SUN2

Summary

SUN2 (Sad1 and UNC84 domain containing 2, HGNC:14210) is a protein-coding gene on chromosome 22q13.1, encoding SUN domain-containing protein 2 (Q9UH99). As a component of the LINC (LInker of Nucleoskeleton and Cytoskeleton) complex, involved in the connection between the nuclear lamina and the cytoskeleton.

SUN1 (MIM 607723) and SUN2 are inner nuclear membrane (INM) proteins that play a major role in nuclear-cytoplasmic connection by formation of a ‘bridge’ across the nuclear envelope, known as the LINC complex, via interaction with the conserved luminal KASH domain of nesprins (e.g., SYNE1; MIM 608441) located in the outer nuclear membrane (ONM). The LINC complex provides a direct connection between the nuclear lamina and the cytoskeleton, which contributes to nuclear positioning and cellular rigidity (summary by Haque et al., 2010 [PubMed 19933576]).

Source: NCBI Gene 25777 — RefSeq curated summary.

At a glance

• GWAS associations: 5
• Clinical variants (ClinVar): 252 total
• Druggable target: yes
• MANE Select transcript: NM_015374

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:14210
Approved symbol	SUN2
Name	Sad1 and UNC84 domain containing 2
Location	22q13.1
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000100242
Ensembl biotype	protein_coding
OMIM	613569
Entrez	25777

Gene structure

Transcript identifiers

Ensembl transcripts: 73 — 66 protein_coding, 6 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000405018, ENST00000405510, ENST00000406622, ENST00000417332, ENST00000430185, ENST00000433561, ENST00000438058, ENST00000439339, ENST00000452294, ENST00000455125, ENST00000456894, ENST00000464202, ENST00000469086, ENST00000470642, ENST00000477262, ENST00000480307, ENST00000494273, ENST00000689035, ENST00000690927, ENST00000870831, ENST00000870832, ENST00000870833, ENST00000870834, ENST00000870835, ENST00000870836, ENST00000870837, ENST00000870838, ENST00000870839, ENST00000870840, ENST00000870841, ENST00000870842, ENST00000870843, ENST00000870844, ENST00000870845, ENST00000870846, ENST00000870847, ENST00000870848, ENST00000870849, ENST00000870850, ENST00000870851, ENST00000870852, ENST00000870853, ENST00000870854, ENST00000870855, ENST00000870856, ENST00000870857, ENST00000919862, ENST00000956729, ENST00000956730, ENST00000956731, ENST00000956732, ENST00000956733, ENST00000956734, ENST00000956735, ENST00000956736, ENST00000956737, ENST00000956738, ENST00000956739, ENST00000956740, ENST00000956741, ENST00000956742, ENST00000956743, ENST00000956744, ENST00000956745, ENST00000956746, ENST00000956747, ENST00000956748, ENST00000956749, ENST00000956750, ENST00000956751, ENST00000956752, ENST00000956753, ENST00000956754

RefSeq mRNA: 22 — MANE Select: NM_015374 NM_001199579, NM_001199580, NM_001394427, NM_001394428, NM_001394429, NM_001394430, NM_001394431, NM_001394432, NM_001394433, NM_001394434, NM_001394435, NM_001394436, NM_001394437, NM_001394438, NM_001394439, NM_001394440, NM_001394441, NM_001394442, NM_001394443, NM_001394444, NM_001394445, NM_015374

CCDS: CCDS13978, CCDS56231, CCDS93165, CCDS93166

Canonical transcript exons

ENST00000689035 — 18 exons

Exon	Start	End
ENSE00001650030	38738873	38738988
ENSE00001707177	38738173	38738265
ENSE00001725835	38742301	38742555
ENSE00001742710	38751210	38751373
ENSE00002162891	38745684	38745811
ENSE00003471065	38738587	38738754
ENSE00003506418	38750898	38751035
ENSE00003544364	38739342	38739426
ENSE00003548379	38749766	38749859
ENSE00003553989	38741494	38741571
ENSE00003595913	38741007	38741050
ENSE00003646288	38739722	38739943
ENSE00003655277	38752507	38752665
ENSE00003662601	38740267	38740432
ENSE00003788680	38748713	38748783
ENSE00003790760	38750225	38750320
ENSE00003926847	38734734	38736380
ENSE00003932510	38755763	38755998

Expression profiles

Bgee: expression breadth ubiquitous, 288 present calls, max score 99.37.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 80.3722 / max 2751.8398, expressed in 1822 samples.

FANTOM5 promoters (11 alternative TSS)

Promoter ID	TPM avg	Samples expressed
194228	43.5878	1816
194227	35.0353	1804
194231	16.2463	1804
194224	0.8625	267
194225	0.2118	78
194226	0.1923	56
194218	0.1333	50
194222	0.1331	60
194223	0.1308	59
194217	0.0519	15

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	99.37	gold quality
mucosa of stomach	UBERON:0001199	99.21	gold quality
right coronary artery	UBERON:0001625	99.01	gold quality
thoracic aorta	UBERON:0001515	98.95	gold quality
popliteal artery	UBERON:0002250	98.94	gold quality
descending thoracic aorta	UBERON:0002345	98.94	gold quality
ascending aorta	UBERON:0001496	98.93	gold quality
tibial artery	UBERON:0007610	98.93	gold quality
aorta	UBERON:0000947	98.92	gold quality
right lung	UBERON:0002167	98.71	gold quality
left coronary artery	UBERON:0001626	98.67	gold quality
sural nerve	UBERON:0015488	98.54	gold quality
coronary artery	UBERON:0001621	98.50	gold quality
left uterine tube	UBERON:0001303	98.46	gold quality
tibial nerve	UBERON:0001323	98.40	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	98.38	gold quality
lower esophagus muscularis layer	UBERON:0035833	98.33	gold quality
lower esophagus	UBERON:0013473	98.32	gold quality
body of uterus	UBERON:0009853	98.11	gold quality
right ovary	UBERON:0002118	98.10	gold quality
medial globus pallidus	UBERON:0002477	98.07	gold quality
left ovary	UBERON:0002119	98.04	gold quality
ectocervix	UBERON:0012249	98.04	gold quality
upper lobe of left lung	UBERON:0008952	98.00	gold quality
globus pallidus	UBERON:0001875	97.97	gold quality
muscle layer of sigmoid colon	UBERON:0035805	97.93	gold quality
endocervix	UBERON:0000458	97.86	gold quality
leukocyte	CL:0000738	97.83	gold quality
small intestine Peyer’s patch	UBERON:0003454	97.83	gold quality
blood	UBERON:0000178	97.82	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-GEOD-149689	yes	658.10
E-CURD-122	yes	41.01
E-MTAB-6701	yes	29.63
E-ANND-3	yes	14.08
E-GEOD-124858	no	30.08

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

87 targeting SUN2, 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-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-103A-3P	99.98	69.14	1595
HSA-MIR-107	99.98	69.14	1595
HSA-MIR-507	99.97	70.11	1915
HSA-MIR-557	99.96	70.01	1640
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-450B-5P	99.92	71.48	3175
HSA-MIR-454-3P	99.91	74.01	1925
HSA-MIR-130A-3P	99.90	73.31	1861
HSA-MIR-130B-3P	99.90	73.27	1850
HSA-MIR-301A-3P	99.90	73.15	1839
HSA-MIR-301B-3P	99.90	73.19	1836
HSA-MIR-3666	99.90	73.24	1833
HSA-MIR-4295	99.90	73.11	1838
HSA-MIR-129-5P	99.88	70.26	3273
HSA-MIR-4271	99.88	68.32	2244
HSA-MIR-30A-3P	99.87	69.74	2928
HSA-MIR-30D-3P	99.87	69.92	2917
HSA-MIR-30E-3P	99.87	69.68	2942
HSA-MIR-221-3P	99.86	71.56	1329
HSA-MIR-222-3P	99.86	71.35	1337
HSA-MIR-3151-5P	99.86	63.83	1069
HSA-MIR-3941	99.86	70.54	2735
HSA-MIR-5582-3P	99.86	72.48	4221
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-448	99.79	72.37	2103

Literature-anchored findings (GeneRIF, showing 26)

• SUN1 and SUN2 may form a physical interaction between the nuclear envelope and the centrosome (PMID:17132086)
• perturbations in lamin A-SUN1 and SUN2 protein interactions may underlie the opposing effects of EDMD and HGPS mutations on nuclear and cellular mechanics (PMID:19933576)
• Nesprins, but not sun proteins, switch isoforms at the nuclear envelope during muscle development (PMID:20108321)
• Data suggest that SUN2 represents the first mammalian inner nuclear membrane (INM) protein relying on a functional nuclear localization signal, a Golgi retrieval signal and a perinuclear domain to mediate targeting to the INM. (PMID:20551905)
• Data found that expression of lamin A but not lamin C partly restored the nuclear envelope localization of SUN2. (PMID:21655223)
• the crystal structure of the SUN2 protein SUN domain (PMID:22170055)
• Study presents crystal structures of the human SUN2-KASH1/2 complex, i.e. SUN2 complexed with the C-terminal 29 residues of human Nesprin-1 or -2 (the core of the LINC complex). (PMID:22632968)
• Codepletion of SUN1/2 slows cell proliferation and results in an accumulation of morphologically defective and disoriented mitotic spindles. (PMID:24662567)
• SUN2 as a tumor suppressor mediates miR-221 and miR-222 functions in central nervous system embryonal tumors. (PMID:24832085)
• An important role for SUN1 and SUN2 in muscle disease pathogenesis. (PMID:25210889)
• Nuclear envelope associated endosome-mediated transfer depends on the nuclear envelope proteins SUN1 and SUN2, as well as the Sec61 translocon complex. (PMID:26356418)
• SUN2 exerts tumor suppressor functions by suppressing the Warburg effect in lung cancer (PMID:26658802)
• SUN2 overexpression perturbs both nuclear shape and early events of HIV infection (PMID:26865710)
• These results demonstrate that SUN2 is required for the optimal activation and proliferation of primary CD4 T cells and suggest that the disruption of these processes explains the contribution of endogenous SUN2 to HIV infection in primary lymphocytes and show that CypA is not required for the decreased infection observed in SUN2-silenced cells. (PMID:28077629)
• SUN1/SUN2 may function redundantly in early HIV-1 infection steps and therefore influence HIV-1 replication and pathogenesis. (PMID:28747499)
• Thus, AID is a conserved functional domain in SUN proteins and this work provides the structural evidence to support the conversation of the AID-mediated autoinhibition of SUN proteins. (PMID:29408528)
• SUN2 is a novel chromatin reassembly factor that helps to maintain chromatin in a repressive state and consequently inhibits HIV-1 transcription. (PMID:29717016)
• While Sun1 and Sun2 in HeLa cells are each able to bind KASH-domains, Sun1 is more efficiently incorporated into LINC complexes under normal growth conditions. Furthermore, the balance of Sun1 and Sun2 incorporated into LINC complexes is cell type-specific and is correlated with SRF/Mkl1-dependent gene expression. (PMID:29813079)
• a fragment of SUN2 containing CC1, CC2, and the SUN domain model is reported. (PMID:29995584)
• SUN1/2 Are Essential for RhoA/ROCK-Regulated Actomyosin Activity in Isolated Vascular Smooth Muscle Cells. (PMID:31935926)
• Structural Analysis of Different LINC Complexes Reveals Distinct Binding Modes. (PMID:33058875)
• Splicing factors control triple-negative breast cancer cell mitosis through SUN2 interaction and sororin intron retention. (PMID:33648524)
• The SUN2-nesprin-2 LINC complex and KIF20A function in the Golgi dispersal. (PMID:33686165)
• Downregulation of SUN2 promotes metastasis of colon cancer by activating BDNF/TrkB signalling by interacting with SIRT1. (PMID:33931868)
• SUN2 Modulates the Propagation of HSV-1. (PMID:35435724)
• FBXO2 targets glycosylated SUN2 for ubiquitination and degradation to promote ovarian cancer development. (PMID:35525855)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	sun2	ENSDARG00000086490
mus_musculus	Sun2	ENSMUSG00000042524
rattus_norvegicus	Sun2	ENSRNOG00000015177

Paralogs (4): SPAG4 (ENSG00000061656), SUN3 (ENSG00000164744), SUN1 (ENSG00000164828), SUN5 (ENSG00000167098)

Protein

Protein identifiers

SUN domain-containing protein 2 — Q9UH99 (reviewed: Q9UH99)

Alternative names: Protein unc-84 homolog B, Rab5-interacting protein, Sad1/unc-84 protein-like 2

All UniProt accessions (9): Q9UH99, A0A8I5QKM0, B0QY60, B0QY63, B0QY64, B0QY66, B0QY67, B0QY68, B0QY69

UniProt curated annotations — full annotation on UniProt →

Function. As a component of the LINC (LInker of Nucleoskeleton and Cytoskeleton) complex, involved in the connection between the nuclear lamina and the cytoskeleton. The nucleocytoplasmic interactions established by the LINC complex play an important role in the transmission of mechanical forces across the nuclear envelope and in nuclear movement and positioning. Specifically, SYNE2 and SUN2 assemble in arrays of transmembrane actin-associated nuclear (TAN) lines which are bound to F-actin cables and couple the nucleus to retrograde actin flow during actin-dependent nuclear movement. Required for interkinetic nuclear migration (INM) and essential for nucleokinesis and centrosome-nucleus coupling during radial neuronal migration in the cerebral cortex and during glial migration. Required for nuclear migration in retinal photoreceptor progenitors implicating association with cytoplasmic dynein-dynactin and kinesin motor complexes, and probably B-type lamins; SUN1 and SUN2 seem to act redundantly. The SUN1/2:KASH5 LINC complex couples telomeres to microtubules during meiosis; SUN1 and SUN2 seem to act at least partial redundantly. Anchors chromosome movement in the prophase of meiosis and is involved in selective gene expression of coding and non-coding RNAs needed for gametogenesis. Required for telomere attachment to nuclear envelope and gametogenesis. May also function on endocytic vesicles as a receptor for RAB5-GDP and participate in the activation of RAB5.

Subunit / interactions. Core component of the LINC complex which is composed of inner nuclear membrane SUN domain-containing proteins coupled to outer nuclear membrane KASH domain-containing nesprins. SUN and KASH domain-containing proteins seem to bind each other promiscuously; however, differentially expression of LINC complex constituents is giving rise to specific assemblies. At least SUN1/2-containing core LINC complexes are proposed to be hexameric composed of three protomers of each KASH and SUN domain-containing protein. Interacts with SYNE2; the SUN2:SYNE2/KASH2 LINC complex is a heterohexamer; the homotrimeric cloverleave-like conformation of the SUN domain is a prerequisite for LINC complex formation in which three separate SYNE2/KASH2 peptides bind at the interface of adjacent SUN domains. Component of a probable SUN2:KASH5 LINC complex. Interacts with SYNE1 and SYNE3; probably forming respective LINC complexes. Interacts with A-type lamin. Interaction with lamins B1 and C is hardly detectable. Interacts with EMD and RAB5A. Interacts with TMEM43. Interacts with TMEM201.

Subcellular location. Nucleus inner membrane. Nucleus envelope. Endosome membrane.

Tissue specificity. Widely expressed. Highly expressed in heart, lung and muscle. Weakly expressed in fetal heart. Slightly overexpressed in some heart tissues form patients with congenital heart defects.

Post-translational modifications. The disulfide bond with SYNE2 is required for stability of the SUN2:SYNE2/KASH2 LINC complex under tensile forces though not required for the interaction. The disulfide bond is proposed to be conserved in LINC complexes involved in force transmission.

Domain organisation. The coiled coil domains differentially mediate trimerization required for binding to nesprins and are proposed to dynamically regulate the oligomeric state by locking the SUN domain in an inactive confirmation. The coiled coil domains are proposed to be involved in load-bearing and force transmission from the cytoskeleton. The SUN domain may play a role in nuclear anchoring and/or migration.

Isoforms (3)

UniProt ID	Names	Canonical?
Q9UH99-1	1	yes
Q9UH99-2	2
Q9UH99-3	3

RefSeq proteins (22): NP_001186508, NP_001186509, NP_001381356, NP_001381357, NP_001381358, NP_001381359, NP_001381360, NP_001381361, NP_001381362, NP_001381363, NP_001381364, NP_001381365, NP_001381366, NP_001381367, NP_001381368, NP_001381369, NP_001381370, NP_001381371, NP_001381372, NP_001381373, NP_001381374, NP_056189* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR012919	SUN_dom	Domain
IPR040994	Sun_CC2	Domain
IPR045119	SUN1-5	Family

Pfam: PF07738, PF18580

UniProt features (59 total): strand 12, mutagenesis site 10, modified residue 8, helix 6, sequence variant 4, coiled-coil region 3, region of interest 3, topological domain 2, disulfide bond 2, splice variant 2, chain 1, compositionally biased region 1, transmembrane region 1, glycosylation site 1, sequence conflict 1, domain 1, turn 1

Structure

Experimental structures (PDB)

9 structures.

PDB	Method	Resolution (Å)
6WMD	X-RAY DIFFRACTION	1.5
6WME	X-RAY DIFFRACTION	1.53
6WMG	X-RAY DIFFRACTION	1.9
4DXT	X-RAY DIFFRACTION	2.22
4DXR	X-RAY DIFFRACTION	2.32
3UNP	X-RAY DIFFRACTION	2.39
6WMF	X-RAY DIFFRACTION	2.6
4DXS	X-RAY DIFFRACTION	2.71
4FI9	X-RAY DIFFRACTION	3.05

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UH99-F1	68.48	0.27

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 (8): 12, 38, 54, 107, 110, 113, 116, 136

Disulfide bonds (2): 563, 601–705

Glycosylation sites (1): 636

Mutagenesis-validated functional residues (10):

Position	Phenotype
536	disrupts interaction with syne2.
538	disrupts interaction with syne2.
542	disrupts interaction with syne2.
563	decreases stability of the sun2:syne2/kash2 complex under tensile forces and inhibits force transmission through the com
603	decreases interaction with syne2. disrupts interaction with syne2; when associated with e-641 and e-703.
609	decreases interaction with syne2.
628	disrupts interaction with syne2.
641	decreases interaction with syne2. disrupts interaction with syne2; when associated with e-603 and e-703.
703	decreases interaction with syne2. disrupts interaction with syne2; when associated with e-603 and e-641.
707	disrupts interaction with syne2, impairs localization to the nuclear envelope.

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-1221632	Meiotic synapsis
R-HSA-9918487	Dengue Virus Genome Translation and Replication
R-HSA-1474165	Reproduction
R-HSA-1500620	Meiosis
R-HSA-1640170	Cell Cycle

MSigDB gene sets: 344 (showing top): RNGTGGGC_UNKNOWN, REACTOME_MEIOTIC_SYNAPSIS, BASSO_B_LYMPHOCYTE_NETWORK, GOBP_NEUROGENESIS, GOBP_ORGANELLE_TRANSPORT_ALONG_MICROTUBULE, CTATGCA_MIR153, GNF2_ZAP70, GOBP_FOREBRAIN_DEVELOPMENT, SRF_Q5_01, GOBP_FOREBRAIN_CELL_MIGRATION, NFKB_C, SRF_C, GOBP_TELENCEPHALON_GLIAL_CELL_MIGRATION, GOBP_MAINTENANCE_OF_LOCATION, GOBP_CEREBRAL_CORTEX_DEVELOPMENT

GO Biological Process (8): mitotic spindle organization (GO:0007052), nuclear migration (GO:0007097), nucleokinesis involved in cell motility in cerebral cortex radial glia guided migration (GO:0021817), positive regulation of cell migration (GO:0030335), nuclear migration along microfilament (GO:0031022), meiotic cell cycle (GO:0051321), centrosome localization (GO:0051642), nuclear matrix anchoring at nuclear membrane (GO:0090292)

GO Molecular Function (6): lamin binding (GO:0005521), microtubule binding (GO:0008017), identical protein binding (GO:0042802), protein-membrane adaptor activity (GO:0043495), cytoskeleton-nuclear membrane anchor activity (GO:0140444), protein binding (GO:0005515)

GO Cellular Component (10): chromosome, telomeric region (GO:0000781), condensed nuclear chromosome (GO:0000794), nuclear envelope (GO:0005635), nuclear inner membrane (GO:0005637), endosome membrane (GO:0010008), nuclear membrane (GO:0031965), meiotic nuclear membrane microtubule tethering complex (GO:0034993), nucleus (GO:0005634), endosome (GO:0005768), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Meiosis	1
Dengue Virus Infection	1
Reproduction	1
Cell Cycle	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
nucleus	3
protein binding	2
endomembrane system	2
mitotic cell cycle	1
spindle organization	1
microtubule cytoskeleton organization involved in mitosis	1
intracellular transport	1
nucleus localization	1
establishment of organelle localization	1
modulation of microtubule cytoskeleton involved in cerebral cortex radial glia guided migration	1
nuclear migration along microtubule	1
cell migration	1
regulation of cell migration	1
positive regulation of cell motility	1
nuclear migration	1
actin filament-based movement	1
actin filament-based transport	1
cell cycle	1
sexual reproduction	1
reproductive process	1
meiotic nuclear division	1
microtubule organizing center localization	1
nuclear matrix organization	1
maintenance of protein location in nucleus	1
tubulin binding	1
protein-macromolecule adaptor activity	1
protein-membrane adaptor activity	1
binding	1
chromosomal region	1
nuclear chromosome	1
condensed chromosome	1
organelle envelope	1
organelle inner membrane	1
nuclear membrane	1
endosome	1
cytoplasmic vesicle membrane	1
bounding membrane of organelle	1
nuclear envelope	1
organelle membrane	1
microtubule organizing center attachment site	1

Protein interactions and networks

STRING

1592 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SUN2	SYNE2	Q8WXH0	999
SUN2	SYNE1	Q8NF91	999
SUN2	EMD	P50402	990
SUN2	LMNA	P02545	982
SUN2	SUN1	O94901	966
SUN2	KASH5	Q8N6L0	963
SUN2	SYNE3	Q6ZMZ3	873
SUN2	SYNE4	Q8N205	846
SUN2	TMEM43	Q9BTV4	828
SUN2	TMEM201	Q5SNT2	808
SUN2	LMNB1	P20700	751
SUN2	TERB2	Q8NHR7	745
SUN2	TERB1	Q8NA31	740
SUN2	ZMPSTE24	O75844	734
SUN2	LBR	Q14739	731

IntAct

219 interactions, top by confidence:

A	B	Type	Score
PRKAA1	PRKAB2	psi-mi:“MI:0914”(association)	0.950
SYNE2	SUN2	psi-mi:“MI:0403”(colocalization)	0.890
SUN2	SYNE2	psi-mi:“MI:0407”(direct interaction)	0.890
SYNE2	SUN2	psi-mi:“MI:0407”(direct interaction)	0.890
SUN2	RAB5A	psi-mi:“MI:0915”(physical association)	0.840
SUN2	SYNE1	psi-mi:“MI:0407”(direct interaction)	0.810
SUN2	SYNE1	psi-mi:“MI:0915”(physical association)	0.810
SYNE1	SUN2	psi-mi:“MI:0407”(direct interaction)	0.810
	HMOX1	psi-mi:“MI:0914”(association)	0.740
SUN2	LMNA	psi-mi:“MI:0914”(association)	0.720
SUN2	LMNA	psi-mi:“MI:0915”(physical association)	0.720
SUN2	SYNE4	psi-mi:“MI:0407”(direct interaction)	0.710
ANKRD44	ANKRD28	psi-mi:“MI:0914”(association)	0.710
SYNE1	SUN1	psi-mi:“MI:0914”(association)	0.710
SUN2	KASH5	psi-mi:“MI:0407”(direct interaction)	0.680
SUN2	SUN2	psi-mi:“MI:0407”(direct interaction)	0.680
SUN2		psi-mi:“MI:0915”(physical association)	0.660
NOP53	RRP8	psi-mi:“MI:0914”(association)	0.640
SUN2	NRM	psi-mi:“MI:0915”(physical association)	0.560
NRM	SUN2	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (312): SUN2 (Affinity Capture-MS), SUN2 (Affinity Capture-MS), SUN2 (Two-hybrid), SUN2 (Affinity Capture-MS), SUN2 (Affinity Capture-MS), SUN2 (Affinity Capture-MS), SUN2 (Affinity Capture-MS), SUN2 (Affinity Capture-MS), SUN2 (Affinity Capture-MS), SUN2 (Affinity Capture-MS), SUN2 (Affinity Capture-Western), SUN2 (Affinity Capture-MS), SUN2 (Affinity Capture-MS), SUN2 (Affinity Capture-RNA), SUN2 (Affinity Capture-MS)

ESM2 similar proteins: A2AV25, A5PJQ2, A5PMY6, A6H6E2, B7ZNG0, O00548, O35764, O43278, O70340, O95502, P21757, P21758, P30204, P47970, P47971, P47972, P48759, P58660, P59900, P97738, Q05585, Q15818, Q24K15, Q2M1P5, Q5RFW0, Q61483, Q62443, Q6AZY7, Q6MG84, Q6ZMJ2, Q86VZ4, Q8BJS4, Q8C850, Q8CB67, Q8K299, Q8N539, Q8NI99, Q8R0Z6, Q95LU3, Q96NZ8

Diamond homologs: A0A0B4KEE4, O55034, O94901, Q09825, Q0II64, Q20745, Q5SS91, Q8BJS4, Q8TAQ9, Q8TC36, Q95LV7, Q9D666, Q9DA32, Q9JJF2, Q9NPE6, Q9UH99, Q9SG79, Q558Z2, Q9FF75

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
SUN2	“up-regulates activity”	RAB5A	binding
LMNA	“up-regulates activity”	SUN2	relocalization
SUN2	“form complex”	“LINC complex”	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	124
Likely benign	97
Benign	21

Top pathogenic / likely-pathogenic (0)

SpliceAI

3908 predictions. Top by Δscore:

Variant	Effect	Δscore
22:38736379:GCCT:G	acceptor_loss	1.0000
22:38736381:C:CA	acceptor_loss	1.0000
22:38738168:CGTAC:C	donor_loss	1.0000
22:38738169:GTACC:G	donor_loss	1.0000
22:38738170:TA:T	donor_loss	1.0000
22:38738171:ACCTG:A	donor_loss	1.0000
22:38738261:AACCC:A	acceptor_gain	1.0000
22:38738262:ACCC:A	acceptor_gain	1.0000
22:38738263:CCC:C	acceptor_gain	1.0000
22:38738263:CCCC:C	acceptor_gain	1.0000
22:38738264:CC:C	acceptor_gain	1.0000
22:38738264:CCC:C	acceptor_gain	1.0000
22:38738265:CC:C	acceptor_gain	1.0000
22:38738265:CCTG:C	acceptor_loss	1.0000
22:38738266:C:CC	acceptor_gain	1.0000
22:38738266:C:T	acceptor_gain	1.0000
22:38738266:CT:C	acceptor_loss	1.0000
22:38738269:C:CT	acceptor_gain	1.0000
22:38738270:A:T	acceptor_gain	1.0000
22:38738581:A:AC	donor_gain	1.0000
22:38738581:ACTC:A	donor_loss	1.0000
22:38738582:C:CC	donor_gain	1.0000
22:38738583:TCAC:T	donor_loss	1.0000
22:38738584:CA:C	donor_loss	1.0000
22:38738585:A:AC	donor_gain	1.0000
22:38738586:C:CC	donor_gain	1.0000
22:38738586:CA:C	donor_gain	1.0000
22:38738586:CAA:C	donor_gain	1.0000
22:38738586:CAAA:C	donor_gain	1.0000
22:38738586:CAAAG:C	donor_gain	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000161603 (22:38757746 A>T), RS1000331374 (22:38747503 G>A), RS1000371829 (22:38741312 G>C), RS1000536773 (22:38736723 C>T), RS1000600280 (22:38735562 G>A), RS1000719607 (22:38748481 G>A,T), RS1000888793 (22:38749843 A>T), RS1001116369 (22:38747847 G>A), RS1001168757 (22:38747647 T>C), RS1001229338 (22:38757107 C>T), RS1001265006 (22:38757299 C>T), RS1001492614 (22:38737005 G>A), RS1001517552 (22:38746931 G>A), RS1001825457 (22:38742225 C>G,T), RS1001890220 (22:38752905 G>A)

Disease associations

OMIM: gene MIM:613569 | disease phenotypes: MIM:310300

GenCC curated gene-disease

Mondo (1): Emery-Dreifuss muscular dystrophy (MONDO:0016830)

Orphanet (1): Emery-Dreifuss muscular dystrophy (Orphanet:261)

HPO phenotypes

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

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST003818_40	Resting heart rate	5.000000e-16
GCST006288_416	Heel bone mineral density	6.000000e-06
GCST006288_696	Heel bone mineral density	3.000000e-09
GCST007561_72	Sleep duration	4.000000e-08
GCST008860_14	Prostate cancer	1.000000e-15

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0009270	heel bone mineral density

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D020389	Muscular Dystrophy, Emery-Dreifuss	C05.651.534.500.350; C10.668.491.175.500.350; C16.320.322.625; C16.320.577.350

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6067177 (SINGLE PROTEIN)

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

ChEMBL bioactivities

2 potent at pChembl≥5 of 4 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.95	Kd	111.4	nM	CHEMBL5653589
6.95	ED50	111.4	nM	CHEMBL5653589

PubChem BioAssay actives

1 with measured affinity, of 4 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149528: Binding affinity to human SUN2 incubated for 45 mins by Kinobead based pull down assay	kd	0.1114	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression, decreases methylation, increases expression, affects cotreatment	4
sodium arsenite	decreases expression, increases expression	4
Particulate Matter	affects cotreatment, increases expression, decreases expression, increases abundance	4
perfluoro-n-nonanoic acid	decreases expression	2
Valproic Acid	affects expression, decreases expression, increases methylation	2
aristolochic acid I	decreases expression	1
FR900359	affects phosphorylation	1
tremortin	decreases expression	1
bufotalin	increases expression	1
deoxynivalenol	decreases expression	1
lead acetate	increases expression	1
butyraldehyde	decreases expression	1
perfluorooctanoic acid	decreases expression	1
coumarin	increases phosphorylation	1
nivalenol	decreases expression	1
ciglitazone	affects binding, increases expression	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	decreases expression	1
bisphenol B	increases expression	1
bisphenol S	affects cotreatment, decreases expression	1
bisphenol AF	increases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	increases expression	1
Temozolomide	decreases expression	1
Decitabine	decreases expression, affects reaction	1
Air Pollutants	decreases expression, increases abundance	1
Aspirin	increases expression	1
Vehicle Emissions	decreases expression, increases abundance	1
Benzo(a)pyrene	decreases expression	1
Caffeine	increases phosphorylation	1
Cisplatin	decreases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5652570	Binding	Binding affinity to human SUN2 incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_C7YP	HAP1 SUN1 (-) SUN2 (-)	Cancer cell line	Male
CVCL_E2L9	HAP1 SUN2 (-) 2	Cancer cell line	Male
CVCL_XU03	HAP1 SUN2 (-) 1	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01403402	Not specified	RECRUITING	Congenital Muscle Disease Study of Patient and Family Reported Medical Information