CSMD2

Summary

CSMD2 (CUB and Sushi multiple domains 2, HGNC:19290) is a protein-coding gene on chromosome 1p35.1, encoding CUB and sushi domain-containing protein 2 (Q7Z408).

The protein encoded by this gene is thought to be involved in the control of complement cascade of the immune system. Defects in this gene have been associated with schizophrenia. This gene may act as a tumor suppressor for colorectal cancer.

Source: NCBI Gene 114784 — RefSeq curated summary.

At a glance

• GWAS associations: 20
• Clinical variants (ClinVar): 566 total (top 6% of genes corpus-wide)
• Regional missense constraint (gnomAD): 1 of 5 regions constrained (≈0% of expected missense variation)
• GTEx eGene: eQTL in 22 tissues, sQTL in 1 (q < 0.05)
• Constraint (gnomAD): pLI 1.00 (loss-of-function intolerant), LOEUF 0.36 (moderately constrained)
• MANE Select transcript: NM_001281956
• Notable: 566 clinical variants but no curated precision-oncology (CIViC) evidence yet

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:19290
Approved symbol	CSMD2
Name	CUB and Sushi multiple domains 2
Location	1p35.1
Locus type	gene with protein product
Status	Approved
Aliases	KIAA1884
Ensembl gene	ENSG00000121904
Ensembl biotype	protein_coding
OMIM	608398
Entrez	114784

Gene structure

Transcript identifiers

Ensembl transcripts: 11 — 6 protein_coding, 3 protein_coding_CDS_not_defined, 2 retained_intron

MANE Select: ENST00000373381

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 3, TSL 2: 3, TSL 5: 3

ENST00000373381, ENST00000338325, ENST00000373377, ENST00000373380, ENST00000373388, ENST00000465819, ENST00000471438, ENST00000489419, ENST00000619121, ENST00001108105, ENST00001111815

RefSeq mRNA: 2 — MANE Select: NM_001281956 NM_001281956, NM_052896

CCDS: CCDS380, CCDS60082

Canonical transcript exons

ENST00000373381 — 71 exons

Exon	Start	End
ENSE00000826597	33580753	33580899
ENSE00000826598	33583642	33583830
ENSE00000826600	33602369	33602546
ENSE00000826601	33605282	33605470
ENSE00000826602	33611041	33611250
ENSE00000826603	33614504	33614620
ENSE00001049669	33542720	33542896
ENSE00001066092	33537022	33537095
ENSE00001066099	33533796	33533907
ENSE00001066111	33716286	33716501
ENSE00001145114	33622167	33622271
ENSE00001145143	33600865	33601010
ENSE00001145179	33550177	33550350
ENSE00001207259	33935760	33935954
ENSE00001207268	33918094	33918301
ENSE00001207473	33519465	33519677
ENSE00001207491	33527196	33527258
ENSE00001218243	33617499	33617617
ENSE00001226924	33524882	33525043
ENSE00001330892	33572506	33572691
ENSE00001339084	33577296	33577484
ENSE00001339093	33586504	33586617
ENSE00001339097	33587088	33587168
ENSE00001339107	33616906	33616975
ENSE00001360800	33519812	33519950
ENSE00001360803	33521463	33521550
ENSE00001360805	33523307	33523419
ENSE00001360813	33533050	33533229
ENSE00001360825	33537436	33537609
ENSE00001360832	33540525	33540698
ENSE00001360838	33541130	33541309
ENSE00001360848	33546037	33546219
ENSE00001360998	33709089	33709258
ENSE00001361004	33714587	33714775
ENSE00001361180	33724516	33724704
ENSE00001361183	33725349	33725536
ENSE00001361188	33726547	33726685
ENSE00001361196	33739140	33739334
ENSE00001361200	33743280	33743606
ENSE00001361202	33772569	33772751
ENSE00001361206	33788600	33788712
ENSE00001361211	33792423	33792526
ENSE00001361222	33819713	33819837
ENSE00001361225	33820469	33820556
ENSE00001361229	33825697	33825774
ENSE00001361235	33846884	33846996
ENSE00001399888	33724197	33724313
ENSE00001413718	34032594	34032706
ENSE00001427918	34088977	34089193
ENSE00001460418	33557734	33557922
ENSE00001460419	33559300	33559473
ENSE00001460420	33567593	33567841
ENSE00002302677	34164911	34165230
ENSE00003476937	33569374	33569547
ENSE00003485212	33571532	33571726
ENSE00003486992	33623370	33623466
ENSE00003535878	33810743	33810864
ENSE00003603108	33624519	33624643
ENSE00003633593	33625051	33625254
ENSE00003711868	33652323	33652461
ENSE00003720125	33646648	33646835
ENSE00003721180	33692930	33693056
ENSE00003723210	33633422	33633535
ENSE00003730491	33698753	33698944
ENSE00003736519	33657946	33658137
ENSE00003737724	33626486	33626581
ENSE00003743051	33662890	33663092
ENSE00003745662	33636360	33636554
ENSE00003748500	33700517	33700673
ENSE00003752158	33635214	33635330
ENSE00003920570	33513998	33516570

Expression profiles

Bgee: expression breadth ubiquitous, 166 present calls, max score 88.55.

FANTOM5 (CAGE): breadth broad, TPM avg 5.8218 / max 336.2663, expressed in 730 samples.

Highest expression (Bgee): buccal mucosa cell, ventricular zone, kidney epithelium, cortical plate, primary visual cortex.

Genetic regulation across tissues (GTEx eQTL / sQTL)

CSMD2 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 22 tissues and its splicing (sQTL) in 1 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 23 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Thyroid	eqtl	5.2e-22	+0.46	1:33562221:AG:A
Cells Cultured fibroblasts	eqtl	2.8e-17	-0.25	1:34270451:T:C
Pancreas	eqtl	2.1e-11	-0.47	1:33563862:G:T
Brain Nucleus accumbens basal ganglia	eqtl	1.0e-07	+0.31	1:33814742:G:A
Nerve Tibial	eqtl	1.2e-06	+0.84	1:34154153:C:T
Brain Cortex	eqtl	1.7e-06	+0.35	1:33842129:G:T
Brain Putamen basal ganglia	eqtl	8.6e-06	+0.28	1:33833834:C:T
Brain Cerebellum	eqtl	1.2e-05	-0.40	1:34353005:T:C
Colon Transverse	eqtl	4.4e-05	-0.24	1:34165500:C:T
Brain Cerebellar Hemisphere	eqtl	5.2e-05	-0.35	1:34357249:G:A
Artery Aorta	eqtl	8.3e-05	+0.25	1:33883206:G:T
Brain Caudate basal ganglia	eqtl	3.3e-04	+0.23	1:33814742:G:A
Testis	sqtl	8.3e-04	+1.85	1:33171575:C:T
Lung	eqtl	1.4e-03	+0.20	1:33564914:T:C
Adipose Visceral Omentum	eqtl	1.8e-03	-0.26	1:33567912:G:C
Heart Atrial Appendage	eqtl	1.9e-03	+0.23	1:33572373:T:C
Brain Hippocampus	eqtl	3.4e-03	+0.22	1:33841104:A:G
Brain Hypothalamus	eqtl	5.0e-03	+0.23	1:33814742:G:A
Brain Frontal Cortex BA9	eqtl	8.7e-03	+0.28	1:33814742:G:A
Skin Sun Exposed Lower leg	eqtl	1.4e-02	+0.35	1:34416358:C:G

FANTOM5 promoters

5 alternative TSS:

Promoter ID	TPM avg	Samples expressed
11634	4.6043	668
11632	0.4871	252
11631	0.3382	191
11633	0.3174	156
11635	0.0747	30

Top tissues by expression

showing 100 of 233 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
buccal mucosa cell	CL:0002336	88.55	gold quality
ventricular zone	UBERON:0003053	83.36	gold quality
kidney epithelium	UBERON:0004819	83.09	silver quality
cortical plate	UBERON:0005343	81.48	gold quality
primary visual cortex	UBERON:0002436	77.92	gold quality
ganglionic eminence	UBERON:0004023	77.26	gold quality
Brodmann (1909) area 23	UBERON:0013554	76.73	silver quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	76.65	gold quality
epithelial cell of pancreas	CL:0000083	75.75	gold quality
occipital lobe	UBERON:0002021	74.94	gold quality
middle temporal gyrus	UBERON:0002771	73.48	silver quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	73.43	gold quality
corpus callosum	UBERON:0002336	73.27	gold quality
sural nerve	UBERON:0015488	72.28	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	72.22	gold quality
nasal cavity epithelium	UBERON:0005384	71.59	gold quality
vena cava	UBERON:0004087	71.44	silver quality
prefrontal cortex	UBERON:0000451	70.65	gold quality
Brodmann (1909) area 46	UBERON:0006483	70.45	silver quality
neocortex	UBERON:0001950	70.03	gold quality
stromal cell of endometrium	CL:0002255	69.88	gold quality
frontal cortex	UBERON:0001870	69.67	gold quality
frontal lobe	UBERON:0016525	69.67	gold quality
right frontal lobe	UBERON:0002810	69.30	gold quality
lateral nuclear group of thalamus	UBERON:0002736	69.19	gold quality
cerebral cortex	UBERON:0000956	69.17	gold quality
nucleus accumbens	UBERON:0001882	68.99	gold quality
hypothalamus	UBERON:0001898	68.83	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	68.81	gold quality
subthalamic nucleus	UBERON:0001906	67.83	silver quality
Brodmann (1909) area 9	UBERON:0013540	67.79	gold quality
ventral tegmental area	UBERON:0002691	67.70	silver quality
dorsal plus ventral thalamus	UBERON:0001897	67.63	silver quality
cardia of stomach	UBERON:0001162	67.59	gold quality
anterior cingulate cortex	UBERON:0009835	67.55	gold quality
body of tongue	UBERON:0011876	67.42	gold quality
superior frontal gyrus	UBERON:0002661	67.37	gold quality
heart right ventricle	UBERON:0002080	67.33	gold quality
substantia nigra pars compacta	UBERON:0001965	67.23	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	67.23	gold quality
layer of synovial tissue	UBERON:0007616	67.15	gold quality
Ammon’s horn	UBERON:0001954	67.14	gold quality
amygdala	UBERON:0001876	67.01	gold quality
midbrain	UBERON:0001891	67.00	gold quality
temporal lobe	UBERON:0001871	66.99	gold quality
substantia nigra	UBERON:0002038	66.99	gold quality
superficial temporal artery	UBERON:0001614	66.62	gold quality
pharyngeal mucosa	UBERON:0000355	66.52	gold quality
caudate nucleus	UBERON:0001873	66.52	gold quality
superior vestibular nucleus	UBERON:0007227	66.47	silver quality
tongue	UBERON:0001723	66.42	gold quality
brain	UBERON:0000955	66.39	gold quality
medulla oblongata	UBERON:0001896	66.33	silver quality
substantia nigra pars reticulata	UBERON:0001966	66.33	silver quality
forebrain	UBERON:0001890	66.30	gold quality
putamen	UBERON:0001874	66.12	gold quality
entorhinal cortex	UBERON:0002728	66.04	silver quality
gall bladder	UBERON:0002110	65.96	gold quality
mucosa of paranasal sinus	UBERON:0005030	65.89	gold quality
pericardium	UBERON:0002407	65.77	gold quality
islet of Langerhans	UBERON:0000006	65.72	gold quality
saphenous vein	UBERON:0007318	65.67	gold quality
right hemisphere of cerebellum	UBERON:0014890	65.53	gold quality
cerebellar vermis	UBERON:0004720	65.37	silver quality
cerebellar cortex	UBERON:0002129	65.35	gold quality
cerebellum	UBERON:0002037	65.33	gold quality
cerebellar hemisphere	UBERON:0002245	65.32	gold quality
superior surface of tongue	UBERON:0007371	65.28	gold quality
pons	UBERON:0000988	65.27	silver quality
lateral globus pallidus	UBERON:0002476	65.27	silver quality
trachea	UBERON:0003126	65.26	gold quality
biceps brachii	UBERON:0001507	65.10	gold quality
muscle tissue	UBERON:0002385	64.81	gold quality
parietal lobe	UBERON:0001872	64.56	silver quality
postcentral gyrus	UBERON:0002581	63.92	silver quality
germinal epithelium of ovary	UBERON:0001304	63.88	gold quality
secondary oocyte	CL:0000655	63.86	gold quality
synovial joint	UBERON:0002217	63.21	gold quality
pancreatic ductal cell	CL:0002079	62.76	silver quality
penis	UBERON:0000989	62.18	gold quality
endothelial cell	CL:0000115	62.10	gold quality
urethra	UBERON:0000057	61.93	gold quality
lower lobe of lung	UBERON:0008949	61.66	silver quality
thymus	UBERON:0002370	61.55	gold quality
ascending aorta	UBERON:0001496	61.54	gold quality
thoracic aorta	UBERON:0001515	61.51	gold quality
jejunum	UBERON:0002115	61.00	gold quality
gingival epithelium	UBERON:0001949	60.76	gold quality
descending thoracic aorta	UBERON:0002345	60.36	gold quality
duodenum	UBERON:0002114	60.29	gold quality
amniotic fluid	UBERON:0000173	60.28	gold quality
epithelium of mammary gland	UBERON:0003244	60.05	gold quality
epithelium of nasopharynx	UBERON:0001951	60.01	gold quality
spinal cord	UBERON:0002240	59.99	gold quality
left adrenal gland	UBERON:0001234	59.94	gold quality
mammary duct	UBERON:0001765	59.78	gold quality
adrenal cortex	UBERON:0001235	59.76	gold quality
oocyte	CL:0000023	59.66	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	59.47	gold quality
adrenal gland	UBERON:0002369	59.41	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	8.32
E-GEOD-93593	yes	4.52
E-GEOD-99795	no	2.09

HPA expression

RNA tissue specificity: Tissue enhanced

showing 60 of 62 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM
Hippocampus	tissue	14.4
Locus coeruleus	tissue	11.8
Cerebellum	tissue	11.7
Postcentral gyrus	tissue	10.7
Nucleus accumbens	tissue	10.3
Cerebral cortex	tissue	9.8
Insular cortex	tissue	9.8
Amygdala	tissue	9.2
Retrosplenial cortex	tissue	8.2
Hippocampal formation	tissue	8.0
Retrosplenial and cingulate cortex	tissue	7.9
Entorhinal cortex	tissue	7.8
Olfactory bulb	tissue	7.8
Temporal cortex	tissue	7.7
Prefrontal cortex	tissue	7.6
Somatosensory cortex	tissue	7.5
Motor cortex	tissue	7.4
Frontal cortex	tissue	7.3
Occipital cortex	tissue	7.1
Basal ganglia	tissue	6.5
Ventral forebrain	tissue	6.2
Hypothalamus	tissue	5.8
Septum	tissue	5.7
Putamen	tissue	5.0
Midbrain	tissue	4.9
Periaqueductal gray	tissue	4.8
Thalamus	tissue	4.6
Substantia nigra	tissue	4.4
Pons	tissue	4.2
Caudate putamen	tissue	4.0
Spinal cord	tissue	3.8
Medulla oblongata	tissue	3.7
Corpus callosum	tissue	3.5
Superior colliculi	tissue	3.3
Pancreas	tissue	1.3
Gallbladder	tissue	1.1
Choroid plexus	tissue	0.9
Retina	tissue	0.8
Duodenum	tissue	0.8
Thyroid gland	tissue	0.4
Testis	tissue	0.3
Spleen	tissue	0.3
Tonsil	tissue	0.3
Appendix	tissue	0.3
Cervix	tissue	0.2
Heart muscle	tissue	0.2
Smooth muscle	tissue	0.2
Adrenal gland	tissue	0.2
Pituitary gland	tissue	0.1
Skin 1	tissue	0.1
Lymph node	tissue	0.1
Seminal vesicle	tissue	0.1
Adipose tissue	tissue	0.1
Esophagus	tissue	0.1
Parathyroid gland	tissue	0.1
Colon	tissue	0.1
Urinary bladder	tissue	0.1
Tongue	tissue	0.1
Placenta	tissue	0.1
Lung	tissue	0.1

Brain sub-regions (HPA Brain Atlas): detected in 189; highest nTPM — Ventromedial nucleus (27.1), Entorhinal gyrus (21.8), Arcuate nucleus (19.8), Stria terminalis, bed nucleus (18.9), Temporo-occipital transitional zone (18.8).

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

Targeting CSMD2 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 122 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-574-5P	100.00	66.01	989
HSA-MIR-3689D	100.00	66.14	1181
HSA-MIR-6851-5P	100.00	65.63	1294
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-568	99.98	69.86	2084
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-570-3P	99.96	72.41	4910
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-1236-3P	99.94	68.04	1695
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-22-3P	99.93	68.13	917
HSA-MIR-95-5P	99.89	72.17	3973
HSA-MIR-129-5P	99.88	70.26	3273
HSA-MIR-4271	99.88	68.32	2244
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-4447	99.85	67.81	2900

Functional genomics

gnomAD constraint: pLI 1, LOEUF 0.364, missense Z 5.48 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD)

ENST00000373381 splits into 5 regions with different missense tolerance; 1 is missense-constrained (≈0% of the expected missense variation). Missense variants in a constrained region (low observed/expected) are more likely to be pathogenic. gnomAD

Region (GRCh38)	Missense obs / exp	o/e	Constrained
1:33,519,521–33,567,793	917 / 1199.5	0.76	no
1:33,567,794–33,605,390	723 / 758.6	0.95	no
1:33,605,391–33,935,934	2001 / 2567.1	0.78	no
1:33,935,935–34,032,623	4 / 22.0	0.18	yes (p 1.3e-04)
1:34,032,624–34,165,097	184 / 217.7	0.85	no

Literature-anchored findings (GeneRIF, showing 3)

• CSMD2 protein domain structure and the sequence of the cytoplasmic tail are highly conserved between mammals and fish. (PMID:12906867)
• data demonstrate a significant role of complement control-related genes in the etiology of schizophrenia. (PMID:21439553)
• CSMD1 and CSMD2 expressions were associated with overall survival (PMID:24408017)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Csmd2	ENSMUSG00000028804
rattus_norvegicus	Csmd2	ENSRNOG00000007057

Paralogs (39): CFH (ENSG00000000971), SELE (ENSG00000007908), C8B (ENSG00000021852), C6 (ENSG00000039537), SEZ6 (ENSG00000063015), CFHR2 (ENSG00000080910), APOH (ENSG00000091583), SEZ6L (ENSG00000100095), SUSD6 (ENSG00000100647), SRPX (ENSG00000101955), SRPX2 (ENSG00000102359), C7 (ENSG00000112936), C9 (ENSG00000113600), PAPPA2 (ENSG00000116183), CFHR3 (ENSG00000116785), CR2 (ENSG00000117322), CD46 (ENSG00000117335), C4BPA (ENSG00000123838), C4BPB (ENSG00000123843), CFHR4 (ENSG00000134365), CFHR5 (ENSG00000134389), F13B (ENSG00000143278), SUSD4 (ENSG00000143502), C8A (ENSG00000157131), SUSD3 (ENSG00000157303), CSMD3 (ENSG00000164796), SVEP1 (ENSG00000165124), C2 (ENSG00000166278), SELP (ENSG00000174175), SEZ6L2 (ENSG00000174938), PRF1 (ENSG00000180644), PAPPA (ENSG00000182752), CSMD1 (ENSG00000183117), SELL (ENSG00000188404), CD55 (ENSG00000196352), CR1L (ENSG00000197721), CR1 (ENSG00000203710), CFB (ENSG00000243649), CFHR1 (ENSG00000244414)

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Papio hamadryas	Q28768	99.7%	Diamond
Macaca mulatta	Q95198	99.7%	Diamond
Gorilla gorilla gorilla	Q864V9	99.6%	Diamond
Pongo pygmaeus	Q8SQ75	99.6%	Diamond
Pan troglodytes	Q8SQ74	99.5%	Diamond
Pongo abelii	Q5RA73	99.2%	Diamond
Macaca fascicularis	Q9BE74	99.0%	Diamond
Oryctolagus cuniculus	P98065	93.5%	Diamond
Gallus gallus	P0DJJ2	93.2%	Diamond
Coturnix japonica	P42662	93.2%	Diamond
Bos taurus	A0JNA2	89.9%	Diamond
Gekko japonicus	A8WCC4	87.2%	Diamond
Sus scrofa	Q03710	85.9%	Diamond
Xenopus laevis	P98070	81.8%	Diamond
Strongylocentrotus purpuratus	P10079	74.9%	Diamond
Cavia porcellus	O08569	60.3%	Diamond
Drosophila melanogaster	Q0KHY3	59.0%	Diamond
Danio rerio	C6KFA3	51.0%	Diamond
Acropora millepora	B3EX01	49.0%	Diamond
Caenorhabditis elegans	Q22328	39.8%	Diamond
Vaccinia virus WR	P68638	100.0%	Diamond
Vaccinia virus Copenhagen	P68639	100.0%	Diamond
Vaccinia virus Ankara	O57254	98.4%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
HMGB4	protein-coding	127540
CSMD2-AS1	ncRNA	402779
MIR552	ncRNA	693137
C1orf94	protein-coding	84970
ZSCAN20	protein-coding	7579
PHC2-AS1	ncRNA	101929464
PHC2	protein-coding	1912

Protein

Protein identifiers

CUB and sushi domain-containing protein 2 — Q7Z408 (reviewed: Q7Z408)

Alternative names: CUB and sushi multiple domains protein 2

All UniProt accessions (3): A0A087X0K4, A0A8I5KWH5, Q7Z408

UniProt curated annotations — full annotation on UniProt →

Subcellular location. Cell membrane.

Tissue specificity. Weakly expressed in most tissues, except in brain. Expressed at intermediate level in brain, including cerebellum, substantia nigra, hippocampus and fetal brain. Overexpressed in some head and neck cancer cell lines.

Similarity. Belongs to the CSMD family.

Isoforms (4)

UniProt ID	Names	Canonical?
Q7Z408-1	1	yes
Q7Z408-2	2
Q7Z408-3	3
Q7Z408-4	4

RefSeq proteins (2): NP_001268885, NP_443128 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000436	Sushi_SCR_CCP_dom	Domain
IPR000859	CUB_dom	Domain
IPR035914	Sperma_CUB_dom_sf	Homologous_superfamily
IPR035976	Sushi/SCR/CCP_sf	Homologous_superfamily
IPR051277	SEZ6_CSMD_C4BPB_Regulators	Family

Pfam: PF00084, PF00431

UniProt features (170 total): disulfide bond 66, domain 40, glycosylation site 35, splice variant 12, sequence variant 8, sequence conflict 5, topological domain 2, chain 1, transmembrane region 1

Structure

Predicted structure (AlphaFold)

No AlphaFold model available for Q7Z408 — AlphaFold DB does not currently provide models for proteins above ~3000 aa.

Human Protein Atlas

Protein class: Predicted membrane proteins, Predicted intracellular proteins, Plasma proteins

Protein evidence: Evidence at protein level

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 (66)

Type

Positions

Disulfide bond

1271–1298, 1385–1425, 1411–1441, 1445–1471, 1558–1598, 1584–1615, 1619–1645, 1735–1775, 1761–1792, 1796–1822, 1909–1949, 1935–1964, 1968–1994, 2123–2163, 2149–2178, 2182–2208, 2294–2336, 2322–2351, 2355–2383, 2468–2509, 2495–2526, 2531–2573, 2557–2588, 2593–2638, 2624–2653, 2658–2698, 2684–2711, 2716–2756, 2742–2769, 2774–2814, 2800–2827, 2835–2875, 2861–2888, 2893–2934, 2920–2947, 2952–2994, 2978–3007, 3012–3052, 3038–3065, 3070–3110 … (+26)

Glycosylation sites (35)

Type	Positions
N-linked (glcnac…) asparagine	25, 34, 51, 581, 680, 949, 983, 1009, 1028, 1158, 1178, 1194, 1393, 1566, 1638, 1786, 1799, 1876, 2012, 2185, 2190, 2223, 2394, 2430, 2731, 2809, 2878, 2937, 2971, 3001, 3055, 3143, 3175, 3307, 3407

Function

Pathways and Gene Ontology

Reactome pathways

0 curated (TAS) of 0; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

MSigDB gene sets: 98 (showing top): AAGCAAT_MIR137, BENPORATH_ES_WITH_H3K27ME3, GOBP_SYNAPSE_ASSEMBLY, TATTATA_MIR374, GOBP_CELLULAR_COMPONENT_MAINTENANCE, GOBP_CELL_JUNCTION_ORGANIZATION, MODULE_301, GOBP_ORGANELLE_ASSEMBLY, GOBP_CELL_JUNCTION_ASSEMBLY, GOCC_POSTSYNAPSE, GOCC_SYNAPSE, GOCC_POSTSYNAPTIC_MEMBRANE, chr1p35, GOCC_PLASMA_MEMBRANE_REGION, GOCC_SYNAPTIC_MEMBRANE

GO Biological Process (2): postsynaptic density assembly (GO:0097107), maintenance of postsynaptic density structure (GO:0099562)

GO Cellular Component (4): postsynaptic density membrane (GO:0098839), glutamatergic synapse (GO:0098978), plasma membrane (GO:0005886), membrane (GO:0016020)

GO top-level categories

11 GO namespaces:

Category	Terms
postsynaptic density organization	1
postsynaptic specialization assembly	1
excitatory synapse assembly	1
maintenance of postsynaptic specialization structure	1
postsynaptic density	1
postsynaptic membrane	1
postsynaptic specialization membrane	1
synapse	1
membrane	1
cell periphery	1
cellular anatomical structure	1

Protein interactions and networks

STRING

showing 15 of 762 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CSMD2	OR52E4	Q8NGH9	460
CSMD2	BLTP2	Q14667	392
CSMD2	CWH43	Q9H720	375
CSMD2	KLRD1	Q13241	370
CSMD2	FAU	P35544	370
CSMD2	PDE1A	P54750	370
CSMD2	SCN9A	Q15858	370
CSMD2	ERAP2	Q6P179	370
CSMD2	BPIFB4	P59827	367
CSMD2	CFAP90	A4QMS7	366
CSMD2	LRRC41	Q15345	366
CSMD2	ZBTB39	O15060	363
CSMD2	SCN7A	Q01118	363
CSMD2	TSSC4	Q9Y5U2	359
CSMD2	CNTNAP5	Q8WYK1	340

IntAct

Human interaction partners of CSMD2 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

7 partners by confidence:

Partner	Interaction type	MIscore	Records
ABL1	physical association	0.400	1
CRK	physical association	0.400	1
FYN	physical association	0.400	1
MDH1	physical association	0.400	1
NCK1	physical association	0.400	1
PLCG1	physical association	0.400	1
DISC1	physical association	0.000	1

BioGRID (5 interactions; top human partners by supporting records): DDX58 (Affinity Capture-RNA), MDH1 (Cross-Linking-MS (XL-MS)), NR3C1 (Proximity Label-MS), PARP9 (Proximity Label-MS), RNF123 (Affinity Capture-MS)

Disease & clinical

Genetic variants

Variant evidence for CSMD2: 566 ClinVar records (0 pathogenic / likely pathogenic); 20 GWAS associations.

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	493
Likely benign	31
Benign	1

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 25 predictions of 7,252):

Position(s)	Effect	Δscore	Sites
1:33519707	acceptor_gain	1.0000
1:33519810–33519811	donor_loss	1.0000	4
1:33533048–33533049	donor_loss	1.0000	5
1:33567779	acceptor_gain	1.0000
1:33571530–33571531	donor_loss	1.0000	4
1:33571727–33571728	acceptor_loss	1.0000	4
1:33571735	acceptor_gain	1.0000
1:33580751–33580752	donor_loss	1.0000	3
1:33583662	donor_gain	1.0000
1:33583832	acceptor_gain	1.0000

AlphaMissense

6,100 missense substitutions predicted likely pathogenic (of 23,823 scored), across 1,490 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
D1848	8	0.998	1.000
D1324	8	0.997	1.000
D1497	8	0.996	0.999
D2020	8	0.995	0.999
D1889	8	0.992	0.999
D1538	8	0.989	0.997
D1365	8	0.987	0.997
F1841	8	0.986	0.999
F1546	8	0.985	0.999
F1897	8	0.982	1.000
F1373	8	0.981	0.999
D2061	8	0.978	0.996
F3273	8	0.978	0.998
F1535	8	0.977	0.998
D1854	8	0.977	0.997
D2409	8	0.976	0.993
F2069	8	0.974	0.999
D1330	8	0.973	0.996
D1670	8	0.973	0.995
F2459	8	0.972	0.998

HPA cancer prognostics

RNA cancer specificity: Cancer enhanced (Glioblastoma Multiforme)

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

1 prognostic cancer types:

Cancer	Prognostic	p-value
Glioblastoma Multiforme (validation)	favorable	1.07e-05

Disease associations

OMIM: gene MIM:608398 | disease phenotypes:

GWAS associations

20 associations:

Study	Trait	p-value
GCST010206_2	Anorectal malformation	5e-18
GCST010988_222	Adult body size	5e-9
GCST006464_1	Endometrial cancer	5e-8
GCST001428_7	Intelligence	8e-8
GCST006465_9	Endometrial cancer (endometrioid histology)	9e-8
GCST000246_25	Attention deficit hyperactivity disorder	5e-7
GCST012324_1	LDL levels x SSRI defined daily dose interaction in schizophrenia or bipolar disorder	5e-7
GCST012487_2	Response to lithium treatment in bipolar disorder (continuous phenotype)	5e-7
GCST008368_1	Plasma anti-thyroid peroxidase levels	6e-7
GCST000597_7	Brain structure	1e-6
GCST002755_5	Depressive symptoms (SSRI exposure interaction)	1e-6
GCST002868_14	Response to serotonin reuptake inhibitors in major depressive disorder	1e-6
GCST008156_28	Hip circumference adjusted for BMI	3e-6
GCST003560_15	Coronary artery aneurysm in Kawasaki disease	5e-6
GCST008171_7	Platelet aggregation	6e-6
GCST004250_51	Alanine aminotransferase (ALT) levels after remission induction therapy in actute lymphoblastic leukemia (ALL)	7e-6
GCST001823_11	Metabolite levels (HVA/MHPG ratio)	8e-6
GCST003329_6	Response to anti-TNF therapy in rheumatoid arthritis	8e-6
GCST001651_51	Response to amphetamines	9e-6
GCST004273_2	Venlafaxine response in generalised anxiety disorder (remitters vs non-remitters after 24 weeks)	9e-6

EFO canonical traits (from GWAS)

11 canonical traits:

EFO ID	Trait name
EFO:0004337	intelligence
EFO:0005131	HVA measurement
EFO:0005133	MHPG measurement
EFO:0007006	depressive symptom measurement
EFO:0007010	drug use measurement
EFO:0007011	SSRI use measurement
EFO:0005658	response to selective serotonin reuptake inhibitor
EFO:0004653	response to TNF antagonist
EFO:0007965	response to combination chemotherapy
EFO:0008039	BMI-adjusted hip circumference
EFO:0004611	low density lipoprotein cholesterol measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (CPIC guideline: no)

CTD chemical–gene interactions

26 total (human), top 26 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	increases methylation, increases mutagenesis, affects methylation, decreases methylation	3
Valproic Acid	increases methylation	2
bisphenol A	affects cotreatment, affects methylation	1
2,5,2’,5’-tetrachlorobiphenyl	increases expression	1
benzo(e)pyrene	increases methylation	1
aflatoxin B2	increases methylation	1
tebuconazole	decreases expression	1
CGP 52608	affects binding, increases reaction	1
2-palmitoylglycerol	increases expression	1
Grape Seed Proanthocyanidins	affects cotreatment, decreases expression	1
(+)-JQ1 compound	decreases expression	1
Temozolomide	decreases expression	1
Fulvestrant	affects cotreatment, affects methylation, increases methylation	1
Acetaminophen	decreases expression	1
Atrazine	decreases expression	1
Calcitriol	increases expression	1
Catechin	decreases expression, affects cotreatment	1
Diethylhexyl Phthalate	decreases expression	1
Doxorubicin	increases expression	1
Estradiol	affects cotreatment, increases expression	1
Methapyrilene	increases methylation	1
Progesterone	affects cotreatment, increases expression	1
Tobacco Smoke Pollution	increases methylation	1
Triclosan	increases expression	1
Aflatoxin B1	decreases methylation	1
Okadaic Acid	increases expression	1

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.

showing 60 of 300 trials:

NCT	Phase	Status	Title
NCT00029224	Phase 4	COMPLETED	Treatment With Zoledronic Acid in Patients With Breast Cancer, Multiple Myeloma, and Prostate Cancer With Cancer Related Bone Lesions
NCT00035997	Phase 4	COMPLETED	Open-label Trial on the Effect of I.V. Zoledronic Acid 4 mg on Bone Density in Hormone Sensitive Prostate Cancer Patients With Bone Metastasis
NCT00063609	Phase 4	COMPLETED	The Effect of Zoledronic Acid on Bone Loss in Prostate Cancer Patients Undergoing Androgen Deprivation Therapy
NCT00103623	Phase 4	SUSPENDED	The Plenaxis® Experience Study
NCT00106392	Phase 4	COMPLETED	A Safety and Efficacy Study of Prograf in the Prevention of Erectile Dysfunction After Radical Prostatectomy
NCT00185029	Phase 4	UNKNOWN	MR-Lymphography and Lymph Node Staging in Prostate Cancer
NCT00199485	Phase 4	COMPLETED	Angelica Sinensis for the Treatment of Hot Flashes in Men Undergoing LHRH Therapy for Prostate Cancer
NCT00219219	Phase 4	COMPLETED	Zoledronic Acid in the Prevention of Skeletal-related Events in Hormone Refractory and Hormone-sensitive Prostate Cancer Patients With Bone Metastases
NCT00219271	Phase 4	COMPLETED	Effect Of Zoledronic Acid On Circulating And Bone Marrow-Residing Prostate Cancer Cells In Patients With Clinically Localized Prostate Cancer
NCT00237146	Phase 4	COMPLETED	Study to Evaluate Zoledronic Acid on Quality of Life and Skeletal-related Events as Adjuvant Treatment in Patients With Hormone-naïve Prostate Cancer and Bone Metastasis Who Have Undergone Orchiectomy
NCT00242554	Phase 4	COMPLETED	Open-label Phase IV Clinical Trial to Evaluate the Safety and Tolerability of Zoledronic Acid in Patients With Prostate Cancer and Bone Metastases
NCT00280098	Phase 4	COMPLETED	Docetaxel in the Treatment of Hormone Refractory Prostate Cancer
NCT00293696	Phase 4	COMPLETED	Casodex/Zoladex Biomarkers in Localised Prostate Cancer
NCT00334139	Phase 4	COMPLETED	Effect of Zoledronic Acid on Bone Metabolism in Patients With Bone Metastasis and Prostate or Breast Cancer
NCT00375765	Phase 4	COMPLETED	Effects On Dihydrotestosterone Regulated Gene Expression In Benign Prostatic Hyperplasia Or Prostate Cancer
NCT00391690	Phase 4	COMPLETED	Evaluation of Bone Markers as Diagnostic Tools for Early Detection of Bone Metastases in Patients With High Risk Prostate Cancer
NCT00422708	Phase 4	COMPLETED	Local Anesthesia for Prostate Biopsy
NCT00526331	Phase 4	COMPLETED	Evaluation of Arterial Pressure Based Cardiac Output for Goal-Directed Perioperative Therapy
NCT00590213	Phase 4	COMPLETED	Compare the Value of Prophylactic Versus Therapeutic Breast Radiotherapy in CASODEX
NCT00629330	Phase 4	TERMINATED	Dissemination of Prostate Cancer Screening to PCP’s in African American Communities
NCT00771966	Phase 4	COMPLETED	Radical Prostatectomy and Perioperative Fluid Therapy
NCT00805701	Phase 4	COMPLETED	Study Assessing The Efficacy And Safety Of Avodart (Dutasteride) At Improving Urinary Symptoms In Men With Prostate Cancer Who Are Undergoing Seed Implantation
NCT00859027	Phase 4	COMPLETED	Effect Of Risedronate On Bone Mass In Older Men Receiving Neoadjuvant Therapy For Prostate Cancer
NCT00906269	Phase 4	UNKNOWN	Can Hyperbaric Oxygen Improve Erectile Function Following Surgery for Prostate Cancer
NCT00953277	Phase 4	COMPLETED	Study of Nerve Reconstruction Using AVANCE in Subjects Who Undergo Robotic Assisted Prostatectomy for Treatment of Prostate Cancer
NCT00982800	Phase 4	COMPLETED	Does Postoperative Gabapentin Reduce Pain, Opioid Consumption and Anxiety and Have a Positive Effect on Health Related Quality of Life After Radical Prostatectomy?
NCT01083199	Phase 4	COMPLETED	Global Performance Evaluation of the AMS CONTINUUM™ Device
NCT01136226	Phase 4	COMPLETED	Evaluate Recovery of Testosterone for Patients Using Eligard
NCT01161563	Phase 4	COMPLETED	Randomized Crossover Trial to Assess the Tolerability of Gonadotropin Releasing Hormone (GnRH) Analogue Administration
NCT01230905	Phase 4	COMPLETED	Study to Monitor the Effects of Androgen Suppression Treatment on the Heart
NCT01296672	Phase 4	COMPLETED	3 Month Finasteride Challenge Test Can Significantly Improve the Performance of Screening for Prostate Cancer
NCT01365143	Phase 4	TERMINATED	Prospective Randomized Trial Comparing Robotic Versus Open Radical Prostatectomy
NCT01379742	Phase 4	UNKNOWN	Comparison of Between ThinSeed™ and OncoSeed™ for Permanent Prostate Brachytherapy
NCT01486563	Phase 4	COMPLETED	Hydroxyethyl Starch and Renal Function After Radical Prostatectomy
NCT01511874	Phase 4	COMPLETED	Efficacy and Safety Study of ELIGARD 22.5mg With Prostate Cancer
NCT01512472	Phase 4	TERMINATED	Firmagon (Degarelix) Intermittent Therapy
NCT01547416	Phase 4	COMPLETED	The Effect of Combined General/Epidural Anesthesia Versus General Anesthesia on Diaphragmatic Function
NCT01571544	Phase 4	COMPLETED	The Use of Thermal Suits as Preventing Hypothermia During Surgery
NCT01581749	Phase 4	UNKNOWN	Evaluation of Truebeam for Low-Intermediate Risk Prostate Cancer
NCT01649635	Phase 4	COMPLETED	Study of Cabazitaxel Combined With Prednisone and Prophylaxis of Neutropenia Complications in the Treatment of Patients With Metastatic Castration-resistant Prostate Cancer
NCT01673984	Phase 4	TERMINATED	GP Extended Action Triptorelin
NCT01753297	Phase 4	COMPLETED	A Study of Immediate 9 Months Adjuvant Hormone Therapy With Triptorelin 11.25 mg Versus Active Surveillance After Radical Prostatectomy in High Risk Prostate Cancer Patients.
NCT01794793	Phase 4	COMPLETED	Study to Allow Access to Pasireotide for Patients Benefiting From Pasireotide Treatment in Novartis-sponsored Studies
NCT01950871	Phase 4	TERMINATED	Prostate Guided Biopsy Study Evaluating the Diagnostic Performance of Prostate HistoScanning
NCT01995513	Phase 4	COMPLETED	Safety Study of Continued Enzalutamide Treatment In Prostate Cancer Patients
NCT02102646	Phase 4	COMPLETED	MRI Substudy; Metabolic Changes Due to Iatrogenic Hypogonadism
NCT02116582	Phase 4	COMPLETED	A Study to Evaluate Enzalutamide After Abiraterone in Metastatic Castration-Resistant Prostate Cancer
NCT02149628	Phase 4	COMPLETED	The Effect of Propofol Based Total Intravenous Anesthesia on Oxidative Stress and Nitric Oxide
NCT02405858	Phase 4	COMPLETED	A Study of Abiraterone Acetate in Metastatic Castration-Resistant Prostate Cancer Participants Who Responded Poorly to the First-line Combined Androgen Blockade Therapy
NCT02441517	Phase 4	TERMINATED	A Study of Enzalutamide Re-treatment in Metastatic Castration-resistant Prostate Cancer After Docetaxel and/or Cabazitaxel Treatment
NCT02441894	Phase 4	COMPLETED	Combination of Cabazitaxel With Prednisolone With Primary Prophylaxis With PEG-G-CSF in Treatment of Patients With Prostate Cancer
NCT02475057	Phase 4	COMPLETED	Endothelial Function in Prostate Cancer Patients on Degarelix vs. Luteinizing Hormone-Releasing Hormone Agonists
NCT02511665	Phase 4	UNKNOWN	Metformin And Longevity
NCT02651948	Phase 4	COMPLETED	Transperineal, MRI-guided, Prostate Biopsy
NCT02721433	Phase 4	COMPLETED	4-weekly Versus 12-weekly Administration of Bone-targeted Agents in Patients With Bone Metastases
NCT02726009	Phase 4	COMPLETED	A Trial to Evaluate Safety of Firmagon® (Degarelix) in Indian Patients Diagnosed With Advanced Hormone-dependent Prostate Cancer
NCT02749825	Phase 4	TERMINATED	Comparison of Trelstar Versus Lupron or Zoladex in Advanced Prostate Cancer
NCT02757365	Phase 4	UNKNOWN	Efficiency Study of Aspirin to Prevent the Occurrence of Prostate Cancer
NCT02773251	Phase 4	COMPLETED	The Effect of Guardix-solution for the Prevention of Postoperative Intestinal Adhesion and Intestinal Obstruction After Laparoscopic Pelvic Cavity Surgery
NCT02812186	Phase 4	COMPLETED	Deep Versus Moderate Neuromuscular Blockade During Laparoscopic Surgery