ITSN2

Summary

ITSN2 (intersectin 2, HGNC:6184) is a protein-coding gene on chromosome 2p23.3, encoding Intersectin-2 (Q9NZM3). Adapter protein that may provide indirect link between the endocytic membrane traffic and the actin assembly machinery.

This gene encodes a cytoplasmic protein which contains SH3 domains. This protein is a member of a family of proteins involved in clathrin-mediated endocytosis. Intersectin 2 is thought to regulate the formation of clathrin-coated vesicles and also may function in the induction of T cell antigen receptor (TCR) endocytosis.

Source: NCBI Gene 50618 — RefSeq curated summary.

At a glance

• Gene–disease (curated): nephrotic syndrome (Strong, GenCC)
• GWAS associations: 12
• Clinical variants (ClinVar): 502 total
• MANE Select transcript: NM_006277

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6184
Approved symbol	ITSN2
Name	intersectin 2
Location	2p23.3
Locus type	gene with protein product
Status	Approved
Aliases	KIAA1256, SWAP, SH3P18, SWA, PRO2015
Ensembl gene	ENSG00000198399
Ensembl biotype	protein_coding
OMIM	604464
Entrez	50618

Gene structure

Transcript identifiers

Ensembl transcripts: 16 — 10 protein_coding, 3 retained_intron, 2 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000355123, ENST00000361999, ENST00000406921, ENST00000407704, ENST00000412011, ENST00000416160, ENST00000427234, ENST00000443927, ENST00000449392, ENST00000469848, ENST00000478720, ENST00000479575, ENST00000905942, ENST00000905943, ENST00000926830, ENST00000926831

RefSeq mRNA: 9 — MANE Select: NM_006277 NM_001348181, NM_001348182, NM_001348183, NM_001348184, NM_001348185, NM_001348186, NM_006277, NM_019595, NM_147152

CCDS: CCDS1710, CCDS1711, CCDS46230

Canonical transcript exons

ENST00000355123 — 40 exons

Exon	Start	End
ENSE00000722102	24310284	24310380
ENSE00000722299	24303799	24303862
ENSE00000722350	24301965	24302102
ENSE00000722427	24299909	24300171
ENSE00000722490	24298665	24298814
ENSE00000722555	24295664	24295804
ENSE00000808870	24301154	24301239
ENSE00000808873	24308617	24308756
ENSE00001486636	24202864	24203783
ENSE00001605766	24270671	24270768
ENSE00001629269	24246797	24246893
ENSE00001630907	24254367	24254431
ENSE00001642410	24261106	24261250
ENSE00001650641	24271766	24271941
ENSE00001665782	24212650	24212748
ENSE00001674611	24209818	24210033
ENSE00001679214	24284763	24284843
ENSE00001690566	24216049	24216232
ENSE00001696254	24248837	24248882
ENSE00001705683	24275713	24275849
ENSE00001729710	24252345	24252511
ENSE00001740845	24246129	24246320
ENSE00001747856	24248629	24248750
ENSE00001768638	24261561	24261742
ENSE00001771235	24310489	24310692
ENSE00001772990	24210780	24210947
ENSE00001775662	24217907	24218013
ENSE00001784679	24257888	24258093
ENSE00001785423	24220945	24221066
ENSE00001820402	24360304	24360536
ENSE00002236520	24293688	24293775
ENSE00002699796	24286212	24286351
ENSE00003463937	24312212	24312375
ENSE00003493643	24313460	24313523
ENSE00003540396	24315132	24315224
ENSE00003540456	24209100	24209221
ENSE00003566909	24208237	24208319
ENSE00003656871	24328052	24328115
ENSE00003673701	24205214	24205297
ENSE00003683750	24204245	24204418

Expression profiles

Bgee: expression breadth ubiquitous, 292 present calls, max score 97.61.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 23.4008 / max 758.6153, expressed in 1782 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
27330	20.0011	1771
27331	2.3100	941
27329	0.8967	348
27328	0.1273	47
27325	0.0371	8
27327	0.0270	13
27326	0.0017	2

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
buccal mucosa cell	CL:0002336	97.61	gold quality
parietal pleura	UBERON:0002400	97.60	gold quality
visceral pleura	UBERON:0002401	97.51	gold quality
pleura	UBERON:0000977	97.50	gold quality
Brodmann (1909) area 23	UBERON:0013554	97.48	gold quality
epithelium of nasopharynx	UBERON:0001951	96.98	gold quality
choroid plexus epithelium	UBERON:0003911	96.86	gold quality
oral cavity	UBERON:0000167	96.76	gold quality
upper leg skin	UBERON:0004262	96.56	gold quality
seminal vesicle	UBERON:0000998	96.32	gold quality
germinal epithelium of ovary	UBERON:0001304	96.31	gold quality
tongue squamous epithelium	UBERON:0006919	96.14	gold quality
thyroid gland	UBERON:0002046	96.11	gold quality
right lobe of thyroid gland	UBERON:0001119	96.07	gold quality
calcaneal tendon	UBERON:0003701	96.03	gold quality
left lobe of thyroid gland	UBERON:0001120	95.88	gold quality
trabecular bone tissue	UBERON:0002483	95.85	gold quality
sperm	CL:0000019	95.82	gold quality
tonsil	UBERON:0002372	95.74	gold quality
lower esophagus mucosa	UBERON:0035834	95.57	gold quality
superficial temporal artery	UBERON:0001614	95.44	gold quality
endothelial cell	CL:0000115	95.43	gold quality
caput epididymis	UBERON:0004358	95.38	gold quality
lymph node	UBERON:0000029	95.37	gold quality
sural nerve	UBERON:0015488	95.32	gold quality
skin of hip	UBERON:0001554	95.25	gold quality
cauda epididymis	UBERON:0004360	95.25	gold quality
esophagus squamous epithelium	UBERON:0006920	95.24	gold quality
male germ cell	CL:0000015	95.12	gold quality
monocyte	CL:0000576	95.00	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	15.55
E-MTAB-8271	no	211.10

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

77 targeting ITSN2, 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-5692A	100.00	74.40	6850
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-MIR-9-3P	99.96	70.88	2068
HSA-MIR-493-5P	99.96	72.47	2382
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-144-3P	99.94	73.98	2698
HSA-MIR-10523-5P	99.91	69.22	2038
HSA-MIR-6809-3P	99.91	71.45	3814
HSA-MIR-4753-3P	99.90	71.03	3786
HSA-MIR-3686	99.90	70.53	2432
HSA-MIR-345-3P	99.89	70.23	1421
HSA-MIR-3681-3P	99.88	70.46	2254
HSA-MIR-130B-5P	99.83	68.50	1888
HSA-MIR-6739-5P	99.80	67.87	2806
HSA-MIR-448	99.79	72.37	2103
HSA-MIR-4694-3P	99.79	69.53	2640
HSA-MIR-548AJ-5P	99.78	71.12	3085
HSA-MIR-548F-5P	99.78	71.02	3093
HSA-MIR-548G-5P	99.78	71.12	3085
HSA-MIR-548X-5P	99.78	71.12	3085

Literature-anchored findings (GeneRIF, showing 9)

• These results highlight a role of Numb for dendritic spine development and synaptic functions with intersectin and EphB2. (PMID:16394100)
• ITSN2C may be specifically expressed in neurons hinting to a physiologic role in neuronal cell function. (PMID:17390067)
• We show that the PPLP motif of K15 protein selectively binds the SH3-C domain of an endocytic adaptor protein, Intersectin 2 (ITSN2). (PMID:17696407)
• ITSN-2L, a guanine nucleotide exchange factor for Cdc42, regulates different steps of caveola endocytosis in ECs by controlling the temporal and spatial actin polymerization and remodeling sub-adjacent to the plasma membrane. (PMID:19622753)
• The ITSN2 interacts with Eps8 and stimulates the degradation of Eps8 proteins. (PMID:22449706)
• The sequence and structural alignment of ITSN-2L C2 domain with other members of C2 domain protein family indicate its vital cellular roles in membrane trafficking, the generation of lipid-second messengers and activation of GTPases. Moreover, our data show the possible roles of ITSN-2L C2 domain in regulating the activity of Cdc42. (PMID:23274495)
• ITSN1 and ITSN2 bind similar proline-rich ligands but are differentially recognized by SH2 domain-containing proteins. (PMID:23936226)
• ITSN2L interacts with RABEP1 and stimulates its degradation in regulation of endocytosis. (PMID:26633357)
• These findings provide the basis for further functional investigations of the ITSN/CR16 complex that may play an important role in actin remodeling and cellular invasion. (PMID:28161632)

Cross-species orthologs

8 orthologs

Organism	Symbol	Gene ID
danio_rerio	itsn2a	ENSDARG00000000161
danio_rerio	itsn2b	ENSDARG00000054973
mus_musculus	Itsn2	ENSMUSG00000020640
rattus_norvegicus	Itsn2	ENSRNOG00000046741
drosophila_melanogaster	Dap160	FBGN0023388
drosophila_melanogaster	Eps-15	FBGN0035060
caenorhabditis_elegans		WBGENE00001224
caenorhabditis_elegans		WBGENE00006405

Paralogs (10): EHD3 (ENSG00000013016), EHD2 (ENSG00000024422), EPS15 (ENSG00000085832), EHD4 (ENSG00000103966), EHD1 (ENSG00000110047), EPS15L1 (ENSG00000127527), REPS1 (ENSG00000135597), REPS2 (ENSG00000169891), SRL (ENSG00000185739), ITSN1 (ENSG00000205726)

Protein

Protein identifiers

Intersectin-2 — Q9NZM3 (reviewed: Q9NZM3)

Alternative names: SH3 domain-containing protein 1B, SH3P18, SH3P18-like WASP-associated protein

All UniProt accessions (6): Q9NZM3, E7EPJ2, F8W719, H7BZD4, H7C0L8, H7C3E2

UniProt curated annotations — full annotation on UniProt →

Function. Adapter protein that may provide indirect link between the endocytic membrane traffic and the actin assembly machinery. May regulate the formation of clathrin-coated vesicles (CCPs). Seems to be involved in CCPs maturation including invagination or budding. Involved in endocytosis of integrin beta-1 (ITGB1) and transferrin receptor (TFR). Plays a role in dendrite formation by melanocytes.

Subunit / interactions. Belongs to a complex that may contain multimers of ITSN1, ITSN2 and EPS15, and different partners according to the step in the endocytic process. Interacts with ADAM15. Interacts with FASLG. Interacts with ANKRD54. Interacts with FCHO2. (Microbial infection) Interacts with herpes virus 8 protein K15.

Subcellular location. Cytoplasm.

Tissue specificity. Expressed in melanocytes. Ubiquitous. Isoform 1 is primarily expressed in adult heart and liver.

Miscellaneous. Overexpression results in the inhibition of the transferrin uptake and the blockage of the clathrin-mediated endocytosis.

Isoforms (4)

UniProt ID	Names	Canonical?
Q9NZM3-1	1, ITSN2-L	yes
Q9NZM3-2	2
Q9NZM3-3	3, ITSN2-S1
Q9NZM3-4	4, ITSN2-S2, SH3P18

RefSeq proteins (9): NP_001335110, NP_001335111, NP_001335112, NP_001335113, NP_001335114, NP_001335115, NP_006268, NP_062541, NP_671494 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000008	C2_dom	Domain
IPR000219	DH_dom	Domain
IPR000261	EH_dom	Domain
IPR001452	SH3_domain	Domain
IPR001849	PH_domain	Domain
IPR002048	EF_hand_dom	Domain
IPR011992	EF-hand-dom_pair	Homologous_superfamily
IPR011993	PH-like_dom_sf	Homologous_superfamily
IPR018247	EF_Hand_1_Ca_BS	Binding_site
IPR035737	Intersectin-2_SH3_1	Domain
IPR035738	Intersectin-2_SH3_2	Domain
IPR035739	Intersectin-2_SH3_3	Domain
IPR035740	Intersectin-2_SH3_4	Domain
IPR035741	Intersectin-2_SH3_5	Domain
IPR035892	C2_domain_sf	Homologous_superfamily
IPR035899	DBL_dom_sf	Homologous_superfamily
IPR036028	SH3-like_dom_sf	Homologous_superfamily
IPR051480	Endocytic_GEF_Adapter	Family

Pfam: PF00018, PF00168, PF00621, PF07653, PF12763, PF14604, PF16652

UniProt features (103 total): strand 39, helix 13, domain 12, modified residue 9, binding site 8, sequence conflict 6, splice variant 4, sequence variant 4, region of interest 3, turn 2, chain 1, coiled-coil region 1, compositionally biased region 1

Structure

Experimental structures (PDB)

8 structures.

PDB	Method	Resolution (Å)
3JZY	X-RAY DIFFRACTION	1.56
4IIO	X-RAY DIFFRACTION	1.7
3GF9	X-RAY DIFFRACTION	2.5
1J3T	SOLUTION NMR
1UDL	SOLUTION NMR
1UE9	SOLUTION NMR
1UFF	SOLUTION NMR
1UHF	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NZM3-F1	72.50	0.26

Functional residue map

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

Ligand- & substrate-binding residues (8): 67; 69; 71; 73; 78; 1640; 1643; 1646

Post-translational modifications (9): 110, 210, 230, 553, 573, 882, 884, 889, 968

Function

Pathways and Gene Ontology

Reactome pathways

9 pathways

ID	Pathway
R-HSA-8856825	Cargo recognition for clathrin-mediated endocytosis
R-HSA-8856828	Clathrin-mediated endocytosis
R-HSA-9013420	RHOU GTPase cycle
R-HSA-162582	Signal Transduction
R-HSA-194315	Signaling by Rho GTPases
R-HSA-199991	Membrane Trafficking
R-HSA-5653656	Vesicle-mediated transport
R-HSA-9012999	RHO GTPase cycle
R-HSA-9716542	Signaling by Rho GTPases, Miro GTPases and RHOBTB3

MSigDB gene sets: 186 (showing top): BROWNE_HCMV_INFECTION_30MIN_DN, MYOGENIN_Q6, GRUETZMANN_PANCREATIC_CANCER_DN, YAGI_AML_WITH_INV_16_TRANSLOCATION, GOBP_REGULATION_OF_CELL_MORPHOGENESIS, GOBP_NEURON_PROJECTION_EXTENSION, GOBP_REGULATION_OF_DEVELOPMENTAL_GROWTH, PEREZ_TP63_TARGETS, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GOBP_GROWTH, GOBP_NEUROGENESIS, GOBP_VESICLE_MEDIATED_TRANSPORT, MODULE_453, REACTOME_MEMBRANE_TRAFFICKING, CTATGCA_MIR153

GO Biological Process (5): endosomal transport (GO:0016197), cell differentiation (GO:0030154), clathrin-dependent synaptic vesicle endocytosis (GO:0150007), positive regulation of dendrite extension (GO:1903861), endocytosis (GO:0006897)

GO Molecular Function (6): guanyl-nucleotide exchange factor activity (GO:0005085), calcium ion binding (GO:0005509), protein-macromolecule adaptor activity (GO:0030674), DNA binding (GO:0003677), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (7): cytoplasm (GO:0005737), centrosome (GO:0005813), cytosol (GO:0005829), plasma membrane (GO:0005886), presynaptic membrane (GO:0042734), extracellular exosome (GO:0070062), intracellular vesicle (GO:0097708)

Reactome top-level categories

Rollup of top-7 pathways:

Category	Pathways
Clathrin-mediated endocytosis	1
Membrane Trafficking	1
RHO GTPase cycle	1
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1
Vesicle-mediated transport	1
Signaling by Rho GTPases	1
Signal Transduction	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
vesicle-mediated transport	2
intracellular transport	2
intracellular anatomical structure	2
cellular anatomical structure	2
cellular developmental process	1
synaptic vesicle recycling via endosome	1
synaptic vesicle endocytosis	1
clathrin-dependent endocytosis	1
positive regulation of cell growth	1
positive regulation of developmental growth	1
dendrite extension	1
regulation of dendrite extension	1
vesicle budding from membrane	1
membrane invagination	1
import into cell	1
GTP binding	1
GDP binding	1
GTPase regulator activity	1
metal ion binding	1
protein binding	1
molecular adaptor activity	1
nucleic acid binding	1
binding	1
cation binding	1
centriole	1
microtubule organizing center	1
cytoplasm	1
membrane	1
cell periphery	1
synaptic membrane	1
presynapse	1
extracellular vesicle	1
vesicle	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

3442 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ITSN2	FCHO1	O14526	996
ITSN2	EPS15	P42566	986
ITSN2	WASL	O00401	980
ITSN2	FCHO2	Q0JRZ9	970
ITSN2	CDC42	P21181	961
ITSN2	EPN2	O95208	958
ITSN2	EPN3	Q9H201	957
ITSN2	EPS15L1	Q9UBC2	894
ITSN2	AMPH	P49418	884
ITSN2	BIN1	O00499	863
ITSN2	SYNJ1	O43426	861
ITSN2	TRIP10	Q15642	847
ITSN2	STON2	Q8WXE9	843
ITSN2	SNAP91	O60641	819
ITSN2	EPHB2	P29323	795

IntAct

78 interactions, top by confidence:

A	B	Type	Score
DNM2	DNM1	psi-mi:“MI:0914”(association)	0.740
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
EGFR	ITSN2	psi-mi:“MI:0915”(physical association)	0.650
ITSN2	EGFR	psi-mi:“MI:0915”(physical association)	0.650
NCKIPSD	GEMIN2	psi-mi:“MI:0914”(association)	0.640
ITSN2	EPS15L1	psi-mi:“MI:0915”(physical association)	0.560
K15-M	ITSN2	psi-mi:“MI:0407”(direct interaction)	0.560
PRKCZ	IPO5	psi-mi:“MI:0914”(association)	0.530
EPS15L1	NDC80	psi-mi:“MI:0914”(association)	0.530
FBXL19	MED19	psi-mi:“MI:0914”(association)	0.530
ADAM12	ITSN2	psi-mi:“MI:0407”(direct interaction)	0.440
FASLG	ITSN2	psi-mi:“MI:0407”(direct interaction)	0.440
Itsn2	EIF3H	psi-mi:“MI:0915”(physical association)	0.400
CBLB	ITSN2	psi-mi:“MI:0915”(physical association)	0.400
MEGF10	ITSN2	psi-mi:“MI:0915”(physical association)	0.370
SYNJ2	ITSN2	psi-mi:“MI:0915”(physical association)	0.370
SEMA6A	ITSN2	psi-mi:“MI:0915”(physical association)	0.370
KIAA1549	ITSN2	psi-mi:“MI:0915”(physical association)	0.370
ITSN2		psi-mi:“MI:0915”(physical association)	0.370
ESR1	ESYT2	psi-mi:“MI:0914”(association)	0.350
PRKCZ	POLRMT	psi-mi:“MI:0914”(association)	0.350
ITSN2	Ppp1cc	psi-mi:“MI:0914”(association)	0.350
RIN3		psi-mi:“MI:0914”(association)	0.350
DYRK1A	TEX13D	psi-mi:“MI:0914”(association)	0.350
RNPS1	C1orf226	psi-mi:“MI:0914”(association)	0.350
AP2M1	C1orf226	psi-mi:“MI:0914”(association)	0.350

BioGRID (197): ITSN2 (Two-hybrid), ITSN2 (Affinity Capture-MS), EPS15 (Co-fractionation), EPS15L1 (Co-fractionation), ITSN2 (Proximity Label-MS), ITSN2 (Proximity Label-MS), ITSN2 (Affinity Capture-MS), ITSN2 (Affinity Capture-MS), ITSN2 (Affinity Capture-MS), ITSN2 (Affinity Capture-MS), ITSN2 (Affinity Capture-MS), ITSN2 (Affinity Capture-MS), ITSN2 (Affinity Capture-MS), ITSN2 (PCA), ITSN2 (Affinity Capture-MS)

ESM2 similar proteins: A6QP06, A7KAX9, F1LRS8, F1QIC4, G5EBZ8, O18195, O42287, O43432, O43491, O60237, O75167, O76337, O82171, O94519, O97902, P11171, P11434, P34416, P41110, P41993, P48820, Q09459, Q15811, Q1AAU6, Q501J7, Q52KW0, Q5HYK7, Q5M775, Q5RAU1, Q5RDE1, Q69ZW3, Q6NZJ6, Q801E2, Q8BG95, Q8IZ21, Q8R550, Q91X43, Q925Q9, Q96B97, Q9HCH5

Diamond homologs: A0A075F932, A0FGR8, A0FGR9, A1ZBD6, A8KBH6, D4ABL6, K8FE10, O00443, O00750, O08835, O35681, O43581, P13677, P21521, P21579, P21707, P24506, P24507, P27715, P29101, P34693, P40748, P40749, P41823, P41885, P46096, P46097, P47191, P47708, P47709, P48018, P50232, P70169, P70610, P97610, Q06846, Q14183, Q14184, Q15811, Q3TZZ7

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 89 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
Nef-mediates down modulation of cell surface receptors by recruiting them to clathrin adapters	5	51.2×	2e-06
The role of Nef in HIV-1 replication and disease pathogenesis	5	51.2×	2e-06
Host Interactions of HIV factors	5	27.1×	4e-05
Recycling pathway of L1	7	25.3×	1e-06
Dengue Virus Attachment and Entry	5	20.9×	1e-04
Clathrin-mediated endocytosis	14	19.2×	4e-12
EPH-ephrin mediated repulsion of cells	5	17.7×	2e-04
Cargo recognition for clathrin-mediated endocytosis	10	16.9×	4e-08

GO biological processes:

GO term	Partners	Fold	FDR
clathrin-dependent endocytosis	6	47.8×	9e-07
synaptic vesicle endocytosis	8	47.4×	3e-09
protein autophosphorylation	5	9.9×	7e-03
endocytosis	7	9.1×	2e-03
positive regulation of ERK1 and ERK2 cascade	6	7.0×	9e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	297
Likely benign	99
Benign	56

Top pathogenic / likely-pathogenic (0)

SpliceAI

6483 predictions. Top by Δscore:

Variant	Effect	Δscore
2:24204238:CACTT:C	donor_loss	1.0000
2:24204239:ACTT:A	donor_loss	1.0000
2:24204240:CTTAC:C	donor_loss	1.0000
2:24204241:TTA:T	donor_loss	1.0000
2:24204242:T:TG	donor_loss	1.0000
2:24204243:A:AC	donor_gain	1.0000
2:24204243:A:C	donor_loss	1.0000
2:24204243:AC:A	donor_gain	1.0000
2:24204244:C:CC	donor_gain	1.0000
2:24204244:CC:C	donor_gain	1.0000
2:24204244:CCAT:C	donor_gain	1.0000
2:24204414:CTTTC:C	acceptor_gain	1.0000
2:24204417:TCC:T	acceptor_loss	1.0000
2:24204419:CT:C	acceptor_loss	1.0000
2:24204420:T:C	acceptor_loss	1.0000
2:24205209:TTTA:T	donor_loss	1.0000
2:24205210:TTACC:T	donor_loss	1.0000
2:24205211:TA:T	donor_loss	1.0000
2:24205212:ACCA:A	donor_loss	1.0000
2:24205213:C:CA	donor_loss	1.0000
2:24205293:GCGGG:G	acceptor_gain	1.0000
2:24205294:CGGG:C	acceptor_gain	1.0000
2:24205294:CGGGC:C	acceptor_gain	1.0000
2:24205295:GGG:G	acceptor_gain	1.0000
2:24205296:GG:G	acceptor_gain	1.0000
2:24205297:GCTA:G	acceptor_loss	1.0000
2:24205298:C:CC	acceptor_gain	1.0000
2:24205298:C:CG	acceptor_loss	1.0000
2:24208233:ATAC:A	donor_loss	1.0000
2:24208234:TA:T	donor_loss	1.0000

AlphaMissense

11131 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:24203775:C:G	G1649R	1.000
2:24204335:A:G	W1616R	1.000
2:24204335:A:T	W1616R	1.000
2:24205264:A:G	L1571P	1.000
2:24208312:A:G	W1535R	1.000
2:24208312:A:T	W1535R	1.000
2:24209912:A:G	L1460P	1.000
2:24209930:A:G	L1454P	1.000
2:24220994:A:G	L1217P	1.000
2:24246847:A:T	V1112D	1.000
2:24246862:A:G	F1107S	1.000
2:24248639:C:T	G1093E	1.000
2:24248640:C:G	G1093R	1.000
2:24248640:C:T	G1093R	1.000
2:24248646:A:G	W1091R	1.000
2:24248646:A:T	W1091R	1.000
2:24248678:A:T	I1080K	1.000
2:24248744:G:T	A1058D	1.000
2:24252364:A:T	V1034D	1.000
2:24252379:A:G	F1029S	1.000
2:24252406:C:T	G1020E	1.000
2:24257924:A:T	V951D	1.000
2:24257939:A:G	F946S	1.000
2:24257943:A:G	W945R	1.000
2:24257943:A:T	W945R	1.000
2:24257966:C:T	G937E	1.000
2:24257967:C:A	G937W	1.000
2:24258020:A:G	F919S	1.000
2:24258049:C:A	W909C	1.000
2:24258049:C:G	W909C	1.000

dbSNP variants (sampled 300 via entrez): RS1000003473 (2:24230343 TATC>T), RS1000023027 (2:24362156 G>A), RS1000029986 (2:24221263 A>C,G), RS1000036534 (2:24330775 T>C), RS1000070185 (2:24206397 C>G), RS1000103995 (2:24287100 C>T), RS1000149608 (2:24317308 C>T), RS1000156481 (2:24273299 G>A,T), RS1000211302 (2:24237607 A>G), RS1000225892 (2:24291164 C>G), RS1000265881 (2:24245859 G>C), RS1000303677 (2:24204114 G>A,T), RS1000312933 (2:24292891 C>T), RS1000339108 (2:24344062 T>G), RS1000374685 (2:24253263 C>T)

Disease associations

OMIM: gene MIM:604464 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
nephrotic syndrome	Strong	Autosomal recessive

Mondo (2): Landau-Kleffner syndrome (MONDO:0009509), nephrotic syndrome (MONDO:0005377)

Orphanet (3): Self-limited epilepsy with centrotemporal spikes (Orphanet:1945), Developmental and epileptic encephalopathy with spike-wave activation in sleep (Orphanet:725), Landau-Kleffner syndrome (Orphanet:98818)

HPO phenotypes

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

GWAS associations

12 associations (top):

Study	Trait	p-value
GCST000883_11	Response to antipsychotic treatment in schizophrenia (working memory)	3.000000e-06
GCST002636_1	Diffuse large B cell lymphoma	4.000000e-08
GCST002929_19	Chromium levels	7.000000e-06
GCST004748_78	Lung cancer	4.000000e-06
GCST004749_90	Lung cancer in ever smokers	6.000000e-06
GCST004879_2	Sjögren’s syndrome	2.000000e-06
GCST005212_4	Asthma	2.000000e-07
GCST006947_37	Feeling fed-up	2.000000e-09
GCST010204_147	Low density lipoprotein cholesterol levels	5.000000e-11
GCST011346_10	Total cholesterol levels	5.000000e-12
GCST011347_12	Low density lipoprotein cholesterol levels	4.000000e-13
GCST90000025_798	Appendicular lean mass	1.000000e-27

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0004335	short-term memory
EFO:0009588	feeling “fed-up” measurement
EFO:0004611	low density lipoprotein cholesterol measurement
EFO:0004574	total cholesterol measurement
EFO:0004980	appendicular lean mass

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D018887	Landau-Kleffner Syndrome	C10.228.140.490.493.500
D009404	Nephrotic Syndrome	C12.050.351.968.419.630.643; C12.200.777.419.630.643; C12.950.419.630.643

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression, increases expression, increases methylation	2
Benzo(a)pyrene	affects methylation, decreases methylation	2
Valproic Acid	affects cotreatment, increases expression, decreases methylation	2
Aflatoxin B1	decreases methylation, increases methylation	2
FR900359	affects phosphorylation	1
bisphenol F	affects cotreatment, increases methylation	1
trichostatin A	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
sodium arsenite	increases expression	1
gossypol acetic acid	decreases expression	1
coumarin	affects phosphorylation	1
1-hydroxypyrene	increases expression	1
CMF regimen	increases response to substance	1
N,N,N’,N’-tetrakis(2-pyridylmethyl)ethylenediamine	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	decreases expression	1
CGP 52608	increases reaction, affects binding	1
abrine	increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Sunitinib	increases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Vorinostat	decreases expression	1
Acetaminophen	decreases expression	1
Gemcitabine	increases expression	1
Air Pollutants, Occupational	increases expression	1
Caffeine	decreases phosphorylation	1
Calcitriol	increases expression	1
Estradiol	increases expression	1
Ethyl Methanesulfonate	increases expression	1
Hydralazine	increases expression, affects cotreatment	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00308321	PHASE4	UNKNOWN	Long Term Tapering or Standard Steroids for Nephrotic Syndrome
NCT01021540	PHASE4	COMPLETED	Prospective Study Evaluating the Effect of Repository Corticotropin in the Treatment of Various Nephrotic Syndromes
NCT01028287	PHASE4	COMPLETED	Adrenocorticotropic Hormone (ACTH) Treatment of Nephrotic Range Proteinuria in Diabetic Nephropathy (NRDN)
NCT01162005	PHASE4	COMPLETED	Therapeutic Effect of Tacrolimus on Primary Nephrotic Syndrome in Children
NCT01895894	PHASE4	COMPLETED	Mycophenolate Mofetil in Pediatric Steroid Dependent Nephrotic Syndrome
NCT02238418	PHASE4	COMPLETED	Efficacy of Usual Vitamin D Supplementation and Its Impact on Children and Adolescents Calciuria.
NCT02382575	PHASE4	UNKNOWN	Efficacy and Safety of Rituximab to That of Calcineurin Inhibitors in Children With Steroid Resistant Nephrotic Syndrome
NCT02427880	PHASE4	COMPLETED	Role of Acetazolamide and Hydrochlorothiazide Followed by Furosemide in Treating Nephrotic Edema
NCT03210688	PHASE4	COMPLETED	Active Vitamin D And Reduced Dose Prednisolone for Treatment in Minimal Change Nephropathy
NCT03347357	PHASE4	COMPLETED	Pharmacokinetics of Tacrolimus in Children
NCT05696977	PHASE4	UNKNOWN	Effect of Obesity on Cyclosporine Blood Trough Level in Nephrotic Syndrome Patients
NCT05966818	PHASE4	UNKNOWN	Effect of Dapagliflozin in Non-Diabetic Patients With Nephrotic Syndrome.
NCT06026787	PHASE4	COMPLETED	Clinical Value of Adding Dapagliflozin in Patients With Nephrotic Syndrome
NCT00354731	PHASE3	COMPLETED	Efficacy of Pentoxifylline on Primary Nephrotic Syndrome
NCT00615667	PHASE3	COMPLETED	Prospective, Multicenter Study of the Efficacy and Tolerance of Tacrolimus on Refractory Nephrotic Syndrome (RNS)
NCT00981838	PHASE3	COMPLETED	Rituximab in Multirelapsing Minimal Change Disease (MCD) or Focal Segmental Glomerulosclerosis (FSGS)
NCT01197040	PHASE3	COMPLETED	Evaluation of Low Dose Corticosteroids Efficiency, Associated With Myfortic ® in the Treatment of Nephrotic Syndrome
NCT01309477	PHASE3	COMPLETED	The Efficacy and Tolerance of Tacrolimus Sustained-release Capsules on Refractory Nephrotic Syndrome (RNS)
NCT02132195	PHASE3	COMPLETED	Adrenocorticotropic Hormone (ACTH) for Frequently Relapsing and Steroid Dependent Nephrotic Syndrome
NCT02257697	PHASE3	COMPLETED	A Study to Evaluate the Efficacy and Safety of Mizoribine in the Treatment of Refractory Nephrotic Syndrome
NCT02438982	PHASE3	COMPLETED	Efficacy and Safety of Rituximab to That of Calcineurin Inhibitors in Children With Steroid Dependent Nephrotic Syndrome
NCT03141970	PHASE3	COMPLETED	Prednisolone Trial in Children Younger Than 4 Years
NCT03501459	PHASE3	UNKNOWN	Lymphocyte Markers As Predictors Of Responsiveness To Rituximab Among Patients With Idiopathic Nephrotic Syndrome
NCT05079789	PHASE3	TERMINATED	Amiloride in Nephrotic Syndrome
NCT05716880	PHASE3	RECRUITING	Ketoanalogues for Muscle Mass Loss in Nephrotic Syndrome
NCT06635720	PHASE3	ACTIVE_NOT_RECRUITING	REduced-dose Steroid PrOtocol for Childhood Nephrotic SyndromE (RESPONSE)
NCT00001212	PHASE2	COMPLETED	Drug Therapy in Lupus Nephropathy
NCT00001959	PHASE2	COMPLETED	Pirfenidone to Treat Kidney Disease (Focal Segmental Glomerulosclerosis)
NCT00004466	PHASE2	TERMINATED	Pilot Study of Atorvastatin in Children With Chronic Hyperlipidemia Secondary to Nephrotic Syndrome
NCT00004990	PHASE2	COMPLETED	Once-A-Month Steroid Treatment for Patients With Focal Segmental Glomerulosclerosis
NCT00977977	PHASE2	RECRUITING	Rituximab Plus Cyclosporine in Idiopathic Membranous Nephropathy
NCT02394106	PHASE2	TERMINATED	Ofatumumab in Children With Drug Resistant Idiopathic Nephrotic Syndrome
NCT02394119	PHASE2	COMPLETED	Ofatumumab Versus Rituximab in Children With Steroid and Calcineurin Inhibitor Dependent Idiopathic Nephrotic Syndrome
NCT02592798	PHASE2	COMPLETED	Pilot Study to Evaluate the Safety and Efficacy of Abatacept in Adults and Children 6 Years and Older With Excessive Loss of Protein in the Urine Due to Either Focal Segmental Glomerulosclerosis (FSGS) or Minimal Change Disease (MCD)
NCT02966717	PHASE2	UNKNOWN	Rituximab Combined With MSCs in the Treatment of PNS (3-4 Stage of CKD)
NCT03004001	PHASE2	TERMINATED	Effect of PCSK9-Antibody (Alirocumab) on Dyslipidemia Secondary to Nephrotic Syndrome
NCT03949855	PHASE2	RECRUITING	Belimumab With Rituximab for Primary Membranous Nephropathy
NCT05599815	PHASE2	WITHDRAWN	Part 1 - A Clinical Trial in Patients With Frequently Relapsing and Steroid-Dependent Nephrotic Syndrome
NCT05704400	PHASE2	UNKNOWN	Efficacy of Anti-CD20 Ab Associated With Anti-CD38 in the Childhood Multidrug Dependent and Resistant Nephrotic Syndrome
NCT06983028	PHASE2	RECRUITING	Atacicept in Multiple Glomerular Diseases