IGSF21

Summary

IGSF21 (immunoglobin superfamily member 21, HGNC:28246) is a protein-coding gene on chromosome 1p36.13, encoding Immunoglobulin superfamily member 21 (Q96ID5). Involved in synaptic inhibition in the brain.

This gene encodes a protein which has two immunoglobulin (Ig) domains and is a member of the immunoglobulin superfamily. Proteins in this superfamily are usually found on or in cell membranes and act as receptors in immune response pathways.

Source: NCBI Gene 84966 — RefSeq curated summary.

At a glance

• GWAS associations: 9
• Clinical variants (ClinVar): 109 total
• MANE Select transcript: NM_032880

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:28246
Approved symbol	IGSF21
Name	immunoglobin superfamily member 21
Location	1p36.13
Locus type	gene with protein product
Status	Approved
Aliases	MGC15730, RP11-121A23.1
Ensembl gene	ENSG00000117154
Ensembl biotype	protein_coding
Entrez	84966

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 4 protein_coding, 2 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000251296, ENST00000412684, ENST00000473951, ENST00000497331, ENST00000873157, ENST00000873158, ENST00000931381

RefSeq mRNA: 1 — MANE Select: NM_032880 NM_032880

CCDS: CCDS184

Canonical transcript exons

ENST00000251296 — 10 exons

Exon	Start	End
ENSE00000753919	18291866	18291987
ENSE00000850903	18334892	18335010
ENSE00001065617	18362115	18362230
ENSE00001065618	18227898	18228010
ENSE00001267449	18107798	18108198
ENSE00001635513	18378256	18378483
ENSE00003515704	18377393	18377431
ENSE00003634334	18365223	18365697
ENSE00003665904	18376310	18376395
ENSE00003688512	18376800	18376992

Expression profiles

Bgee: expression breadth ubiquitous, 185 present calls, max score 98.05.

FANTOM5 (CAGE): breadth broad, TPM avg 5.4856 / max 331.2535, expressed in 350 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
1025	4.8305	336
1024	0.3850	148
1027	0.0819	44
1023	0.0806	39
1026	0.0795	40
1022	0.0281	14

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right hemisphere of cerebellum	UBERON:0014890	98.05	gold quality
cerebellar hemisphere	UBERON:0002245	97.86	gold quality
cerebellar cortex	UBERON:0002129	97.85	gold quality
cerebellum	UBERON:0002037	97.48	gold quality
cortical plate	UBERON:0005343	97.14	gold quality
right frontal lobe	UBERON:0002810	95.52	gold quality
prefrontal cortex	UBERON:0000451	94.85	gold quality
anterior cingulate cortex	UBERON:0009835	94.48	gold quality
cerebellar vermis	UBERON:0004720	94.23	gold quality
Brodmann (1909) area 9	UBERON:0013540	94.21	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	94.20	gold quality
frontal cortex	UBERON:0001870	93.66	gold quality
frontal lobe	UBERON:0016525	93.66	gold quality
neocortex	UBERON:0001950	93.22	gold quality
cerebral cortex	UBERON:0000956	91.97	gold quality
Brodmann (1909) area 46	UBERON:0006483	89.90	gold quality
amygdala	UBERON:0001876	89.61	gold quality
Ammon’s horn	UBERON:0001954	89.36	gold quality
superior frontal gyrus	UBERON:0002661	88.41	gold quality
postcentral gyrus	UBERON:0002581	87.75	gold quality
parietal lobe	UBERON:0001872	87.30	gold quality
temporal lobe	UBERON:0001871	87.08	gold quality
hypothalamus	UBERON:0001898	87.05	gold quality
brain	UBERON:0000955	86.37	gold quality
primary visual cortex	UBERON:0002436	85.34	gold quality
forebrain	UBERON:0001890	85.16	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	85.06	gold quality
entorhinal cortex	UBERON:0002728	84.01	gold quality
occipital lobe	UBERON:0002021	83.97	gold quality
substantia nigra	UBERON:0002038	83.60	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-GEOD-137537	yes	17.42
E-ANND-3	yes	5.84

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

21 targeting IGSF21, 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-223-3P	99.99	70.14	1140
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-5680	99.91	69.83	3421
HSA-MIR-4697-3P	99.89	67.09	1123
HSA-MIR-4668-5P	99.79	70.58	3782
HSA-MIR-148A-3P	99.74	73.77	1700
HSA-MIR-148B-3P	99.74	73.75	1700
HSA-MIR-152-3P	99.74	73.75	1703
HSA-MIR-5093	99.67	69.26	2291
HSA-MIR-875-3P	99.63	69.47	2548
HSA-MIR-548B-3P	99.38	67.26	1000
HSA-MIR-4786-3P	99.36	68.35	1390
HSA-MIR-4463	98.56	66.05	1071
HSA-MIR-4511	98.32	67.97	1500
HSA-MIR-550A-3-5P	97.56	65.35	823
HSA-MIR-550A-5P	97.56	65.35	823
HSA-MIR-1271-3P	97.56	64.85	865
HSA-MIR-4440	90.29	63.67	61
HSA-MIR-6510-3P	84.92	61.55	36

Literature-anchored findings (GeneRIF, showing 1)

• Results suggest that LEKR1-CCNL1 and IGSF21-KLHDC7A gene polymorphisms influence the development of diabetic retinopathy (DR). (PMID:27607899)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	igsf21a	ENSDARG00000031049
danio_rerio	igsf21b	ENSDARG00000056084
mus_musculus	Igsf21	ENSMUSG00000040972
rattus_norvegicus	Igsf21	ENSRNOG00000049959

Paralogs (36): CNTN1 (ENSG00000018236), CDON (ENSG00000064309), NEO1 (ENSG00000067141), SDK2 (ENSG00000069188), IGSF9B (ENSG00000080854), IGSF9 (ENSG00000085552), NRCAM (ENSG00000091129), MXRA5 (ENSG00000101825), IGDCC4 (ENSG00000103742), CNTN3 (ENSG00000113805), CNTN6 (ENSG00000134115), CHL1 (ENSG00000134121), PTPRQ (ENSG00000139304), CNTN4 (ENSG00000144619), BOC (ENSG00000144857), SDK1 (ENSG00000146555), HMCN2 (ENSG00000148357), NCAM1 (ENSG00000149294), CNTN5 (ENSG00000149972), IGSF10 (ENSG00000152580), ROBO4 (ENSG00000154133), ROBO3 (ENSG00000154134), NCAM2 (ENSG00000154654), VCAM1 (ENSG00000162692), NFASC (ENSG00000163531), PRTG (ENSG00000166450), ROBO1 (ENSG00000169855), DSCAM (ENSG00000171587), IGDCC3 (ENSG00000174498), VSIG10 (ENSG00000176834), DSCAML1 (ENSG00000177103), CNTN2 (ENSG00000184144), ROBO2 (ENSG00000185008), VSIG10L (ENSG00000186806), DCC (ENSG00000187323), L1CAM (ENSG00000198910)

Protein

Protein identifiers

Immunoglobulin superfamily member 21 — Q96ID5 (reviewed: Q96ID5)

All UniProt accessions (1): Q96ID5

UniProt curated annotations — full annotation on UniProt →

Function. Involved in synaptic inhibition in the brain. Selectively regulates inhibitory presynaptic differentiation through interacting with presynaptic NRXN2.

Subunit / interactions. Interacts (Ig-like 1 domain) with NRXN2 (via Laminin G-like 1 domain) in a trans-interaction manner.

Subcellular location. Postsynaptic cell membrane.

Domain organisation. Ig-like 1 domain is indispensable for synaptogenic activity whereas Ig-like 2 domain is secondarily responsible for the activity.

RefSeq proteins (1): NP_116269* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003599	Ig_sub	Domain
IPR007110	Ig-like_dom	Domain
IPR013106	Ig_V-set	Domain
IPR013783	Ig-like_fold	Homologous_superfamily
IPR036179	Ig-like_dom_sf	Homologous_superfamily
IPR051427	Nectin/Nectin-like	Family

Pfam: PF07686

UniProt features (15 total): glycosylation site 4, sequence variant 3, domain 2, signal peptide 1, chain 1, disulfide bond 1, sequence conflict 1, region of interest 1, compositionally biased region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96ID5-F1	76.60	0.52

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 (1): 46–116

Glycosylation sites (4): 82, 165, 407, 444

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 109 (showing top): YAATNRNNNYNATT_UNKNOWN, BENPORATH_ES_WITH_H3K27ME3, WHITEHURST_PACLITAXEL_SENSITIVITY, LFA1_Q6, GOCC_CELL_SURFACE, GOBP_CELL_CELL_SIGNALING, GOBP_CELL_JUNCTION_ORGANIZATION, TGANTCA_AP1_C, GOBP_SYNAPTIC_SIGNALING, AACTTT_UNKNOWN, FOXJ2_02, OCT1_B, CTAWWWATA_RSRFC4_Q2, PITX2_Q2, AR_01

GO Biological Process (2): synapse maturation (GO:0060074), trans-synaptic signaling, modulating synaptic transmission (GO:0099550)

GO Molecular Function (0):

GO Cellular Component (10): plasma membrane (GO:0005886), external side of plasma membrane (GO:0009897), cell junction (GO:0030054), presynaptic membrane (GO:0042734), inhibitory synapse (GO:0060077), postsynaptic density membrane (GO:0098839), membrane (GO:0016020), synapse (GO:0045202), postsynaptic membrane (GO:0045211), side of membrane (GO:0098552)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
membrane	2
synaptic membrane	2
nervous system development	1
developmental maturation	1
synapse organization	1
chemical synaptic transmission	1
modulation of chemical synaptic transmission	1
trans-synaptic signaling	1
cell periphery	1
plasma membrane	1
cell surface	1
side of membrane	1
presynapse	1
synapse	1
postsynaptic density	1
postsynaptic membrane	1
postsynaptic specialization membrane	1
cell junction	1
postsynapse	1
leaflet of membrane bilayer	1

Protein interactions and networks

STRING

2057 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
IGSF21	IGSF9	Q9P2J2	576
IGSF21	KCNH7	Q9NS40	505
IGSF21	CLVS1	Q8IUQ0	491
IGSF21	CDH8	P55286	490
IGSF21	IGSF9B	Q9UPX0	490
IGSF21	NRXN2	Q9P2S2	464
IGSF21	PALMD	Q9NP74	460
IGSF21	IGSF22	Q8N9C0	452
IGSF21	LRMDA	Q9H2I8	449
IGSF21	CLSTN3	Q9BQT9	435
IGSF21	TLR3	O15455	432
IGSF21	VPS13D	Q5THJ4	427
IGSF21	NPAS3	Q8IXF0	422
IGSF21	PPP1R36	Q96LQ0	419
IGSF21	DAG1	Q14118	417

IntAct

38 interactions, top by confidence:

A	B	Type	Score
IGSF21	GADD45A	psi-mi:“MI:0915”(physical association)	0.370
IGSF21	GSK3B	psi-mi:“MI:0915”(physical association)	0.370
IGSF21	KRAS	psi-mi:“MI:0915”(physical association)	0.370
ITM2B	ILVBL	psi-mi:“MI:0914”(association)	0.350
GZMK	ITGB7	psi-mi:“MI:0914”(association)	0.350
IGSF21	HOXD13	psi-mi:“MI:0914”(association)	0.350
CACNG8	CLTCL1	psi-mi:“MI:0914”(association)	0.350
MIER3	BAHD1	psi-mi:“MI:0914”(association)	0.350
GIPC2	IGSF21	psi-mi:“MI:0915”(physical association)	0.000
NACA	IGSF21	psi-mi:“MI:0915”(physical association)	0.000
SERPINB9	IGSF21	psi-mi:“MI:0915”(physical association)	0.000
UBE2V2	IGSF21	psi-mi:“MI:0915”(physical association)	0.000
ALDH2	IGSF21	psi-mi:“MI:0915”(physical association)	0.000
ANXA3	IGSF21	psi-mi:“MI:0915”(physical association)	0.000
ATF3	IGSF21	psi-mi:“MI:0915”(physical association)	0.000
BCR	IGSF21	psi-mi:“MI:0915”(physical association)	0.000
BTBD2	IGSF21	psi-mi:“MI:0915”(physical association)	0.000
ERH	IGSF21	psi-mi:“MI:0915”(physical association)	0.000
GSTM4	IGSF21	psi-mi:“MI:0915”(physical association)	0.000
PRMT1	IGSF21	psi-mi:“MI:0915”(physical association)	0.000
HSPB1	IGSF21	psi-mi:“MI:0915”(physical association)	0.000
MAD2L1BP	IGSF21	psi-mi:“MI:0915”(physical association)	0.000
CRCT1	IGSF21	psi-mi:“MI:0915”(physical association)	0.000
PAEP	IGSF21	psi-mi:“MI:0915”(physical association)	0.000
PAFAH1B3	IGSF21	psi-mi:“MI:0915”(physical association)	0.000
PCDHA4	IGSF21	psi-mi:“MI:0915”(physical association)	0.000
PSMD11	IGSF21	psi-mi:“MI:0915”(physical association)	0.000
S100A8	IGSF21	psi-mi:“MI:0915”(physical association)	0.000
SEPHS1	IGSF21	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (39): IGSF21 (Two-hybrid), IGSF21 (Two-hybrid), IGSF21 (Two-hybrid), IGSF21 (Two-hybrid), IGSF21 (Two-hybrid), IGSF21 (Two-hybrid), IGSF21 (Two-hybrid), IGSF21 (Two-hybrid), IGSF21 (Two-hybrid), IGSF21 (Two-hybrid), IGSF21 (Two-hybrid), IGSF21 (Two-hybrid), IGSF21 (Two-hybrid), IGSF21 (Two-hybrid), IGSF21 (Two-hybrid)

ESM2 similar proteins: D3ZB51, E9PZ19, M0RAS4, O60242, O60245, O70472, O75882, O94779, P13590, P13591, P13595, P13596, P15209, P24786, P31836, P51641, P68500, P78539, P97300, P97527, P97546, Q01973, Q03351, Q15223, Q16288, Q16620, Q5IFJ9, Q5IS37, Q5IS82, Q63604, Q63769, Q6A051, Q6AZB0, Q6GQT9, Q6P1D5, Q6VNS1, Q7TNR6, Q80T74, Q80ZF8, Q8R4I7

Diamond homologs: M0RAS4, P98160, Q7TNR6, Q96ID5

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	91
Likely benign	3
Benign	3

Top pathogenic / likely-pathogenic (0)

SpliceAI

4035 predictions. Top by Δscore:

Variant	Effect	Δscore
1:18130368:G:GT	donor_gain	1.0000
1:18227893:TGTA:T	acceptor_loss	1.0000
1:18227894:GTA:G	acceptor_loss	1.0000
1:18227895:TA:T	acceptor_loss	1.0000
1:18227896:A:AG	acceptor_gain	1.0000
1:18227896:A:T	acceptor_loss	1.0000
1:18227896:AG:A	acceptor_gain	1.0000
1:18227897:G:GA	acceptor_gain	1.0000
1:18227897:GG:G	acceptor_gain	1.0000
1:18227897:GGC:G	acceptor_gain	1.0000
1:18227897:GGCT:G	acceptor_gain	1.0000
1:18227897:GGCTA:G	acceptor_gain	1.0000
1:18228009:GG:G	donor_gain	1.0000
1:18228010:GG:G	donor_gain	1.0000
1:18228010:GGT:G	donor_loss	1.0000
1:18228011:G:GG	donor_gain	1.0000
1:18228011:GTAAG:G	donor_loss	1.0000
1:18228012:T:A	donor_loss	1.0000
1:18232603:GCT:G	donor_gain	1.0000
1:18291853:T:TA	acceptor_gain	1.0000
1:18291858:T:TA	acceptor_gain	1.0000
1:18291860:T:TA	acceptor_gain	1.0000
1:18291860:TGGCA:T	acceptor_loss	1.0000
1:18291861:G:A	acceptor_gain	1.0000
1:18291861:GGCA:G	acceptor_loss	1.0000
1:18291862:GCA:G	acceptor_loss	1.0000
1:18291863:CA:C	acceptor_loss	1.0000
1:18291864:A:AG	acceptor_gain	1.0000
1:18291864:A:G	acceptor_loss	1.0000
1:18291864:AG:A	acceptor_gain	1.0000

AlphaMissense

3021 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:18227963:T:A	C46S	1.000
1:18227963:T:C	C46R	1.000
1:18227964:G:A	C46Y	1.000
1:18227964:G:C	C46S	1.000
1:18227965:T:G	C46W	1.000
1:18228002:T:A	W59R	1.000
1:18228002:T:C	W59R	1.000
1:18228004:G:C	W59C	1.000
1:18228004:G:T	W59C	1.000
1:18334932:T:A	C116S	1.000
1:18334932:T:C	C116R	1.000
1:18334933:G:A	C116Y	1.000
1:18334933:G:C	C116S	1.000
1:18334934:C:G	C116W	1.000
1:18362198:T:C	C170R	1.000
1:18362199:G:A	C170Y	1.000
1:18362200:C:G	C170W	1.000
1:18376830:T:A	W378R	1.000
1:18376830:T:C	W378R	1.000
1:18227958:T:C	L44S	0.999
1:18227964:G:T	C46F	0.999
1:18227969:T:C	F48L	0.999
1:18227970:T:C	F48S	0.999
1:18227970:T:G	F48C	0.999
1:18227971:C:A	F48L	0.999
1:18227971:C:G	F48L	0.999
1:18228003:G:C	W59S	0.999
1:18291897:T:C	I72T	0.999
1:18291899:T:C	F73L	0.999
1:18291900:T:G	F73C	0.999

dbSNP variants (sampled 300 via entrez): RS1000012454 (1:18267166 G>A), RS1000013171 (1:18323647 G>A), RS1000037340 (1:18260741 T>C,G), RS1000038097 (1:18286754 A>G), RS1000050305 (1:18275388 C>T), RS1000094593 (1:18312180 T>A), RS1000096651 (1:18265845 G>A,C), RS1000099986 (1:18192861 A>G), RS1000100088 (1:18119828 C>A), RS1000101147 (1:18147764 A>G), RS1000116816 (1:18192384 C>A), RS1000125526 (1:18218719 C>T), RS1000138211 (1:18139365 C>G,T), RS1000143381 (1:18367029 T>C), RS1000149887 (1:18345792 CA>C)

Disease associations

OMIM: gene `` | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

9 associations (top):

Study	Trait	p-value
GCST000824_4	Erectile dysfunction and prostate cancer treatment	2.000000e-06
GCST001017_5	Diabetic retinopathy	5.000000e-06
GCST002930_6	Cobalt levels	2.000000e-06
GCST004485_31	Survival in pancreatic cancer	4.000000e-07
GCST006993_1	Hippocampal volume in Alzheimer’s disease dementia	3.000000e-07
GCST007016_7	Serum bilirubin levels x sex interaction in metabolic syndrome	9.000000e-06
GCST008098_5	Atypical femoral fracture in phosphonate treatment	1.000000e-06
GCST008359_3	Response to cognitive-behavioural therapy in anxiety disorder	1.000000e-06
GCST008758_20	Pre-treatment viral load in HIV-1 infection	1.000000e-15

EFO canonical traits (8, from GWAS)

EFO ID	Trait name
EFO:0000638	overall survival
EFO:0005035	hippocampal volume
EFO:0004570	bilirubin measurement
EFO:0008343	sex interaction measurement
EFO:0009958	response to bisphosphonate
EFO:0009960	atypical femoral fracture
EFO:0007820	cognitive behavioural therapy
EFO:0010125	viral load

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

23 total (human), top 23 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression, affects expression	4
mercuric bromide	affects cotreatment, decreases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
methylmercuric chloride	decreases expression	1
bisphenol A	affects cotreatment, increases methylation, decreases methylation	1
trichostatin A	decreases expression	1
benzo(e)pyrene	decreases methylation	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	decreases expression, affects cotreatment	1
dorsomorphin	decreases expression, affects cotreatment	1
Fulvestrant	increases methylation, affects cotreatment	1
Panobinostat	decreases expression, affects cotreatment	1
Arsenic	affects methylation	1
Arsenicals	increases methylation	1
Benzo(a)pyrene	affects methylation, decreases methylation, increases methylation	1
Diethylhexyl Phthalate	decreases expression	1
Methapyrilene	decreases methylation	1
Rotenone	increases expression	1
Tretinoin	decreases expression	1
1-Methyl-4-phenylpyridinium	increases expression	1
Aflatoxin B1	decreases methylation	1
Antirheumatic Agents	decreases expression	1
Cadmium Chloride	increases expression	1

Clinical trials (associated diseases)

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