IGSF5

Summary

IGSF5 (immunoglobulin superfamily member 5, HGNC:5952) is a protein-coding gene on chromosome 21q22.2, encoding Immunoglobulin superfamily member 5 (Q9NSI5). Provides, together with MAGI1, an adhesion machinery at tight junctions, which may regulate the permeability of kidney glomerulus and small intestinal epithelial cells.

Predicted to enable PDZ domain binding activity. Predicted to be involved in cell-cell adhesion. Predicted to be located in apical plasma membrane. Predicted to be active in bicellular tight junction and cell surface.

Source: NCBI Gene 150084 — RefSeq curated summary.

At a glance

• GWAS associations: 6
• Clinical variants (ClinVar): 61 total
• MANE Select transcript: NM_001080444

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:5952
Approved symbol	IGSF5
Name	immunoglobulin superfamily member 5
Location	21q22.2
Locus type	gene with protein product
Status	Approved
Aliases	JAM4
Ensembl gene	ENSG00000183067
Ensembl biotype	protein_coding
OMIM	610638
Entrez	150084

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 1 protein_coding, 1 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000380588, ENST00000459922, ENST00000479378

RefSeq mRNA: 1 — MANE Select: NM_001080444 NM_001080444

CCDS: CCDS33562

Canonical transcript exons

ENST00000380588 — 9 exons

Exon	Start	End
ENSE00001290607	39792008	39792099
ENSE00001328914	39801262	39802081
ENSE00001485574	39746216	39746298
ENSE00001769493	39745183	39745526
ENSE00003495748	39779090	39779305
ENSE00003527190	39788167	39788188
ENSE00003604826	39765535	39765852
ENSE00003647311	39770916	39771215
ENSE00003687559	39793534	39793613

Expression profiles

Bgee: expression breadth ubiquitous, 140 present calls, max score 85.53.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.0050 / max 5.3751, expressed in 3 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
189186	0.0050	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	85.53	gold quality
left ventricle myocardium	UBERON:0006566	84.13	silver quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	82.85	gold quality
epithelial cell of pancreas	CL:0000083	81.72	silver quality
myocardium	UBERON:0002349	81.17	silver quality
placenta	UBERON:0001987	79.91	gold quality
right atrium auricular region	UBERON:0006631	77.40	gold quality
cardiac atrium	UBERON:0002081	77.07	gold quality
heart left ventricle	UBERON:0002084	76.62	gold quality
cardiac ventricle	UBERON:0002082	76.15	gold quality
heart right ventricle	UBERON:0002080	73.87	gold quality
heart	UBERON:0000948	73.25	gold quality
apex of heart	UBERON:0002098	72.18	gold quality
right adrenal gland cortex	UBERON:0035827	70.99	gold quality
pancreatic ductal cell	CL:0002079	69.30	silver quality
right adrenal gland	UBERON:0001233	68.11	gold quality
tibialis anterior	UBERON:0001385	66.91	silver quality
body of pancreas	UBERON:0001150	66.30	gold quality
left adrenal gland	UBERON:0001234	66.08	gold quality
palpebral conjunctiva	UBERON:0001812	64.53	gold quality
caudate nucleus	UBERON:0001873	64.23	gold quality
left adrenal gland cortex	UBERON:0035825	64.22	gold quality
pigmented layer of retina	UBERON:0001782	64.20	gold quality
adrenal cortex	UBERON:0001235	63.86	gold quality
pancreas	UBERON:0001264	63.50	gold quality
nucleus accumbens	UBERON:0001882	63.45	gold quality
adrenal gland	UBERON:0002369	63.09	gold quality
putamen	UBERON:0001874	62.99	gold quality
ventricular zone	UBERON:0003053	62.22	gold quality
hypothalamus	UBERON:0001898	61.58	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.92

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

58 targeting IGSF5, 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-4768-5P	100.00	69.49	2861
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-548AQ-3P	99.93	72.66	4867
HSA-MIR-4760-3P	99.93	70.50	2385
HSA-MIR-145-5P	99.92	71.13	1836
HSA-MIR-5195-3P	99.92	70.92	1877
HSA-MIR-380-3P	99.89	70.18	1978
HSA-MIR-579-3P	99.86	71.66	3628
HSA-MIR-664B-3P	99.84	71.65	3590
HSA-MIR-4420	99.82	70.08	1624
HSA-MIR-181B-2-3P	99.81	70.06	1646
HSA-MIR-181B-3P	99.81	70.06	1646
HSA-MIR-2052	99.79	69.37	2031
HSA-MIR-3659	99.70	67.97	694
HSA-MIR-7161-5P	99.68	68.92	1592
HSA-MIR-6516-3P	99.65	68.57	1238
HSA-MIR-548U	99.65	67.78	1463
HSA-MIR-488-3P	99.61	68.79	1731
HSA-MIR-3942-3P	99.57	69.03	2854
HSA-MIR-4328	99.57	71.06	4094
HSA-MIR-486-3P	99.51	66.82	1901
HSA-MIR-5007-3P	99.51	68.14	1242
HSA-MIR-2392	99.43	67.50	708

Cross-species orthologs

14 orthologs

Organism	Symbol	Gene ID
danio_rerio	ntm	ENSDARG00000018065
drosophila_melanogaster	Ama	FBGN0000071
drosophila_melanogaster	Lac	FBGN0010238
drosophila_melanogaster	klg	FBGN0017590
drosophila_melanogaster	fipi	FBGN0031627
drosophila_melanogaster	DIP-eta	FBGN0031725
drosophila_melanogaster	DIP-iota	FBGN0031837
drosophila_melanogaster	CG13506	FBGN0034723
drosophila_melanogaster	DIP-zeta	FBGN0051708
drosophila_melanogaster	DIP-kappa	FBGN0051814
drosophila_melanogaster	CG33543	FBGN0053543
drosophila_melanogaster	DIP-beta	FBGN0259245
drosophila_melanogaster	DIP-epsilon	FBGN0259714
caenorhabditis_elegans	rig-5	WBGENE00004372

Paralogs (5): IGLON5 (ENSG00000142549), NEGR1 (ENSG00000172260), NTM (ENSG00000182667), OPCML (ENSG00000183715), LSAMP (ENSG00000185565)

Protein

Protein identifiers

Immunoglobulin superfamily member 5 — Q9NSI5 (reviewed: Q9NSI5)

Alternative names: Junctional adhesion molecule 4

All UniProt accessions (1): Q9NSI5

UniProt curated annotations — full annotation on UniProt →

Function. Provides, together with MAGI1, an adhesion machinery at tight junctions, which may regulate the permeability of kidney glomerulus and small intestinal epithelial cells. Mediates calcium-independent homophilic cell adhesion. In testis, it may function as a cell adhesion molecule rather than a tight-junction protein. It may participate in the adhesion between spermatogonia-spermatogonia, spermatogonia-Sertoli cells, and Sertoli cells-Sertoli cells.

Subunit / interactions. Interacts with MAGI1 at tight junctions, forms a tripartite complex with NPHS1. Interacts with LNX1 isoform 2 via its PDZ 2 domain, it may also interact with other isoforms containing this domain.

Subcellular location. Apical cell membrane. Cell junction. Tight junction.

Miscellaneous. A protein of the expected size has been detected by antibody binding and Western blot in at least one of the analyzed tissues or cells.

Similarity. Belongs to the immunoglobulin superfamily.

RefSeq proteins (1): NP_001073913* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003599	Ig_sub	Domain
IPR007110	Ig-like_dom	Domain
IPR013098	Ig_I-set	Domain
IPR013783	Ig-like_fold	Homologous_superfamily
IPR036179	Ig-like_dom_sf	Homologous_superfamily

Pfam: PF07679

UniProt features (19 total): glycosylation site 4, sequence variant 4, topological domain 2, disulfide bond 2, domain 2, compositionally biased region 2, chain 1, transmembrane region 1, region of interest 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NSI5-F1	66.04	0.32

Functional residue map

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

Disulfide bonds (2): 60–123, 163–215

Glycosylation sites (4): 103, 210, 231, 59

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 40 (showing top): GSE18804_BRAIN_VS_COLON_TUMORAL_MACROPHAGE_DN, GOCC_CELL_SURFACE, KEGG_TIGHT_JUNCTION, GOBP_CELL_CELL_ADHESION, SCHAEFFER_PROSTATE_DEVELOPMENT_48HR_UP, GOCC_APICAL_PLASMA_MEMBRANE, GOCC_CELL_CELL_JUNCTION, chr21q22, CUI_TCF21_TARGETS_2_UP, KEGG_EPITHELIAL_CELL_SIGNALING_IN_HELICOBACTER_PYLORI_INFECTION, GOCC_APICAL_PART_OF_CELL, GOCC_ANCHORING_JUNCTION, GOCC_PLASMA_MEMBRANE_REGION, WANG_NEOPLASTIC_TRANSFORMATION_BY_CCND1_MYC, BRUINS_UVC_RESPONSE_VIA_TP53_GROUP_A

GO Biological Process (1): cell-cell adhesion (GO:0098609)

GO Molecular Function (0):

GO Cellular Component (6): bicellular tight junction (GO:0005923), cell surface (GO:0009986), apical plasma membrane (GO:0016324), plasma membrane (GO:0005886), membrane (GO:0016020), anchoring junction (GO:0070161)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
cell adhesion	1
apical junction complex	1
tight junction	1
apical part of cell	1
plasma membrane region	1
membrane	1
cell periphery	1
cell junction	1

Protein interactions and networks

STRING

452 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
IGSF5	MAGI1	Q96QZ7	935
IGSF5	OCLN	Q16625	906
IGSF5	F11R	Q9Y624	789
IGSF5	TJP1	Q07157	756
IGSF5	JAM2	P57087	698
IGSF5	JAM3	Q9BX67	692
IGSF5	JAML	Q86YT9	671
IGSF5	MARVELD2	Q8N4S9	652
IGSF5	LNX1	Q8TBB1	646
IGSF5	ESAM	Q96AP7	604
IGSF5	CXADR	P78310	596
IGSF5	CLMP	Q9H6B4	565
IGSF5	CLDN12	P56749	480
IGSF5	EDRF1	Q3B7T1	474
IGSF5	TMEM236	Q5W0B7	469

IntAct

116 interactions, top by confidence:

A	B	Type	Score
IGSF5	LNX2	psi-mi:“MI:0407”(direct interaction)	0.440
IGSF5	MAST2	psi-mi:“MI:0407”(direct interaction)	0.440
IGSF5	DLG3	psi-mi:“MI:0407”(direct interaction)	0.440
IGSF5	PDZD7	psi-mi:“MI:0407”(direct interaction)	0.440
IGSF5	DLG1	psi-mi:“MI:0407”(direct interaction)	0.440
IGSF5	MAST1	psi-mi:“MI:0407”(direct interaction)	0.440
SNX27	IGSF5	psi-mi:“MI:0407”(direct interaction)	0.440
IGSF5	HTRA1	psi-mi:“MI:0407”(direct interaction)	0.440
IGSF5	DLG4	psi-mi:“MI:0407”(direct interaction)	0.440
IGSF5	MAGI3	psi-mi:“MI:0407”(direct interaction)	0.440
IGSF5	DLG2	psi-mi:“MI:0407”(direct interaction)	0.440
IGSF5	TAMALIN	psi-mi:“MI:0407”(direct interaction)	0.440
IGSF5	GORASP2	psi-mi:“MI:0407”(direct interaction)	0.440
IGSF5	RADIL	psi-mi:“MI:0407”(direct interaction)	0.440
DLG1	IGSF5	psi-mi:“MI:0407”(direct interaction)	0.440
IGSF5	ARHGEF11	psi-mi:“MI:0407”(direct interaction)	0.440
IGSF5	ARHGEF12	psi-mi:“MI:0407”(direct interaction)	0.440
IGSF5	PICK1	psi-mi:“MI:0407”(direct interaction)	0.440
IGSF5	GORASP1	psi-mi:“MI:0407”(direct interaction)	0.440
IGSF5	MAGI2	psi-mi:“MI:0407”(direct interaction)	0.440
IGSF5	PDZD2	psi-mi:“MI:0407”(direct interaction)	0.440
IGSF5	TIAM2	psi-mi:“MI:0407”(direct interaction)	0.440
IGSF5	SNTA1	psi-mi:“MI:0407”(direct interaction)	0.440
IGSF5	SNTB1	psi-mi:“MI:0407”(direct interaction)	0.440
APBA3	IGSF5	psi-mi:“MI:0407”(direct interaction)	0.440
IGSF5	MPP2	psi-mi:“MI:0407”(direct interaction)	0.440
IGSF5	PDZRN4	psi-mi:“MI:0407”(direct interaction)	0.440
IGSF5	PTPN13	psi-mi:“MI:0407”(direct interaction)	0.440
IGSF5	ARHGAP21	psi-mi:“MI:0407”(direct interaction)	0.440

BioGRID (12): IGSF5 (Proximity Label-MS), NOTCH3 (Affinity Capture-MS), NOTCH1 (Affinity Capture-MS), NOTCH2 (Affinity Capture-MS), PASK (Affinity Capture-MS), N4BP2L2 (Affinity Capture-MS), LDLR (Affinity Capture-MS), LRP4 (Affinity Capture-MS), CRELD2 (Affinity Capture-MS), IGSF5 (Two-hybrid), LNX1 (Two-hybrid), LNX2 (Two-hybrid)

ESM2 similar proteins: A0A0R4IGV4, A0A8M2B818, A0JM41, A2VD98, B0CLX4, B6ZK77, D3YX43, F1LW30, O00241, O18906, O54901, O88775, O95256, P00545, P04218, P0C673, P10522, P13369, P17948, P21995, P27931, P35916, P35917, P35969, P37301, P42071, P42703, P53767, Q08DK1, Q15762, Q58EG3, Q5DX21, Q5FWR8, Q5R412, Q5U2P2, Q5VJ70, Q6GMZ9, Q6PCB8, Q6X936, Q7TSN7

Diamond homologs: Q5VJ70, Q7TSN7, Q9NSI5

SIGNOR signaling

0 interactions.

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
Ras activation upon Ca2+ influx through NMDA receptor	5	56.0×	1e-06
Unblocking of NMDA receptors, glutamate binding and activation	5	53.3×	1e-06
Negative regulation of NMDA receptor-mediated neuronal transmission	5	53.3×	1e-06
Long-term potentiation	5	46.6×	2e-06
Assembly and cell surface presentation of NMDA receptors	9	44.8×	3e-11
Neurexins and neuroligins	10	38.6×	1e-11
Protein-protein interactions at synapses	6	31.2×	1e-06
RHOB GTPase cycle	5	15.1×	4e-04

GO biological processes:

GO term	Partners	Fold	FDR
establishment or maintenance of epithelial cell apical/basal polarity	11	84.1×	1e-16
protein localization to synapse	6	60.5×	6e-08
receptor clustering	7	57.5×	6e-09
regulation of postsynaptic membrane neurotransmitter receptor levels	7	45.6×	2e-08
protein-containing complex assembly	9	13.5×	2e-06
cell-cell adhesion	10	13.4×	3e-07
regulation of small GTPase mediated signal transduction	5	9.5×	4e-03
chemical synaptic transmission	7	7.1×	1e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	45
Likely benign	6
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1357 predictions. Top by Δscore:

Variant	Effect	Δscore
21:39749083:G:GT	donor_gain	1.0000
21:39770912:TTA:T	acceptor_loss	1.0000
21:39770914:A:AG	acceptor_gain	1.0000
21:39770914:AG:A	acceptor_loss	1.0000
21:39770915:G:GG	acceptor_gain	1.0000
21:39770915:GTT:G	acceptor_gain	1.0000
21:39770915:GTTAT:G	acceptor_gain	1.0000
21:39771213:AAGG:A	donor_loss	1.0000
21:39771216:G:GA	donor_loss	1.0000
21:39771216:G:GG	donor_gain	1.0000
21:39792096:ACAGG:A	donor_loss	1.0000
21:39792098:AGG:A	donor_loss	1.0000
21:39792099:GGTG:G	donor_loss	1.0000
21:39792100:G:GA	donor_loss	1.0000
21:39792101:T:A	donor_loss	1.0000
21:39793528:TTGCA:T	acceptor_loss	1.0000
21:39793529:TGCA:T	acceptor_loss	1.0000
21:39793530:GCA:G	acceptor_loss	1.0000
21:39793531:CAG:C	acceptor_loss	1.0000
21:39793532:A:AG	acceptor_gain	1.0000
21:39793532:A:C	acceptor_loss	1.0000
21:39793533:G:GC	acceptor_gain	1.0000
21:39793533:G:GT	acceptor_loss	1.0000
21:39793533:GA:G	acceptor_gain	1.0000
21:39793533:GAC:G	acceptor_gain	1.0000
21:39793533:GACA:G	acceptor_gain	1.0000
21:39770915:GT:G	acceptor_gain	0.9900
21:39770915:GTTA:G	acceptor_gain	0.9900
21:39771214:AG:A	donor_gain	0.9900
21:39771215:GG:G	donor_gain	0.9900

AlphaMissense

2669 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
21:39765647:G:C	W71C	0.996
21:39765647:G:T	W71C	0.996
21:39765606:T:C	F58L	0.993
21:39765608:C:A	F58L	0.993
21:39765608:C:G	F58L	0.993
21:39765632:G:C	W66C	0.993
21:39765632:G:T	W66C	0.993
21:39765645:T:A	W71R	0.991
21:39765645:T:C	W71R	0.991
21:39765607:T:C	F58S	0.990
21:39765607:T:G	F58C	0.987
21:39765630:T:A	W66R	0.986
21:39765630:T:C	W66R	0.986
21:39771025:G:C	W176C	0.986
21:39771025:G:T	W176C	0.986
21:39765711:T:C	F93L	0.985
21:39765713:C:A	F93L	0.985
21:39765713:C:G	F93L	0.985
21:39765801:T:A	C123S	0.983
21:39765802:G:C	C123S	0.983
21:39765672:A:C	S80R	0.982
21:39765674:C:A	S80R	0.982
21:39765674:C:G	S80R	0.982
21:39765757:T:C	M108T	0.981
21:39765646:G:C	W71S	0.974
21:39765614:C:G	C60W	0.972
21:39771023:T:A	W176R	0.972
21:39771023:T:C	W176R	0.972
21:39765612:T:A	C60S	0.971
21:39765613:G:C	C60S	0.971

dbSNP variants (sampled 300 via entrez): RS1000015283 (21:39751339 A>G), RS1000101824 (21:39730777 G>C), RS1000102596 (21:39756115 AAACAAACG>A), RS1000110382 (21:39764409 C>T), RS1000125922 (21:39772121 C>T), RS1000133289 (21:39716831 C>A,T), RS1000154485 (21:39730522 C>T), RS1000157123 (21:39772436 A>C), RS1000184017 (21:39776037 A>G), RS1000224972 (21:39737767 T>C), RS1000243901 (21:39770291 C>T), RS1000262570 (21:39736569 A>C,G), RS1000313125 (21:39769884 T>C), RS1000343528 (21:39781610 C>A,T), RS1000349363 (21:39745213 A>G)

Disease associations

OMIM: gene MIM:610638 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST000854_1	Suicide risk	6.000000e-06
GCST000973_3	Hypertension	9.000000e-06
GCST002307_7	Systolic blood pressure (alcohol consumption interaction)	7.000000e-07
GCST002307_8	Systolic blood pressure (alcohol consumption interaction)	8.000000e-07
GCST008513_37	Health literacy	9.000000e-06
GCST008892_18	Working memory	3.000000e-06

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0004321	attempted suicide
EFO:0004329	alcohol drinking
EFO:0006335	systolic blood pressure
EFO:0010104	health literacy measurement
EFO:0004335	short-term memory

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

10 total (human), top 10 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases expression, increases expression	2
p-Chloromercuribenzoic Acid	affects cotreatment, decreases expression	2
methylmercuric chloride	decreases expression	1
perfluorooctanoic acid	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	decreases expression, affects cotreatment	1
dorsomorphin	affects cotreatment, decreases expression	1
Aerosols	increases expression	1
Benzo(a)pyrene	increases methylation	1
Estradiol	decreases expression, increases reaction	1
beta-Naphthoflavone	decreases expression	1

Clinical trials (associated diseases)

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