CNTNAP5

Summary

CNTNAP5 (contactin associated protein family member 5, HGNC:18748) is a protein-coding gene on chromosome 2q14.3, encoding Contactin-associated protein-like 5 (Q8WYK1). May play a role in the correct development and proper functioning of the peripheral and central nervous system and be involved in cell adhesion and intercellular communication.

This gene product belongs to the neurexin family, members of which function in the vertebrate nervous system as cell adhesion molecules and receptors. This protein, like other neurexin proteins, contains epidermal growth factor repeats and laminin G domains. In addition, it includes an F5/8 type C domain, discoidin/neuropilin- and fibrinogen-like domains, and thrombospondin N-terminal-like domains.

Source: NCBI Gene 129684 — RefSeq curated summary.

At a glance

• Gene–disease (curated): complex neurodevelopmental disorder (Disputed, ClinGen)
• GWAS associations: 35
• Clinical variants (ClinVar): 247 total
• Dosage sensitivity (ClinGen): haploinsufficiency little evidence, triplosensitivity no evidence
• MANE Select transcript: NM_001367498

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:18748
Approved symbol	CNTNAP5
Name	contactin associated protein family member 5
Location	2q14.3
Locus type	gene with protein product
Status	Approved
Aliases	caspr5, FLJ31966
Ensembl gene	ENSG00000155052
Ensembl biotype	protein_coding
OMIM	610519
Entrez	129684

Gene structure

Transcript identifiers

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

ENST00000423939, ENST00000431078, ENST00000470921, ENST00000682447

RefSeq mRNA: 2 — MANE Select: NM_001367498 NM_001367498, NM_130773

CCDS: CCDS46401, CCDS92855

Canonical transcript exons

ENST00000682447 — 24 exons

Exon	Start	End
ENSE00001018921	124763672	124763799
ENSE00001018925	124763977	124764147
ENSE00001018927	124747229	124747385
ENSE00001072069	124772799	124773017
ENSE00001072073	124609801	124609920
ENSE00001072074	124527285	124527456
ENSE00001072076	124434484	124434687
ENSE00001072078	124647758	124647958
ENSE00001072079	124446753	124446937
ENSE00001072080	124524303	124524452
ENSE00001072081	124504292	124504556
ENSE00001072082	124417443	124417590
ENSE00001072087	124563217	124563323
ENSE00001072094	124911467	124911538
ENSE00001149374	124902882	124903100
ENSE00001149383	124869675	124869762
ENSE00001265323	124789902	124790141
ENSE00001605896	124798096	124798320
ENSE00001681498	124242200	124242393
ENSE00001749564	124865306	124865436
ENSE00003508677	124025287	124025732
ENSE00003687220	124221705	124221809
ENSE00003916975	124914092	124921219
ENSE00003920756	124474739	124474882

Expression profiles

Bgee: expression breadth broad, 98 present calls, max score 81.45.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 1.9831 / max 122.1052, expressed in 172 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
22367	1.8716	169
22368	0.1115	53

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	81.45	gold quality
cortical plate	UBERON:0005343	77.62	gold quality
corpus callosum	UBERON:0002336	72.37	gold quality
prefrontal cortex	UBERON:0000451	70.48	gold quality
lateral nuclear group of thalamus	UBERON:0002736	70.39	silver quality
postcentral gyrus	UBERON:0002581	69.01	gold quality
Brodmann (1909) area 46	UBERON:0006483	68.93	gold quality
entorhinal cortex	UBERON:0002728	67.69	gold quality
primary visual cortex	UBERON:0002436	67.32	gold quality
superior frontal gyrus	UBERON:0002661	67.13	gold quality
parietal lobe	UBERON:0001872	66.93	gold quality
pons	UBERON:0000988	66.71	gold quality
occipital lobe	UBERON:0002021	66.15	gold quality
islet of Langerhans	UBERON:0000006	65.66	gold quality
frontal cortex	UBERON:0001870	65.39	gold quality
neocortex	UBERON:0001950	64.14	gold quality
middle temporal gyrus	UBERON:0002771	63.51	silver quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	62.30	gold quality
cerebral cortex	UBERON:0000956	62.16	gold quality
gall bladder	UBERON:0002110	61.74	gold quality
Brodmann (1909) area 23	UBERON:0013554	61.27	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	60.78	gold quality
ganglionic eminence	UBERON:0004023	60.53	gold quality
temporal lobe	UBERON:0001871	59.35	gold quality
anterior cingulate cortex	UBERON:0009835	58.54	gold quality
Ammon’s horn	UBERON:0001954	58.03	gold quality
Brodmann (1909) area 9	UBERON:0013540	57.22	gold quality
hypothalamus	UBERON:0001898	56.84	gold quality
right frontal lobe	UBERON:0002810	56.46	gold quality
dorsal plus ventral thalamus	UBERON:0001897	56.28	silver quality

Single-cell (SCXA)

Detected in 8 experiment(s), a significant marker in 8.

Experiment	Marker?	Max mean expression
E-GEOD-180759	yes	2442.02
E-GEOD-83139	yes	74.08
E-HCAD-35	yes	66.29
E-HCAD-25	yes	37.84
E-MTAB-5061	yes	15.22
E-GEOD-81608	yes	7.39
E-ANND-3	yes	5.86
E-ENAD-27	yes	5.63

Regulation

Is transcription factor: no

Functional genomics

ClinGen dosage: haploinsufficiency 1 (little evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 5)

• Data suggest that rare variants in CNTNAP5 may confer autism spectrum disorder (ASD) susceptibility. Genomic disruption of both DOCK4 and CNTNAP5 genes may have an additive effect and may result in a more severe ASD phenotype. (PMID:20346443)
• This exploratory genome-wide association studies confirmed APOE and identified three novel loci: rs76854344 near CNTNAP5 (P = 8 x 10(-10) OR = 1.9 [1.5-2.3]). (PMID:26993346)
• A joint study of whole exome sequencing and structural MRI analysis in major depressive disorder. (PMID:30722798)
• Novel de novo 2q14.3 deletion disrupting CNTNAP5 in a girl with intellectual impairment, thin corpus callosum, and microcephaly. (PMID:32329157)
• Haplotype-based genomic analysis reveals novel association of CNTNAP5 genic region with primary angle closure glaucoma. (PMID:33737499)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	cntnap5l	ENSDARG00000073802
danio_rerio	cntnap5a	ENSDARG00000073920
danio_rerio	cntnap5b	ENSDARG00000075189
caenorhabditis_elegans		WBGENE00003772

Paralogs (35): NRXN3 (ENSG00000021645), TLL1 (ENSG00000038295), CP (ENSG00000047457), DCBLD2 (ENSG00000057019), HEPH (ENSG00000089472), TLL2 (ENSG00000095587), NRP1 (ENSG00000099250), PCOLCE (ENSG00000106333), CNTNAP3 (ENSG00000106714), CUBN (ENSG00000107611), CNTNAP1 (ENSG00000108797), NRXN2 (ENSG00000110076), MEP1A (ENSG00000112818), NRP2 (ENSG00000118257), CUZD1 (ENSG00000138161), MFGE8 (ENSG00000140545), MEP1B (ENSG00000141434), PDGFC (ENSG00000145431), CNTNAP4 (ENSG00000152910), CNTNAP3B (ENSG00000154529), CDCP2 (ENSG00000157211), PCOLCE2 (ENSG00000163710), EDIL3 (ENSG00000164176), NETO1 (ENSG00000166342), BMP1 (ENSG00000168487), PDGFD (ENSG00000170962), NETO2 (ENSG00000171208), CNTNAP2 (ENSG00000174469), NRXN1 (ENSG00000179915), HEPHL1 (ENSG00000181333), F8 (ENSG00000185010), ASTL (ENSG00000188886), F5 (ENSG00000198734), MFRP (ENSG00000235718), CNTNAP3C (ENSG00000283378)

Protein

Protein identifiers

Contactin-associated protein-like 5 — Q8WYK1 (reviewed: Q8WYK1)

Alternative names: Cell recognition molecule Caspr5

All UniProt accessions (2): Q8WYK1, A0A804HKY0

UniProt curated annotations — full annotation on UniProt →

Function. May play a role in the correct development and proper functioning of the peripheral and central nervous system and be involved in cell adhesion and intercellular communication.

Subcellular location. Membrane.

Similarity. Belongs to the neurexin family.

RefSeq proteins (2): NP_001354427, NP_570129 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000421	FA58C	Domain
IPR000742	EGF	Domain
IPR001791	Laminin_G	Domain
IPR002181	Fibrinogen_a/b/g_C_dom	Domain
IPR008979	Galactose-bd-like_sf	Homologous_superfamily
IPR013320	ConA-like_dom_sf	Homologous_superfamily
IPR036056	Fibrinogen-like_C	Homologous_superfamily
IPR050372	Neurexin-related_CASP	Family

Pfam: PF00754, PF02210

UniProt features (34 total): disulfide bond 11, domain 8, glycosylation site 5, sequence conflict 3, topological domain 2, sequence variant 2, signal peptide 1, chain 1, transmembrane region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8WYK1-F1	84.06	0.57

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 (11): 30–174, 329–360, 512–544, 550–561, 555–570, 572–582, 929–956, 960–973, 967–982, 984–994, 1164–1199

Glycosylation sites (5): 282, 355, 496, 571, 622

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 45 (showing top): BENPORATH_ES_WITH_H3K27ME3, LFA1_Q6, CAGCTG_AP4_Q5, AACTTT_UNKNOWN, MODULE_207, chr2q14, GOCC_SYNAPSE, GOCC_NUCLEOLUS, MODULE_49, HATADA_METHYLATED_IN_LUNG_CANCER_UP, RATTENBACHER_BOUND_BY_CELF1, GOCC_FIBRILLAR_CENTER, NFE2L2.V2, GLI1_TARGET_GENES, MIER1_TARGET_GENES

GO Biological Process (1): cell adhesion (GO:0007155)

GO Molecular Function (0):

GO Cellular Component (1): membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular process	1
cellular anatomical structure	1

Protein interactions and networks

STRING

958 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CNTNAP5	ANKS1B	Q7Z6G8	477
CNTNAP5	CNTN5	O94779	471
CNTNAP5	DSCAM	O60469	468
CNTNAP5	CNTN4	Q8IWV2	455
CNTNAP5	FREM3	P0C091	449
CNTNAP5	TMEM132C	Q8N3T6	447
CNTNAP5	CCDC117	Q8IWD4	440
CNTNAP5	GTF3C3	Q9Y5Q9	438
CNTNAP5	NRDE2	Q9H7Z3	431
CNTNAP5	CACNA2D1	P54289	426
CNTNAP5	EGF	P01133	423
CNTNAP5	NRXN1	Q9ULB1	423
CNTNAP5	CSMD2	Q7Z408	418
CNTNAP5	RYR2	Q92736	394
CNTNAP5	CPVL	Q9H3G5	387

IntAct

6 interactions, top by confidence:

A	B	Type	Score
CNTNAP5	H1-1	psi-mi:“MI:0915”(physical association)	0.400
CACNA1C	CACNB4	psi-mi:“MI:0914”(association)	0.350
CACNA1C	DISP2	psi-mi:“MI:0914”(association)	0.350
HCN1	POTEF	psi-mi:“MI:0914”(association)	0.350
ZNF620	CNTNAP5	psi-mi:“MI:0914”(association)	0.350

BioGRID (3): CNTNAP5 (Proximity Label-MS), CNTNAP5 (Affinity Capture-MS), CNTNAP5 (Affinity Capture-MS)

ESM2 similar proteins: A1XQX0, A1XQX2, A1XQX8, A1XQY1, A3KN33, B4F785, B8UU78, D0PRN3, E9Q7X7, P12080, P29319, P29320, P54764, Q02763, Q02858, Q03137, Q06807, Q07310, Q07496, Q0V8S9, Q0V8T0, Q0V8T3, Q0V8T4, Q0V8T5, Q0V8T6, Q0V8T7, Q0V8T8, Q0V8T9, Q19617, Q28146, Q3KN41, Q4VBE4, Q5RD64, Q63372, Q63374, Q63HQ2, Q6P9K9, Q8QFX6, Q8WYK1, Q91694

Diamond homologs: A0EQL2, P04278, P08689, P15196, P97497, Q0V8T5, Q0V8T8, Q62588, Q8WYK1, Q96NU0, Q99P47, A2RUV9, A5A6K7, O14786, O17754, O18806, O35276, O35375, O35474, O43854, O54858, O54991, O60462, O75976, O88783, O89001, P00451, P02886, P02887, P02888, P04836, P12259, P12263, P14384, P15087, P15169, P16870, P21956, P28824, P29068

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	200
Likely benign	24
Benign	12

Top pathogenic / likely-pathogenic (0)

SpliceAI

7835 predictions. Top by Δscore:

Variant	Effect	Δscore
2:124242394:G:GG	donor_gain	1.0000
2:124319457:A:AG	donor_gain	1.0000
2:124417438:TGCA:T	acceptor_loss	1.0000
2:124417438:TGCAG:T	acceptor_gain	1.0000
2:124417439:GCA:G	acceptor_gain	1.0000
2:124417440:CA:C	acceptor_loss	1.0000
2:124417440:CAG:C	acceptor_gain	1.0000
2:124417441:A:AG	acceptor_gain	1.0000
2:124417441:A:C	acceptor_loss	1.0000
2:124417441:AGA:A	acceptor_gain	1.0000
2:124417442:G:GA	acceptor_gain	1.0000
2:124417442:GA:G	acceptor_gain	1.0000
2:124417442:GACC:G	acceptor_gain	1.0000
2:124417442:GACCT:G	acceptor_gain	1.0000
2:124417586:CTATA:C	donor_gain	1.0000
2:124417587:TATA:T	donor_gain	1.0000
2:124417588:ATA:A	donor_gain	1.0000
2:124417588:ATAG:A	donor_loss	1.0000
2:124417589:TA:T	donor_gain	1.0000
2:124417589:TAGT:T	donor_loss	1.0000
2:124417590:AGT:A	donor_loss	1.0000
2:124417591:G:GG	donor_gain	1.0000
2:124417592:T:A	donor_loss	1.0000
2:124434482:A:AG	acceptor_gain	1.0000
2:124434483:G:GC	acceptor_gain	1.0000
2:124434483:G:GT	acceptor_loss	1.0000
2:124434483:GA:G	acceptor_gain	1.0000
2:124434661:G:T	donor_gain	1.0000
2:124446748:CACA:C	acceptor_loss	1.0000
2:124446750:CAGGT:C	acceptor_loss	1.0000

AlphaMissense

8641 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:124772890:G:C	W874C	0.998
2:124772890:G:T	W874C	0.998
2:124504419:G:C	R396P	0.997
2:124772888:T:A	W874R	0.997
2:124772888:T:C	W874R	0.997
2:124242286:G:C	A92P	0.996
2:124474803:G:A	G328E	0.996
2:124527440:T:A	C544S	0.996
2:124527441:G:C	C544S	0.996
2:124563233:T:A	C555S	0.996
2:124563234:G:C	C555S	0.996
2:124474749:G:A	G310E	0.995
2:124524328:G:C	W450C	0.995
2:124524328:G:T	W450C	0.995
2:124563251:T:A	C561S	0.995
2:124563252:G:C	C561S	0.995
2:124563253:C:G	C561W	0.995
2:124434520:T:C	L189P	0.994
2:124434574:T:C	L207P	0.994
2:124474742:A:C	S308R	0.994
2:124474744:T:A	S308R	0.994
2:124474744:T:G	S308R	0.994
2:124524326:T:A	W450R	0.994
2:124524326:T:C	W450R	0.994
2:124527344:T:C	C512R	0.994
2:124527440:T:C	C544R	0.994
2:124563234:G:A	C555Y	0.994
2:124563235:T:G	C555W	0.994
2:124563314:T:A	C582S	0.994
2:124563315:G:C	C582S	0.994

dbSNP variants (sampled 300 via entrez): RS1000000420 (2:124396351 G>T), RS1000009534 (2:124907455 A>G), RS1000011438 (2:124354399 A>T), RS1000012376 (2:124264210 C>T), RS1000013064 (2:124304591 A>G), RS1000017915 (2:124786209 G>A,T), RS1000020515 (2:124759748 T>A), RS1000021086 (2:124184284 G>T), RS1000025481 (2:124269431 T>C), RS1000028349 (2:124642366 A>G), RS1000032924 (2:124229854 T>G), RS1000037518 (2:124917828 C>T), RS1000039447 (2:124908554 G>A), RS1000040016 (2:124130576 A>C,G), RS1000043488 (2:124313571 A>G)

Disease associations

OMIM: gene MIM:610519 | disease phenotypes:

GenCC curated gene-disease

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
complex neurodevelopmental disorder	Disputed	AD

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

35 associations (top):

Study	Trait	p-value
GCST000107_1	Tonometry	3.000000e-06
GCST000473_6	Response to antipsychotic treatment	5.000000e-07
GCST000635_34	Response to statin therapy	6.000000e-06
GCST001657_11	Schizophrenia	9.000000e-06
GCST001657_5	Schizophrenia	6.000000e-06
GCST003264_1000	Post bronchodilator FEV1/FVC ratio	2.000000e-06
GCST003264_1001	Post bronchodilator FEV1/FVC ratio	2.000000e-06
GCST003264_1002	Post bronchodilator FEV1/FVC ratio	2.000000e-06
GCST003264_133	Post bronchodilator FEV1/FVC ratio	2.000000e-06
GCST003264_221	Post bronchodilator FEV1/FVC ratio	4.000000e-06
GCST003264_996	Post bronchodilator FEV1/FVC ratio	2.000000e-06
GCST003264_997	Post bronchodilator FEV1/FVC ratio	2.000000e-06
GCST003264_999	Post bronchodilator FEV1/FVC ratio	2.000000e-06
GCST003452_17	Posterior cortical atrophy and Alzheimer’s disease	8.000000e-10
GCST003992_17	Photic sneeze reflex	9.000000e-09
GCST004490_10	Cerebrospinal fluid t-tau:AB1-42 ratio	8.000000e-08
GCST004490_9	Cerebrospinal fluid t-tau:AB1-42 ratio	8.000000e-08
GCST004491_6	Cerebrospinal fluid t-tau levels	2.000000e-07
GCST004491_7	Cerebrospinal fluid t-tau levels	2.000000e-07
GCST004780_5	Cortisol levels (saliva)	1.000000e-06
GCST005352_4	Paclitaxel disposition in epithelial ovarian cancer	3.000000e-06
GCST005359_8	Disease progression in age-related macular degeneration	9.000000e-06
GCST006292_4	Response to antipsychotic treatment in schizophrenia	2.000000e-08
GCST006292_9	Response to antipsychotic treatment in schizophrenia	4.000000e-06
GCST006945_29	Feeling guilty	4.000000e-08
GCST007094_18	Diastolic blood pressure	1.000000e-08
GCST007098_15	Diastolic blood pressure	6.000000e-06
GCST007576_350	Chronotype	3.000000e-08
GCST009217_2	Corpus callosum Mid-posterior volume	6.000000e-06
GCST010002_369	Refractive error	6.000000e-10

EFO canonical traits (13, from GWAS)

EFO ID	Trait name
EFO:0004713	FEV/FVC ratio
EFO:0007887	autosomal dominant compelling helio-ophthalmic outburst syndrome
EFO:0007708	t-tau:beta-amyloid 1-42 ratio measurement
EFO:0004760	t-tau measurement
EFO:0005843	cortisol measurement
EFO:0008336	disease progression measurement
EFO:0009595	guilt measurement
EFO:0006336	diastolic blood pressure
EFO:0008328	chronotype measurement
EFO:0004869	YKL40 measurement
EFO:0004530	triglyceride measurement
EFO:0004531	urate measurement
EFO:0004980	appendicular lean mass

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

15 total (human), top 15 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol S	decreases expression, increases methylation	2
Benzo(a)pyrene	affects methylation, increases methylation, increases mutagenesis	2
bisphenol A	affects methylation, affects cotreatment, decreases methylation	1
arsenite	increases methylation	1
CGP 52608	affects binding, increases reaction	1
2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazophenyl)amide	affects cotreatment, decreases expression	1
Fulvestrant	affects cotreatment, decreases methylation	1
Vorinostat	decreases expression	1
Acetaminophen	decreases expression	1
Diethylhexyl Phthalate	decreases expression	1
Silicon Dioxide	increases expression	1
Tetrachlorodibenzodioxin	affects cotreatment, decreases expression	1
Aflatoxin B1	decreases methylation	1
Okadaic Acid	decreases expression	1
Acrylamide	decreases expression	1

Clinical trials (associated diseases)

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