiple transcript variants encoding different isoforms.

Source: NCBI Gene 8470 — RefSeq curated summary.

At a glance

• Gene–disease (curated): congenital heart disease (Limited, GenCC)
• GWAS associations: 10
• Clinical variants (ClinVar): 220 total
• MANE Select transcript: NM_001395207

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:24098
Approved symbol	SORBS2
Name	sorbin and SH3 domain containing 2
Location	4q35.1
Locus type	gene with protein product
Status	Approved
Aliases	ARGBP2, KIAA0777
Ensembl gene	ENSG00000154556
Ensembl biotype	protein_coding
OMIM	616349
Entrez	8470

Gene structure

Transcript identifiers

Ensembl transcripts: 202 — 180 protein_coding, 13 protein_coding_CDS_not_defined, 8 retained_intron, 1 nonsense_mediated_decay

ENST00000284776, ENST00000319454, ENST00000319471, ENST00000355634, ENST00000393523, ENST00000393528, ENST00000414724, ENST00000415274, ENST00000419063, ENST00000420158, ENST00000421420, ENST00000421639, ENST00000425679, ENST00000428330, ENST00000429056, ENST00000430503, ENST00000431902, ENST00000432655, ENST00000435480, ENST00000437304, ENST00000438278, ENST00000439049, ENST00000439914, ENST00000444771, ENST00000444781, ENST00000445115, ENST00000445343, ENST00000445625, ENST00000449407, ENST00000450341, ENST00000451701, ENST00000451958, ENST00000451974, ENST00000452351, ENST00000456060, ENST00000456596, ENST00000457247, ENST00000457934, ENST00000462661, ENST00000463104, ENST00000464819, ENST00000464975, ENST00000466289, ENST00000469627, ENST00000470685, ENST00000476311, ENST00000476878, ENST00000478249, ENST00000478461, ENST00000480146, ENST00000485380, ENST00000487184, ENST00000487836, ENST00000488562, ENST00000490562, ENST00000490779, ENST00000492104, ENST00000492810, ENST00000493709, ENST00000494140, ENST00000495932, ENST00000498125, ENST00000650145, ENST00000695409, ENST00000695410, ENST00000695411, ENST00000698536, ENST00000698537, ENST00000698538, ENST00000698539, ENST00000698540, ENST00000698843, ENST00000706921, ENST00000865659, ENST00000865660, ENST00000865661, ENST00000865662, ENST00000865663, ENST00000865664, ENST00000865665, ENST00000865666, ENST00000865667, ENST00000865668, ENST00000865669, ENST00000865670, ENST00000865671, ENST00000865672, ENST00000865673, ENST00000865674, ENST00000865675, ENST00000865676, ENST00000865677, ENST00000865678, ENST00000865679, ENST00000865680, ENST00000865681, ENST00000865682, ENST00000865683, ENST00000865684, ENST00000865685, ENST00000865686, ENST00000865687, ENST00000865688, ENST00000865689, ENST00000865690, ENST00000865691, ENST00000865692, ENST00000865693, ENST00000865694, ENST00000865695, ENST00000865696, ENST00000865697, ENST00000865698, ENST00000865699, ENST00000865700, ENST00000865701, ENST00000865702, ENST00000865703, ENST00000865704, ENST00000865705, ENST00000865706, ENST00000865707, ENST00000865708, ENST00000865709, ENST00000865710, ENST00000865711, ENST00000865712, ENST00000865713, ENST00000865714, ENST00000865715, ENST00000865716, ENST00000865717, ENST00000865718, ENST00000865719, ENST00000865720, ENST00000865721, ENST00000865722, ENST00000865723, ENST00000865724, ENST00000865725, ENST00000865726, ENST00000865727, ENST00000865728, ENST00000865729, ENST00000865730, ENST00000865731, ENST00000865732, ENST00000865733, ENST00000865734, ENST00000865735, ENST00000865736, ENST00000865737, ENST00000865738, ENST00000865739, ENST00000865740, ENST00000865741, ENST00000865742, ENST00000865743, ENST00000865744, ENST00000865745, ENST00000865746, ENST00000865747, ENST00000865748, ENST00000865749, ENST00000865750, ENST00000865751, ENST00000865752, ENST00000865753, ENST00000865754, ENST00000865755, ENST00000865756, ENST00000865757, ENST00000865758, ENST00000865759, ENST00000865760, ENST00000865761, ENST00000865762, ENST00000865763, ENST00000865764, ENST00000865765, ENST00000865766, ENST00000865767, ENST00000865768, ENST00000865769, ENST00000865770, ENST00000865771, ENST00000865772, ENST00000865773, ENST00000865774, ENST00000865775, ENST00000865776, ENST00000865777, ENST00000865778, ENST00000865779, ENST00000865780, ENST00000945967, ENST00000945968, ENST00000945969, ENST00000945970, ENST00000945971, ENST00000945972, ENST00000945973

RefSeq mRNA: 42 — MANE Select: NM_001395207 NM_001145670, NM_001145671, NM_001145672, NM_001145673, NM_001145674, NM_001145675, NM_001270771, NM_001394245, NM_001394246, NM_001394247, NM_001394248, NM_001394249, NM_001394250, NM_001394251, NM_001394252, NM_001394253, NM_001394254, NM_001394255, NM_001394256, NM_001394257, NM_001394258, NM_001394259, NM_001394260, NM_001394261, NM_001394262, NM_001394263, NM_001394264, NM_001394265, NM_001394266, NM_001394267, NM_001394268, NM_001394270, NM_001394271, NM_001394272, NM_001394273, NM_001394274, NM_001394275, NM_001394276, NM_001394277, NM_001395207, NM_003603, NM_021069

CCDS: CCDS3845, CCDS43289, CCDS47173, CCDS47174, CCDS47175, CCDS47176, CCDS54825, CCDS59482, CCDS93677, CCDS93678, CCDS93679

Canonical transcript exons

ENST00000695409 — 27 exons

Exon	Start	End
ENSE00001279400	185775227	185775366
ENSE00001958337	185626832	185627019
ENSE00002244815	185589679	185589785
ENSE00002270306	185593886	185593935
ENSE00003464903	185630549	185630598
ENSE00003494792	185649467	185649656
ENSE00003527911	185651784	185651828
ENSE00003610581	185652662	185652728
ENSE00003623098	185646668	185646782
ENSE00003659631	185611780	185611980
ENSE00003787781	185657424	185657596
ENSE00003963663	185638079	185638162
ENSE00003963664	185585523	185587688
ENSE00003963665	185618585	185618631
ENSE00003963667	185615045	185615159
ENSE00003963669	185662104	185662242
ENSE00003963672	185684754	185684846
ENSE00003963673	185620063	185620151
ENSE00003963675	185734099	185734154
ENSE00003963676	185811664	185812194
ENSE00003963686	185638877	185639035
ENSE00003963690	185678796	185678822
ENSE00003963691	185622914	185624494
ENSE00003963692	185690562	185690611
ENSE00003963693	185635355	185635411
ENSE00003963694	185678423	185678547
ENSE00003963697	185614831	185614959

Expression profiles

Bgee: expression breadth ubiquitous, 291 present calls, max score 99.66.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 26.4540 / max 2350.9612, expressed in 1141 samples.

FANTOM5 promoters (52 alternative TSS)

Promoter ID	TPM avg	Samples expressed
55273	6.2766	342
55292	5.4862	870
55301	1.6110	261
55291	1.5226	596
55311	1.3690	271
55306	1.1145	95
55293	0.9093	393
55289	0.7396	362
55288	0.7047	334
55307	0.6836	75

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
heart right ventricle	UBERON:0002080	99.66	gold quality
popliteal artery	UBERON:0002250	99.55	gold quality
tibial artery	UBERON:0007610	99.55	gold quality
artery	UBERON:0001637	99.42	gold quality
left ventricle myocardium	UBERON:0006566	99.40	gold quality
myocardium	UBERON:0002349	99.34	gold quality
right coronary artery	UBERON:0001625	99.33	gold quality
pigmented layer of retina	UBERON:0001782	99.16	gold quality
cardiac muscle of right atrium	UBERON:0003379	99.16	gold quality
retina	UBERON:0000966	99.13	gold quality
right adrenal gland cortex	UBERON:0035827	99.09	gold quality
adrenal cortex	UBERON:0001235	99.04	gold quality
cardiac ventricle	UBERON:0002082	99.02	gold quality
heart left ventricle	UBERON:0002084	99.00	gold quality
left adrenal gland cortex	UBERON:0035825	99.00	gold quality
aorta	UBERON:0000947	98.91	gold quality
heart	UBERON:0000948	98.89	gold quality
right adrenal gland	UBERON:0001233	98.86	gold quality
left adrenal gland	UBERON:0001234	98.83	gold quality
apex of heart	UBERON:0002098	98.80	gold quality
cardiac atrium	UBERON:0002081	98.70	gold quality
coronary artery	UBERON:0001621	98.63	gold quality
adrenal gland	UBERON:0002369	98.62	gold quality
right atrium auricular region	UBERON:0006631	98.61	gold quality
left coronary artery	UBERON:0001626	98.58	gold quality
descending thoracic aorta	UBERON:0002345	98.55	gold quality
vena cava	UBERON:0004087	98.48	gold quality
blood vessel layer	UBERON:0004797	98.39	gold quality
colonic epithelium	UBERON:0000397	98.34	gold quality
muscle layer of sigmoid colon	UBERON:0035805	98.15	gold quality

Single-cell (SCXA)

Detected in 16 experiment(s), a significant marker in 14.

Experiment	Marker?	Max mean expression
E-ANND-2	yes	4558.81
E-HCAD-35	yes	1556.68
E-GEOD-75688	yes	687.29
E-HCAD-25	yes	75.72
E-MTAB-10287	yes	51.68
E-HCAD-11	yes	27.65
E-MTAB-8410	yes	25.02
E-GEOD-137537	yes	22.23
E-MTAB-10553	yes	20.63
E-HCAD-1	yes	15.08
E-CURD-46	yes	12.12
E-HCAD-9	yes	8.68
E-CURD-112	yes	5.85
E-MTAB-11268	no	9559.98
E-MTAB-9543	no	2.44

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): NR1I2

miRNA regulators (miRDB)

138 targeting SORBS2, 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-3163	100.00	77.23	8605
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-518D-5P	100.00	67.51	979
HSA-MIR-518E-5P	100.00	67.66	954
HSA-MIR-518F-5P	100.00	67.51	979
HSA-MIR-519A-5P	100.00	67.66	954
HSA-MIR-519B-5P	100.00	67.66	954
HSA-MIR-519C-5P	100.00	67.66	954
HSA-MIR-520C-5P	100.00	67.51	979
HSA-MIR-522-5P	100.00	67.66	954
HSA-MIR-523-5P	100.00	67.66	954
HSA-MIR-526A-5P	100.00	67.51	979
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-511-3P	99.99	68.85	1467
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-3617-3P	99.98	67.86	918
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-433-3P	99.98	69.37	1203
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-507	99.97	70.11	1915
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-557	99.96	70.01	1640

Literature-anchored findings (GeneRIF, showing 30)

• complexation with Cbl mediates ubiquitination and degradation of c-Abl (PMID:12475393)
• regulates cytoskeletal organization and signal transduction–review (PMID:12510380)
• The sorbin N- and C-termini were localized in the human ArgBP2 gene locus; they are spliced to the 5’ and 3’ ends of the 95% homologous region; thus, a revised human sorbin nucleotide sequence is proposed. (PMID:15949647)
• Loss of ArgBP2 is associated with pancreatic cancer. (PMID:18559503)
• CIP4 is a new ArgBP2 interacting protein that modulates the ArgBP2 mediated control of WAVE1 phosphorylation and cancer cell migration. (PMID:19631450)
• Results indicate that ArgBP2 may play an important role in the assembly and maintenance of myofibrils in cardiomyocytes. (PMID:20886612)
• Reconstitution of SORBS2 expression resulted significant reduction in cell proliferation, colony formation and anchorage-independent growth in CaSki, HPKII and HaCaT cells, whereby anchorage-independent growth could only be investigated for CaSki cells (PMID:21602178)
• A co-localization of SORBS2 and eEF1A was evidenced at level of plasma membrane, thus suggesting the involvement of eEF1A1 in novel key signal transduction complexes. (PMID:21689717)
• the expression and localization of hArgBP2 in osteosarcoma MG-63 cells (PMID:22394629)
• In epithelial NMuMG cells, immunofluorescence analyses revealed localization of ArgBP2 at tight junctions and mutation analyses found a second SH3 domain to be important for ArgBP2 localization to the cell-cell contact sites. (PMID:22431180)
• SORBS2 and TLR3 induce premature senescence in primary human fibroblasts and keratinocytes. (PMID:24165198)
• Sarcoplasmic sorbin and SH3 domain-containing protein 2 is released from damaged cardiac tissue into the bloodstream upon lethal acute myocardial infarction. (PMID:24342996)
• Tyrosine phosphorylation of ARGBP2 interferes with a SH3 mediated self-interaction, thereby controlling its panel of interacting partners and related functions. (PMID:24475245)
• ArgBP2 interaction with alpha-actinin and actin stress fibers inhibits cell migration (PMID:25429109)
• This study confirmed that SORBS2 as genetic modifiers of age at onset of Alzheimer disease. (PMID:26214276)
• SORBS2 transcription is activated by telomere position effect-over long distance upon telomere shortening in muscle cells from patients with facioscapulohumeral dystrophy (PMID:26359233)
• ArgBP2 inhibits proliferation, migration, and invasion of gastric cancer cells.MORC2 down-regulates the ArgBP2 via histone methylation in gastric cancer cells. (PMID:26476214)
• In spite of our finding that SORBS2 is clearly a component of the apical junction complex, it does not appear to be required for either normal tight- or adherens junction assembly, structure or function or for growth factor-mediated changes in tight junction dynamics (PMID:28961272)
• results thus contribute to the knowledge of the regulatory mechanism of HSF1 in down-regulating ArgBP2, providing new insight into the HSF1&MORC2-PRC2-ArgBP2 signaling pathway and a better understanding of their functions in gastric cancer cells. (PMID:29339121)
• By enhancing the stability of gene transcripts, SORBS2 suppresses ovarian cancer invasiveness and affects monocyte to myeloid-derived suppressor cell and M2-like macrophage polarization, eliciting a tumor-suppressive immune microenvironment. (PMID:29548303)
• The RNA-binding protein SORBS2 suppresses hepatocellular carcinoma tumourigenesis and metastasis by stabilizing RORA mRNA. (PMID:31365778)
• Elevated myocardial SORBS2 and the underlying implications in left ventricular noncompaction cardiomyopathy. (PMID:32143182)
• Knockout of SORBS2 Protein Disrupts the Structural Integrity of Intercalated Disc and Manifests Features of Arrhythmogenic Cardiomyopathy. (PMID:32808564)
• LncRNA H19 Inhibits the Progression of Sepsis-Induced Myocardial Injury via Regulation of the miR-93-5p/SORBS2 Axis. (PMID:32996061)
• RNA-binding protein SORBS2 suppresses clear cell renal cell carcinoma metastasis by enhancing MTUS1 mRNA stability. (PMID:33311452)
• Musk ketone induces apoptosis of gastric cancer cells via downregulation of sorbin and SH3 domain containing 2. (PMID:33880576)
• SORBS2 is a genetic factor contributing to cardiac malformation of 4q deletion syndrome patients. (PMID:34099102)
• The RNA-binding protein sorbin and SH3 domain-containing 2 are transcriptionally regulated by specificity protein 1 and function as tumor suppressors in bladder cancer by stabilizing tissue factor pathway inhibitor. (PMID:38501385)
• Sorbs2 regulates seizure activity by influencing AMPAR-mediated excitatory synaptic transmission in temporal lobe epilepsy. (PMID:38555055)
• RNA-binding protein SORBS2 increases human trophoblast cell migration via stabilizing HK2 mRNA in preeclampsia. (PMID:38995729)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	sorbs2a	ENSDARG00000003046
danio_rerio	sorbs2b	ENSDARG00000061603
mus_musculus	Sorbs2	ENSMUSG00000031626
rattus_norvegicus	Sorbs2	ENSRNOG00000013391
drosophila_melanogaster	Dlish	FBGN0034264
caenorhabditis_elegans		WBGENE00012891
caenorhabditis_elegans		WBGENE00015128

Paralogs (12): SORBS1 (ENSG00000095637), SH3GLB1 (ENSG00000097033), NCF4 (ENSG00000100365), SH3GL2 (ENSG00000107295), SH3D19 (ENSG00000109686), SORBS3 (ENSG00000120896), SH3GL3 (ENSG00000140600), SH3GL1 (ENSG00000141985), SH3GLB2 (ENSG00000148341), SH3RF1 (ENSG00000154447), SH3RF2 (ENSG00000156463), SH3RF3 (ENSG00000172985)

Protein

Protein identifiers

Sorbin and SH3 domain-containing protein 2 — O94875 (reviewed: O94875)

Alternative names: Arg-binding protein 2, Arg/Abl-interacting protein 2, Sorbin

All UniProt accessions (44): O94875, A0A1D5RMN3, A0A3B3ITL8, A0A8Q3SHW0, A0A8Q3WKF2, A0A8Q3WKH1, A0A8Q3WKK4, A0A8Q3WLK0, A0A8Q3WLU7, A0A8V8TLU4, A0A8V8TMC7, A0A8V8TMD6, A0A8V8TNC1, A0A8V8TNN1, A0A9L9PXP6, C9IZ89, C9IZT7, C9J348, C9J372, C9J3W4, C9J4K2, C9J4Z9, C9J620, C9J7Q5, C9J8E3, C9J9D3, C9JBB0, C9JBR8, C9JC90, C9JDX2, C9JEA9, C9JFS9, C9JG84, C9JI79, C9JL62, C9JLD6, C9JM25, C9JN77, C9JWC3, C9JZ60, H7BXR3, H7BZK1, H7BZX1, H7C1R7

UniProt curated annotations — full annotation on UniProt →

Function. Adapter protein that plays a role in the assembling of signaling complexes, being a link between ABL kinases and actin cytoskeleton. Can form complex with ABL1 and CBL, thus promoting ubiquitination and degradation of ABL1. May play a role in the regulation of pancreatic cell adhesion, possibly by acting on WASF1 phosphorylation, enhancing phosphorylation by ABL1, as well as dephosphorylation by PTPN12. Isoform 6 increases water and sodium absorption in the intestine and gall-bladder.

Subunit / interactions. Interacts with ABL, CBL, DNM1, DNM2, FLOT1, AFDN, PTK2B/PYK2, SAPAP, SPTAN1, SYNJ1, SYNJ2, VCL/vinculin and WASF. Interacts with ABL1/c-Abl, ABL2/v-Abl/Arg, ACTN, CBL and PALLD. Interacts with PTPN12 and WASF1 via its SH3 domains; this interaction may mediate the partial PTPN12 and WASF1 translocation to focal adhesion sites.

Subcellular location. Cytoplasm. Perinuclear region. Apical cell membrane. Cell junction. Focal adhesion. Cell projection. Lamellipodium.

Tissue specificity. Abundantly expressed in heart. In cardiac muscle cells, located in the Z-disks of sarcomere. Also found, but to a lower extent, in small and large intestine, pancreas, thymus, colon, spleen, prostate, testis, brain, ovary and epithelial cells. In the pancreas, mainly expressed in acinar cells, duct cells and all cell types in islets (at protein level). Tends to be down-regulated in pancreatic adenocarcinomas and metastases.

Post-translational modifications. Ubiquitinated by CBL. Dephosphorylated by PTPN12.

Domain organisation. The first 2 SH3 domains are required for WASF1-binding. All 3 SH3 domains can bind independently to PTPN12.

Isoforms (12)

UniProt ID	Names	Canonical?
O94875-1	1	yes
O94875-2	2, ArgBP2a
O94875-3	3
O94875-4	4
O94875-5	5, ArgBP2b
O94875-6	6, Sorbin
O94875-7	7
O94875-8	8
O94875-9	9
O94875-10	10
O94875-11	11
O94875-12	12

RefSeq proteins (42): NP_001139142, NP_001139143, NP_001139144, NP_001139145, NP_001139146, NP_001139147, NP_001257700, NP_001381174, NP_001381175, NP_001381176, NP_001381177, NP_001381178, NP_001381179, NP_001381180, NP_001381181, NP_001381182, NP_001381183, NP_001381184, NP_001381185, NP_001381186, NP_001381187, NP_001381188, NP_001381189, NP_001381190, NP_001381191, NP_001381192, NP_001381193, NP_001381194, NP_001381195, NP_001381196, NP_001381197, NP_001381199, NP_001381200, NP_001381201, NP_001381202, NP_001381203, NP_001381204, NP_001381205, NP_001381206, NP_001382136, NP_003594, NP_066547 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001452	SH3_domain	Domain
IPR003127	SoHo_dom	Domain
IPR013087	Znf_C2H2_type	Domain
IPR036028	SH3-like_dom_sf	Homologous_superfamily
IPR050384	Endophilin_SH3RF	Family

Pfam: PF00018, PF02208, PF14604

UniProt features (111 total): modified residue 64, splice variant 16, sequence conflict 9, compositionally biased region 8, domain 4, strand 4, region of interest 3, chain 1, sequence variant 1, helix 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
5VEI	X-RAY DIFFRACTION	1.33

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O94875-F1	52.52	0.14

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 (64): 27, 28, 13, 14, 320, 322, 344, 346, 366, 381, 30, 43, 154, 157, 239, 245, 248, 259, 277, 287 …

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 259 (showing top): GCACCTT_MIR18A_MIR18B, GOBP_MUSCLE_TISSUE_DEVELOPMENT, NKX25_02, GOBP_GROWTH, GOBP_STRIATED_MUSCLE_CELL_DIFFERENTIATION, GCAAGGA_MIR502, GAUSSMANN_MLL_AF4_FUSION_TARGETS_E_UP, CACCAGC_MIR138, AAAYRNCTG_UNKNOWN, CHANDRAN_METASTASIS_DN, MODULE_66, PAPASPYRIDONOS_UNSTABLE_ATEROSCLEROTIC_PLAQUE_DN, SOX9_B1, GOBP_MUSCLE_STRUCTURE_DEVELOPMENT, SENGUPTA_NASOPHARYNGEAL_CARCINOMA_DN

GO Biological Process (3): Notch signaling pathway (GO:0007219), cell growth involved in cardiac muscle cell development (GO:0061049), cytoskeleton organization (GO:0007010)

GO Molecular Function (6): RNA binding (GO:0003723), structural constituent of cytoskeleton (GO:0005200), cytoskeletal adaptor activity (GO:0008093), structural constituent of muscle (GO:0008307), identical protein binding (GO:0042802), protein binding (GO:0005515)

GO Cellular Component (15): nucleus (GO:0005634), plasma membrane (GO:0005886), focal adhesion (GO:0005925), actin cytoskeleton (GO:0015629), apical plasma membrane (GO:0016324), Z disc (GO:0030018), lamellipodium (GO:0030027), dendrite (GO:0030425), neuronal cell body (GO:0043025), synapse (GO:0045202), perinuclear region of cytoplasm (GO:0048471), cytoplasm (GO:0005737), membrane (GO:0016020), cell projection (GO:0042995), anchoring junction (GO:0070161)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
structural molecule activity	2
cytoskeleton	2
cell junction	2
cell surface receptor signaling pathway	1
physiological cardiac muscle hypertrophy	1
developmental cell growth	1
cardiac muscle cell development	1
organelle organization	1
nucleic acid binding	1
cytoskeleton organization	1
cytoskeletal protein binding	1
protein-macromolecule adaptor activity	1
protein binding	1
binding	1
intracellular membrane-bounded organelle	1
membrane	1
cell periphery	1
cell-substrate junction	1
apical part of cell	1
plasma membrane region	1
I band	1
cell leading edge	1
plasma membrane bounded cell projection	1
neuron projection	1
dendritic tree	1
somatodendritic compartment	1
cell body	1
cytoplasm	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

1252 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SORBS2	CBL	P22681	830
SORBS2	SHC2	P98077	710
SORBS2	A0A0A0MSP3	A0A0A0MSP3	644
SORBS2	SORBS1	Q9BX66	588
SORBS2	VCL	P18206	585
SORBS2	PALLD	Q8WX93	585
SORBS2	WFDC1	Q9HC57	582
SORBS2	ABL1	P00519	579
SORBS2	PDLIM3	Q53GG5	533
SORBS2	FLOT1	O75955	511
SORBS2	IL17D	Q8TAD2	481
SORBS2	ATXN7	O15265	468
SORBS2	FYN	P06241	464
SORBS2	FAM149A	A5PLN7	447
SORBS2	RPS3A	P33443	436

IntAct

108 interactions, top by confidence:

A	B	Type	Score
YWHAB	PIK3C2A	psi-mi:“MI:0914”(association)	0.800
YWHAZ	SORBS2	psi-mi:“MI:0915”(physical association)	0.710
YWHAG	BLTP3B	psi-mi:“MI:0914”(association)	0.640
YWHAG	BLTP3B	psi-mi:“MI:2364”(proximity)	0.640
YWHAB	BLTP3B	psi-mi:“MI:2364”(proximity)	0.610
YWHAB	BLTP3B	psi-mi:“MI:0914”(association)	0.610
YWHAE	SORBS2	psi-mi:“MI:0915”(physical association)	0.590
YWHAE	PIK3C2A	psi-mi:“MI:0914”(association)	0.570
YWHAH	BLTP3B	psi-mi:“MI:0914”(association)	0.570
YWHAZ	PIK3C2A	psi-mi:“MI:0914”(association)	0.570
YWHAH	BLTP3B	psi-mi:“MI:2364”(proximity)	0.570
SORBS2	VPS37C	psi-mi:“MI:0915”(physical association)	0.560
NCK2	SORBS2	psi-mi:“MI:0915”(physical association)	0.560
EFS	SORBS2	psi-mi:“MI:0915”(physical association)	0.560
HEL2	SORBS2	psi-mi:“MI:0915”(physical association)	0.560
WAS	SORBS2	psi-mi:“MI:0915”(physical association)	0.560
ATPAF2	SORBS2	psi-mi:“MI:0915”(physical association)	0.560
SORBS2	SH2D4A	psi-mi:“MI:0915”(physical association)	0.560
SORBS2	NCK2	psi-mi:“MI:0915”(physical association)	0.560
SORBS2	HEL2	psi-mi:“MI:0915”(physical association)	0.560
VPS37C	SORBS2	psi-mi:“MI:0915”(physical association)	0.560
SORBS2	EFS	psi-mi:“MI:0915”(physical association)	0.560
SORBS2	WAS	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (131): SORBS2 (Two-hybrid), SORBS2 (Two-hybrid), SORBS2 (Two-hybrid), SORBS2 (Two-hybrid), EFS (Two-hybrid), VPS37C (Two-hybrid), SH2D4A (Two-hybrid), ATPAF2 (Two-hybrid), SORBS2 (Affinity Capture-MS), SORBS2 (Two-hybrid), SORBS2 (Affinity Capture-MS), SORBS2 (Affinity Capture-MS), SORBS2 (Affinity Capture-MS), SORBS2 (Affinity Capture-MS), SORBS2 (Affinity Capture-MS)

ESM2 similar proteins: A0A140LFM6, A0A1B0GVH6, A0A1L8H8C0, A0A2K1JJ00, A0JMD2, A2ARZ3, A2AWL7, A4IGV6, A6H5Y1, D3ZJ47, E9Q309, F1QPR4, F5H4B4, H0WFA5, O14513, O35413, O94875, P0CAX8, P48437, Q12912, Q15468, Q1LXZ9, Q1X8D7, Q28FG2, Q3UTJ2, Q3ZBS1, Q499E5, Q49A88, Q4V7H1, Q5T5U3, Q5VT06, Q62417, Q62770, Q69Z38, Q6DFB0, Q80TY4, Q8BLN6, Q8CB14, Q8IWI9, Q8K0T7

Diamond homologs: A1CEK6, A1DFN5, A1DFP5, A2QW93, A2QWA2, A3LXQ8, A4FU49, A4RF61, A6QLK6, B0BNA1, F4KAU9, O08641, O14964, O35179, O35180, O35413, O35964, O43125, O74749, O80910, O94875, P07751, P0CR78, P0CR79, P10569, P19878, P29355, P38753, P62993, P62994, P87379, Q06449, Q07883, Q08012, Q0CJU8, Q0CJV3, Q0U4Z8, Q0U6X7, Q0V8S0, Q15080

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
CBL	down-regulates	SORBS2	ubiquitination

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 79 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
Activation of BAD and translocation to mitochondria	8	119.4×	1e-13
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	7	92.2×	3e-11
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	7	92.2×	3e-11
Activation of BH3-only proteins	8	77.9×	5e-12
RHO GTPases activate PKNs	9	56.0×	5e-12
Intrinsic Pathway for Apoptosis	8	45.9×	3e-10
VEGFR2 mediated vascular permeability	5	40.0×	2e-06
FOXO-mediated transcription	6	39.5×	2e-07

GO biological processes:

GO term	Partners	Fold	FDR
protein targeting	5	29.5×	2e-04
epidermal growth factor receptor signaling pathway	5	20.0×	8e-04
intracellular protein localization	9	15.2×	3e-06
cell migration	12	11.9×	2e-07

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	169
Likely benign	13
Benign	6

Top pathogenic / likely-pathogenic (0)

SpliceAI

6131 predictions. Top by Δscore:

Variant	Effect	Δscore
4:185589785:CCT:C	acceptor_gain	1.0000
4:185611979:CC:C	acceptor_gain	1.0000
4:185611980:CC:C	acceptor_gain	1.0000
4:185614826:GCTAC:G	donor_loss	1.0000
4:185614827:CTACC:C	donor_loss	1.0000
4:185614828:TAC:T	donor_loss	1.0000
4:185614829:ACCTT:A	donor_loss	1.0000
4:185614830:CCTTT:C	donor_gain	1.0000
4:185614955:AGTTT:A	acceptor_gain	1.0000
4:185614956:GTTT:G	acceptor_gain	1.0000
4:185614957:TTT:T	acceptor_gain	1.0000
4:185614958:TT:T	acceptor_gain	1.0000
4:185614959:TCTA:T	acceptor_loss	1.0000
4:185614960:C:CC	acceptor_gain	1.0000
4:185614961:T:G	acceptor_loss	1.0000
4:185615156:CTCC:C	acceptor_gain	1.0000
4:185615158:CC:C	acceptor_gain	1.0000
4:185615159:CC:C	acceptor_gain	1.0000
4:185615159:CCT:C	acceptor_loss	1.0000
4:185615161:T:A	acceptor_loss	1.0000
4:185618579:A:AC	donor_gain	1.0000
4:185618580:C:CC	donor_gain	1.0000
4:185618583:A:AC	donor_gain	1.0000
4:185618584:C:CC	donor_gain	1.0000
4:185627020:C:CC	acceptor_gain	1.0000
4:185635487:A:C	acceptor_gain	1.0000
4:185646666:A:AC	donor_gain	1.0000
4:185646667:C:CT	donor_gain	1.0000
4:185646667:CTGG:C	donor_gain	1.0000
4:185646667:CTGGT:C	donor_gain	1.0000

AlphaMissense

8579 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:185587640:A:T	V1097D	1.000
4:185587661:C:T	G1090D	1.000
4:185587688:C:T	G1081E	1.000
4:185589679:C:A	G1081W	1.000
4:185589679:C:G	G1081R	1.000
4:185589679:C:T	G1081R	1.000
4:185589688:A:G	W1078R	1.000
4:185589688:A:T	W1078R	1.000
4:185589735:A:G	L1062P	1.000
4:185589741:A:G	L1060P	1.000
4:185615101:A:G	W900R	1.000
4:185615101:A:T	W900R	1.000
4:185623436:A:G	C661R	1.000
4:185652691:A:G	F102S	1.000
4:185652705:C:A	W97C	1.000
4:185652705:C:G	W97C	1.000
4:185652707:A:G	W97R	1.000
4:185652707:A:T	W97R	1.000
4:185587655:A:G	F1092S	0.999
4:185587662:C:G	G1090R	0.999
4:185589686:C:A	W1078C	0.999
4:185589686:C:G	W1078C	0.999
4:185589711:A:T	V1070D	0.999
4:185589735:A:T	L1062H	0.999
4:185611932:C:G	G978R	0.999
4:185611941:A:G	W975R	0.999
4:185611941:A:T	W975R	0.999
4:185614844:A:G	L957P	0.999
4:185614880:G:T	A945D	0.999
4:185615061:G:T	P913Q	0.999

dbSNP variants (sampled 300 via entrez): RS1000002536 (4:185818478 C>A,G,T), RS10000195 (4:185932285 A>G), RS10000238 (4:185688941 G>A,T), RS1000024970 (4:185697289 T>A), RS1000025094 (4:185737596 A>C,G), RS1000029868 (4:185653593 G>A), RS1000048183 (4:185851501 A>T), RS1000048932 (4:185725854 A>C,G,T), RS1000056567 (4:185660546 C>A,T), RS1000059062 (4:185912374 C>T), RS1000061615 (4:185949230 G>A,T), RS1000063081 (4:185619672 T>C), RS1000067096 (4:185698644 C>T), RS10000730 (4:185683691 C>T), RS1000073586 (4:185659182 T>G)

Disease associations

OMIM: gene MIM:616349 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
congenital heart disease	Limited	Autosomal dominant

Mondo (1): congenital heart disease (MONDO:0005453)

Orphanet (0):

HPO phenotypes

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

GWAS associations

10 associations (top):

Study	Trait	p-value
GCST001524_13	Visceral adipose tissue/subcutaneous adipose tissue ratio	2.000000e-06
GCST002858_2	Cytokine and corticosteroid-stimulated IL-6 production	9.000000e-10
GCST002859_2	Cytokine-stimulated IL-6 production	3.000000e-08
GCST006617_2	Uterine fibroid size (maximum volume)	9.000000e-08
GCST007471_9	Short-term memory (digit-span task)	6.000000e-06
GCST008310_3	Cardiac Troponin-T levels	2.000000e-09
GCST008839_8	Height	1.000000e-08
GCST010866_104	Coronary artery disease	3.000000e-08
GCST011741_31	LDL cholesterol levels in HIV infection	5.000000e-06
GCST012317_14	Triglyceride levels x SSRI levels (escitalopram or citalopram) interaction in schizophrenia or bipolar disorder	8.000000e-06

EFO canonical traits (7, from GWAS)

EFO ID	Trait name
EFO:0004767	visceral:subcutaneous adipose tissue ratio
EFO:0004810	interleukin-6 measurement
EFO:0009410	uterine fibroid measurement
EFO:0004335	short-term memory
EFO:0005043	cardiac troponin T measurement
EFO:0004611	low density lipoprotein cholesterol measurement
EFO:0004530	triglyceride measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D006330	Heart Defects, Congenital	C14.240.400; C14.280.400; C16.131.240.400

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases expression, increases mutagenesis	8
Valproic Acid	increases expression, increases methylation, affects expression, decreases expression, decreases methylation	6
Aflatoxin B1	affects expression, decreases expression, decreases methylation, increases methylation	6
bisphenol A	affects expression, decreases methylation, increases expression	4
Acetaminophen	decreases expression	3
Ethinyl Estradiol	affects expression, decreases expression	3
Tobacco Smoke Pollution	decreases expression	3
methylmercuric chloride	increases expression	2
trichostatin A	decreases expression, increases expression	2
sodium arsenite	decreases expression, increases methylation	2
(+)-JQ1 compound	decreases expression	2
Air Pollutants	affects cotreatment, increases abundance, increases expression, decreases expression	2
Cadmium	decreases expression, increases abundance, increases expression, decreases reaction	2
Estradiol	decreases expression, affects cotreatment, increases expression	2
Nickel	decreases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Progesterone	affects cotreatment, increases expression, decreases expression	2
Tretinoin	decreases expression	2
Cyclosporine	decreases expression	2
Cadmium Chloride	decreases expression, increases abundance	2
FR900359	affects phosphorylation	1
alpha-pinene	affects cotreatment, increases expression, increases abundance	1
hydroxyhydroquinone	decreases expression	1
sulforaphane	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
cobaltous chloride	decreases expression	1
benzo(e)pyrene	increases methylation	1
periodate-oxidized adenosine	affects expression	1
cupric chloride	decreases expression	1
coumarin	affects phosphorylation	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00668824	PHASE4	UNKNOWN	Improved Diagnosis of Congenital Heart Disease by Magnetic Resonance Imaging Using Vasovist
NCT01368705	PHASE4	COMPLETED	Nitrogen Balance in Infants After Post Cardiothoracic Surgery
NCT01619982	PHASE4	COMPLETED	Pre-operative Prophylaxis With Vancomycin and Cefazolin in Pediatric Cardiovascular Surgery Patients
NCT02122679	PHASE4	WITHDRAWN	Tranexamic Acid Effect on Platelet Aggregation Following Infant Cardiopulmonary Bypass
NCT02527811	PHASE4	UNKNOWN	Ulinastatin Injection in in Pediatric Patients Undergoing Open Heart Surgery
NCT03014700	PHASE4	COMPLETED	Fibrinogen Concentrate vs Cryoprecipitate
NCT03408340	PHASE4	TERMINATED	Paravertebral Nerve Blocks in Neonates
NCT03630796	PHASE4	UNKNOWN	Effect of Sevoflurane in Postoperative Troponin I Levels in Children Undergoing Congenital Heart Defects Surgery
NCT03667703	PHASE4	COMPLETED	Stress Ulcer Prophylaxis Versus Placebo in Critically Ill Infants With Congenital Heart Disease
NCT04453761	PHASE4	UNKNOWN	Thiamine Influenced on Substrate Energy Effectiveness in Indonesian Children Undergoing Cardiopulmonary Bypass
NCT06668389	PHASE4	RECRUITING	Sodium-Glucose Cotransporter 2 Inhibitors for Repaired Tetralogy of Fallot Patients for Enhancement of Cardio-Pulmonary Status Trial
NCT07499154	PHASE4	NOT_YET_RECRUITING	Perioperative Lidocaine for Lung Protection in Infants Undergoing Cardiac Surgery
NCT00000470	PHASE3	COMPLETED	Infant Heart Surgery: Central Nervous System Sequelae of Circulatory Arrest
NCT00000494	PHASE3	COMPLETED	Management of Patent Ductus in Premature Infants
NCT01134302	PHASE3	UNKNOWN	Hybrid Versus Norwood Management Strategies in Infants Undergoing Single Ventricle Palliation
NCT01607983	PHASE3	WITHDRAWN	Effects of Pulmonary Vasodilation Upon VA Coupling in Fontan Patients
NCT01662011	PHASE3	UNKNOWN	Application of Neurally Adjusted Ventilatory Assist to Children After Congenital Cardiac Surgery
NCT02320669	PHASE3	COMPLETED	Phase 3 Triiodothyronine Supplementation for Infants After Cardiopulmonary Bypass
NCT02615262	PHASE3	COMPLETED	Intraoperative Dexamethasone in Pediatric Cardiac Surgery
NCT03153137	PHASE3	COMPLETED	Clinical Study Assessing the Efficacy and Safety of Macitentan in Fontan-palliated Subjects
NCT03154476	PHASE3	COMPLETED	Role of Sildenafil for Fontan Associated Liver Disease (SiFALD) Study
NCT04536194	PHASE3	COMPLETED	Dopamine Versus Norepinephrine Under General Anesthesia
NCT04702373	PHASE3	ACTIVE_NOT_RECRUITING	Training in Exercise Activities and Motion for Growth (TEAM 4 Growth) RCT
NCT05049590	PHASE3	COMPLETED	Acute Normovolemic Hemodilution in Complex Cardiac Surgery
NCT06406517	PHASE3	UNKNOWN	Comparative Effectiveness of Gadopiclenol for Evaluation of Adult Congenital Heart Anatomy and Hemodynamics
NCT06693674	PHASE3	RECRUITING	Effect of Sacubitril-Valsartan on Cardiac Structure and Function
NCT06955260	PHASE3	NOT_YET_RECRUITING	SGLT2 Inhibition With Empagliflozin in Fontan Circulatory Failure
NCT00115375	PHASE2	COMPLETED	Platelet Aggregation Inhibition in Children on Clopidogrel (PICOLO)
NCT00350220	PHASE2	COMPLETED	Transfusion Strategies in Pediatric Cardiothoracic Surgery
NCT00374088	PHASE2	COMPLETED	N-Acetylcysteine in Neonatal Congenital Heart Surgery (INACT Study)
NCT00538785	PHASE2	COMPLETED	A Study to Evaluate MEDI-524 In Children With Hemodynamically Significant Congenital Heart Disease
NCT00770705	PHASE2	WITHDRAWN	Parenteral Phenoxybenzamine During Congenital Heart Disease Surgery
NCT00919945	PHASE2	TERMINATED	Impact of Early Enteral Feeding on Splanchnic Blood Flow After Surgery for Critical Heart Disease in the Newborn
NCT01063712	PHASE2	COMPLETED	Safety and Effectiveness of the Device Nit-Occlud® PDA-R
NCT01069510	PHASE2	COMPLETED	Spironolactone in Adult Congenital Heart Disease
NCT01189981	PHASE2	COMPLETED	Effect of eHealth Encouragements to Intensive Exercise in Adolescents With Congenital Heart Disease
NCT01330433	PHASE2	COMPLETED	Effects of CoSeal on Bleeding & Adhesions in Pediatric Heart Surgery
NCT01662037	PHASE2	COMPLETED	Bosentan Therapy in Children With Functional Single Ventricle
NCT01668264	PHASE2	UNKNOWN	Imaging Assessment of Diastolic Function
NCT01827059	PHASE2	UNKNOWN	Bosentan In Exercise Induced Pulmonary Arterial Hypertension in CongenitaL Heart diseasE