CNTNAP1

Summary

CNTNAP1 (contactin associated protein 1, HGNC:8011) is a protein-coding gene on chromosome 17q21.2, encoding Contactin-associated protein 1 (P78357). Required, with CNTNAP2, for radial and longitudinal organization of myelinated axons.

The gene product was initially identified as a 190-kD protein associated with the contactin-PTPRZ1 complex. The 1,384-amino acid protein, also designated p190 or CASPR for ‘contactin-associated protein,’ includes an extracellular domain with several putative protein-protein interaction domains, a putative transmembrane domain, and a 74-amino acid cytoplasmic domain. Northern blot analysis showed that the gene is transcribed predominantly in brain as a transcript of 6.2 kb, with weak expression in several other tissues tested. The architecture of its extracellular domain is similar to that of neurexins, and this protein may be the signaling subunit of contactin, enabling recruitment and activation of intracellular signaling pathways in neurons.

Source: NCBI Gene 8506 — RefSeq curated summary.

At a glance

• Gene–disease (curated): lethal congenital contracture syndrome 7 (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 5
• Clinical variants (ClinVar): 644 total — 30 pathogenic, 19 likely-pathogenic
• Phenotypes (HPO): 58
• MANE Select transcript: NM_003632

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:8011
Approved symbol	CNTNAP1
Name	contactin associated protein 1
Location	17q21.2
Locus type	gene with protein product
Status	Approved
Aliases	p190, Caspr, CNTNAP
Ensembl gene	ENSG00000108797
Ensembl biotype	protein_coding
OMIM	602346
Entrez	8506

Gene structure

Transcript identifiers

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

ENST00000264638, ENST00000585534, ENST00000586801, ENST00000591662

RefSeq mRNA: 1 — MANE Select: NM_003632 NM_003632

CCDS: CCDS11436

Canonical transcript exons

ENST00000264638 — 24 exons

Exon	Start	End
ENSE00000726984	42684036	42684229
ENSE00000726987	42684991	42685138
ENSE00000726990	42685217	42685420
ENSE00000726996	42685957	42686141
ENSE00001132455	42691137	42691293
ENSE00001132502	42688462	42688611
ENSE00001132525	42686903	42687046
ENSE00001178905	42690739	42690942
ENSE00001178908	42690088	42690207
ENSE00001178910	42689521	42689627
ENSE00001178914	42688876	42689047
ENSE00001178926	42687720	42687981
ENSE00001219424	42683821	42683922
ENSE00001301384	42682531	42682896
ENSE00001312235	42698618	42699993
ENSE00003466041	42693297	42693536
ENSE00003472566	42692499	42692720
ENSE00003472827	42696025	42696152
ENSE00003499667	42697903	42697950
ENSE00003513174	42691384	42691511
ENSE00003538460	42697274	42697367
ENSE00003590905	42697554	42697799
ENSE00003658668	42691806	42691991
ENSE00003659204	42695521	42695874

Expression profiles

Bgee: expression breadth ubiquitous, 209 present calls, max score 97.38.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 6.9271 / max 252.5296, expressed in 1205 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
160980	4.2102	1093
160981	2.6298	779
160982	0.0568	33
160979	0.0304	20

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right hemisphere of cerebellum	UBERON:0014890	97.38	gold quality
cerebellar hemisphere	UBERON:0002245	96.83	gold quality
cerebellar cortex	UBERON:0002129	96.81	gold quality
cerebellum	UBERON:0002037	96.42	gold quality
CA1 field of hippocampus	UBERON:0003881	96.25	gold quality
postcentral gyrus	UBERON:0002581	95.97	gold quality
right frontal lobe	UBERON:0002810	95.56	gold quality
parietal lobe	UBERON:0001872	95.55	gold quality
Brodmann (1909) area 46	UBERON:0006483	95.31	gold quality
superior frontal gyrus	UBERON:0002661	95.05	gold quality
orbitofrontal cortex	UBERON:0004167	94.88	gold quality
lateral nuclear group of thalamus	UBERON:0002736	94.71	gold quality
prefrontal cortex	UBERON:0000451	94.65	gold quality
frontal cortex	UBERON:0001870	94.60	gold quality
frontal lobe	UBERON:0016525	94.60	gold quality
Brodmann (1909) area 9	UBERON:0013540	94.46	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	93.93	gold quality
entorhinal cortex	UBERON:0002728	93.50	gold quality
cingulate cortex	UBERON:0003027	93.45	gold quality
anterior cingulate cortex	UBERON:0009835	93.43	gold quality
neocortex	UBERON:0001950	93.30	gold quality
cerebellar vermis	UBERON:0004720	92.93	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	92.52	gold quality
cerebral cortex	UBERON:0000956	92.50	gold quality
hypothalamus	UBERON:0001898	92.27	gold quality
inferior olivary complex	UBERON:0002127	92.05	gold quality
type B pancreatic cell	CL:0000169	91.78	gold quality
olfactory bulb	UBERON:0002264	91.60	silver quality
occipital lobe	UBERON:0002021	91.50	gold quality
superior vestibular nucleus	UBERON:0007227	91.50	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.37

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

122 targeting CNTNAP1, 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-5011-5P	100.00	83.46	5820
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-103A-3P	99.98	69.14	1595
HSA-MIR-107	99.98	69.14	1595
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-34C-5P	99.97	70.45	1577
HSA-MIR-449B-5P	99.97	70.26	1580
HSA-MIR-4487	99.96	64.58	1252
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-5010-5P	99.94	64.11	705
HSA-MIR-4525	99.94	64.38	675
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-6768-5P	99.92	67.36	1942
HSA-MIR-3119	99.92	71.34	2390
HSA-MIR-7-1-3P	99.91	71.53	4384
HSA-MIR-7-2-3P	99.91	71.40	4394
HSA-MIR-6809-3P	99.91	71.45	3814

Literature-anchored findings (GeneRIF, showing 13)

• VDAC1 and CNTNAP1 associate with gamma-secretase in detergent-resistant membranes and affect amyloid precursor protein processing. (PMID:22315232)
• A protein encoded by this locus was found to be differentially expressed in postmortem brains from patients with atypical frontotemporal lobar degeneration. (PMID:22360420)
• Mutations in CNTNAP1 and ADCY6 are responsible for severe arthrogryposis multiplex congenita with axoglial defects (PMID:24319099)
• In two brothers with severe congenital hypotonia and foot deformities, we identified compound heterozygous variants in CNTNAP1, reporting the first causative missense variant, p.(Cys323Arg). Motor nerve conductions were markedly decreased. (PMID:27782105)
• CNTNAP1 mutations were found to induce characteristic ultrastructural lesions of the paranodal region. (PMID:27818385)
• report a consanguineous Arab family from Qatar with three children having an early lethal form of arthrogryposis multiplex congenita and a novel frameshift mutation in CNTNAP1 (PMID:28254648)
• We identified 9 novel CNTNAP1 variants in 6 families: three missense variants, four nonsense variants, one frameshift variant and one splice site variant. Significant polyhydramnios occurred in 6/7 pregnancies (PMID:29511323)
• E. coli exploits Caspr1 as a host receptor for penetration of the blood-brain barrier, resulting in meningitis (PMID:29895952)
• These results demonstrate that CASPR1 binds with ATP1B3 and thereby contributes to the regulation of Na(+)/K(+)-ATPase maturation and trafficking to the plasma membrane in brain microvascular endothelial cells. (PMID:30792309)
• Mutations of CNTNAP1 led to defects in neuronal development. (PMID:33148880)
• M2-polarization-related CNTNAP1 gene might be a novel immunotherapeutic target and biomarker for clear cell renal cell carcinoma. (PMID:35023290)
• CNTNAP1-encephalopathy: Six novel patients surviving the neonatal period. (PMID:35182943)
• Mouse models of human CNTNAP1-associated congenital hypomyelinating neuropathy and genetic restoration of murine neurological deficits. (PMID:37862170)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Cntnap1	ENSMUSG00000017167
rattus_norvegicus	Cntnap1	ENSRNOG00000020277

Paralogs (35): NRXN3 (ENSG00000021645), TLL1 (ENSG00000038295), CP (ENSG00000047457), DCBLD2 (ENSG00000057019), HEPH (ENSG00000089472), TLL2 (ENSG00000095587), NRP1 (ENSG00000099250), PCOLCE (ENSG00000106333), CNTNAP3 (ENSG00000106714), CUBN (ENSG00000107611), NRXN2 (ENSG00000110076), MEP1A (ENSG00000112818), NRP2 (ENSG00000118257), CUZD1 (ENSG00000138161), MFGE8 (ENSG00000140545), MEP1B (ENSG00000141434), PDGFC (ENSG00000145431), CNTNAP4 (ENSG00000152910), CNTNAP3B (ENSG00000154529), CNTNAP5 (ENSG00000155052), 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 1 — P78357 (reviewed: P78357)

Alternative names: Neurexin IV, Neurexin-4, p190

All UniProt accessions (2): P78357, K7EMM9

UniProt curated annotations — full annotation on UniProt →

Function. Required, with CNTNAP2, for radial and longitudinal organization of myelinated axons. Plays a role in the formation of functional distinct domains critical for saltatory conduction of nerve impulses in myelinated nerve fibers. Demarcates the paranodal region of the axo-glial junction. In association with contactin involved in the signaling between axons and myelinating glial cells.

Subunit / interactions. Interacts with CNTN1/contactin in cis form.

Subcellular location. Membrane. Cell junction. Paranodal septate junction.

Tissue specificity. Predominantly expressed in brain. Weak expression detected in ovary, pancreas, colon, lung, heart, intestine and testis.

Disease relevance. Lethal congenital contracture syndrome 7 (LCCS7) [MIM:616286] A form of lethal congenital contracture syndrome, an autosomal recessive disorder characterized by degeneration of anterior horn neurons, extreme skeletal muscle atrophy and congenital non-progressive joint contractures. The contractures can involve the upper or lower limbs and/or the vertebral column, leading to various degrees of flexion or extension limitations evident at birth. LCCS7 is a severe axoglial disease characterized by congenital distal joint contractures, polyhydramnios, reduced fetal movements, and motor paralysis leading to death early in the neonatal period. The disease is caused by variants affecting the gene represented in this entry. Neuropathy, congenital hypomyelinating, 3 (CHN3) [MIM:618186] A form of congenital hypomyelinating neuropathy, a neurologic disorder characterized by early-onset hypotonia, areflexia, distal muscle weakness, and very slow nerve conduction velocities (NCV) resulting from improper myelination of axons. In its extreme form, it may present with severe joint contractures or arthrogryposis multiplex congenita and respiratory insufficiency. In less severe cases patients may achieve walking. Patients lack both active myelin breakdown and well-organized onion bulbs on sural nerve biopsies, have absence of inflammation, and show hypomyelination of most or all fibers. CHN3 is a severe autosomal recessive form characterized by onset of neurogenic muscle impairment in utero. Affected individuals have profoundly impaired psychomotor development and may die in infancy or early childhood. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the neurexin family.

RefSeq proteins (1): NP_003623* (*=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
IPR003585	Neurexin-like	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 (61 total): glycosylation site 17, sequence variant 14, disulfide bond 11, domain 8, compositionally biased region 3, topological domain 2, signal peptide 1, chain 1, region of interest 1, short sequence motif 1, modified residue 1, transmembrane region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P78357-F1	81.51	0.50

Functional residue map

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

Post-translational modifications (1): 1383

Disulfide bonds (11): 25–168, 323–355, 506–538, 544–555, 549–564, 566–576, 930–957, 961–974, 968–983, 985–995, 1209–1250

Glycosylation sites (17): 120, 128, 276, 420, 499, 518, 597, 653, 664, 763, 804, 843, 860, 948, 956, 1078, 1147

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-447043	Neurofascin interactions

MSigDB gene sets: 320 (showing top): AHRARNT_01, GOBP_NEUROMUSCULAR_JUNCTION_DEVELOPMENT, GGGACCA_MIR133A_MIR133B, GOBP_MUSCLE_TISSUE_DEVELOPMENT, XU_GH1_AUTOCRINE_TARGETS_UP, MODULE_64, AAGCCAT_MIR135A_MIR135B, GOBP_GLIAL_CELL_DEVELOPMENT, GOBP_STRIATED_MUSCLE_CELL_DIFFERENTIATION, GOBP_CELLULAR_COMPONENT_MAINTENANCE, GOBP_NEUROGENESIS, GOBP_NEUROMUSCULAR_PROCESS_CONTROLLING_BALANCE, STARK_HYPPOCAMPUS_22Q11_DELETION_UP, CCANNAGRKGGC_UNKNOWN, CAGCAGG_MIR370

GO Biological Process (22): protein localization to paranode region of axon (GO:0002175), mitochondrion organization (GO:0007005), cytoskeleton organization (GO:0007010), cell adhesion (GO:0007155), signal transduction (GO:0007165), axonogenesis (GO:0007409), neuronal action potential propagation (GO:0019227), central nervous system myelination (GO:0022010), myelination in peripheral nervous system (GO:0022011), paranodal junction assembly (GO:0030913), neuron projection morphogenesis (GO:0048812), neuromuscular process controlling posture (GO:0050884), neuromuscular process controlling balance (GO:0050885), protein localization to juxtaparanode region of axon (GO:0071205), regulation of synapse maturation (GO:0090128), postsynaptic density organization (GO:0097106), neuromuscular junction development, skeletal muscle fiber (GO:0098529), paranodal junction maintenance (GO:1990227), central nervous system development (GO:0007417), neuron projection development (GO:0031175), myelination (GO:0042552), neuromuscular process (GO:0050905)

GO Molecular Function (3): SH3 domain binding (GO:0017124), signaling receptor activity (GO:0038023), protein binding (GO:0005515)

GO Cellular Component (5): membrane (GO:0016020), paranodal junction (GO:0033010), paranode region of axon (GO:0033270), glutamatergic synapse (GO:0098978), anchoring junction (GO:0070161)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
L1CAM interactions	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein localization to axon	2
organelle organization	2
cellular process	2
myelination	2
musculoskeletal movement	2
neuromuscular process	2
cellular anatomical structure	2
cell communication	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
cell morphogenesis involved in neuron differentiation	1
neuron projection morphogenesis	1
axon development	1
transmission of nerve impulse	1
nervous system process	1
action potential propagation	1
oligodendrocyte development	1
axon ensheathment in central nervous system	1
Schwann cell development	1
peripheral nervous system axon ensheathment	1
cell-cell junction assembly	1
cellular component assembly involved in morphogenesis	1
myelin assembly	1
neuron projection development	1
plasma membrane bounded cell projection morphogenesis	1
regulation of developmental process	1
regulation of synapse organization	1
synapse maturation	1
postsynaptic specialization organization	1
neuromuscular junction development	1
skeletal muscle fiber development	1
cell-cell junction maintenance	1
nervous system development	1
system development	1
neuron development	1
plasma membrane bounded cell projection organization	1
protein domain specific binding	1
molecular transducer activity	1
binding	1

Protein interactions and networks

STRING

1084 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CNTNAP1	NFASC	O94856	998
CNTNAP1	CNTN1	Q12860	997
CNTNAP1	CNTN2	P78432	926
CNTNAP1	EPB41L5	Q9HCM4	854
CNTNAP1	EPB41	P11171	854
CNTNAP1	KCNA2	P16389	854
CNTNAP1	PTPRZ1	P23471	853
CNTNAP1	MBP	P02686	816
CNTNAP1	NXN	Q6DKJ4	808
CNTNAP1	KCNA1	Q09470	783
CNTNAP1	GNPAT	O15228	776
CNTNAP1	FLOT1	O75955	762
CNTNAP1	PTPRB	P23467	743
CNTNAP1	GLDN	Q6ZMI3	729
CNTNAP1	SPTBN4	Q9H254	720

IntAct

110 interactions, top by confidence:

A	B	Type	Score
C1QTNF9	C1QTNF9B	psi-mi:“MI:0914”(association)	0.780
CD9	ADAM10	psi-mi:“MI:0914”(association)	0.750
SIL1	HSPA5	psi-mi:“MI:0914”(association)	0.740
FBXO6	MAN2B1	psi-mi:“MI:0914”(association)	0.640
CHST8	CANX	psi-mi:“MI:0914”(association)	0.640
HAVCR2	TCAF2	psi-mi:“MI:0914”(association)	0.530
SPINT2	UPK3BL1	psi-mi:“MI:0914”(association)	0.530
TAFA4	NRP1	psi-mi:“MI:0914”(association)	0.530
SYNGAP1	IGF2BP3	psi-mi:“MI:0914”(association)	0.530
SYNGAP1	SEC16A	psi-mi:“MI:0914”(association)	0.530
FBXO2	TMEM131L	psi-mi:“MI:0914”(association)	0.530
CLGN	NPC1	psi-mi:“MI:0914”(association)	0.530
INSL5	COCH	psi-mi:“MI:0914”(association)	0.530
CD93	RARS1	psi-mi:“MI:0914”(association)	0.530
CRP	QSOX1	psi-mi:“MI:0914”(association)	0.530
DNAJC3	DEDD	psi-mi:“MI:0914”(association)	0.530
EVA1B	NRP1	psi-mi:“MI:0914”(association)	0.530
LPAR1	TMEM223	psi-mi:“MI:0914”(association)	0.530
SYCN	AIP	psi-mi:“MI:0914”(association)	0.500
CLEC4M	GRN	psi-mi:“MI:0914”(association)	0.500
vpu	SCAMP3	psi-mi:“MI:0914”(association)	0.460
ABL1	CNTNAP1	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (98): CNTNAP1 (Affinity Capture-MS), CNTNAP1 (Affinity Capture-MS), CNTNAP1 (Affinity Capture-MS), CNTNAP1 (Affinity Capture-MS), CNTNAP1 (Affinity Capture-MS), CNTNAP1 (Affinity Capture-MS), CNTNAP1 (Affinity Capture-MS), CNTNAP1 (Affinity Capture-MS), CNTNAP1 (Affinity Capture-MS), CNTNAP1 (Affinity Capture-Western), RTN4 (Affinity Capture-Western), KCNA1 (Affinity Capture-Western), KCNA2 (Affinity Capture-Western), ATP1B3 (Two-hybrid), ATP1B3 (Reconstituted Complex)

ESM2 similar proteins: A1XQX0, A1XQX2, A1XQX8, A1XQY1, A3KN33, B4F785, D0PRN3, E9Q7X7, O09127, O54991, P29322, P35590, P48759, P54760, P54761, P78357, P97846, Q06805, Q07310, Q0V8S9, Q0V8T0, Q0V8T3, Q0V8T4, Q0V8T5, Q0V8T6, Q0V8T7, Q0V8T8, Q0V8T9, Q14393, Q28146, Q3KN41, Q4VBE4, Q5RD64, Q61592, Q63372, Q63374, Q63772, Q63HQ2, Q6P9K9, Q8WYK1

Diamond homologs: 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, P37892, P39041, P42787, P70490, P78357, P79385, P79795, P83852, P97333, P97846, P98092

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
PRKCD	“down-regulates activity”	CNTNAP1	phosphorylation
PTK6	“up-regulates activity”	CNTNAP1	phosphorylation
SRC	“down-regulates activity”	CNTNAP1	phosphorylation
CNTNAP1	“up-regulates activity”	CNTN1	relocalization

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 137 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
NCAM signaling for neurite out-growth	5	15.8×	4e-03
FCGR3A-mediated phagocytosis	6	13.1×	3e-03

GO biological processes:

GO term	Partners	Fold	FDR
ERAD pathway	7	10.6×	2e-03
regulation of cell shape	8	8.2×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	30
Likely pathogenic	19
Uncertain significance	292
Likely benign	216
Benign	51

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1032140	NM_003632.3(CNTNAP1):c.3657_3660dup (p.Leu1221fs)	Pathogenic
1195032	NM_003632.3(CNTNAP1):c.2060-2A>C	Pathogenic
1219168	NM_003632.3(CNTNAP1):c.3361C>T (p.Arg1121Ter)	Pathogenic
1444636	NC_000017.10:g.(?40834848)(40850928_?)del	Pathogenic
1452481	NM_003632.3(CNTNAP1):c.2503C>T (p.Arg835Ter)	Pathogenic
1453202	NC_000017.10:g.(?40842169)(40846199_?)del	Pathogenic
1809743	NM_003632.3(CNTNAP1):c.984del (p.Phe329fs)	Pathogenic
189261	NM_003632.3(CNTNAP1):c.3009dup (p.Glu1004Ter)	Pathogenic
189262	NM_003632.3(CNTNAP1):c.2993-1_2995del	Pathogenic
1942386	NM_003632.3(CNTNAP1):c.3767_3768del (p.Leu1256fs)	Pathogenic
204313	NM_003632.3(CNTNAP1):c.2901_2902del (p.Cys968fs)	Pathogenic
242387	NM_003632.3(CNTNAP1):c.1869G>A (p.Trp623Ter)	Pathogenic
2435747	NM_003632.3(CNTNAP1):c.1735+1G>A	Pathogenic
254173	NM_003632.3(CNTNAP1):c.1561dup (p.Leu521fs)	Pathogenic
3603932	NM_003632.3(CNTNAP1):c.1852C>T (p.Arg618Ter)	Pathogenic
3764630	NM_003632.3(CNTNAP1):c.808C>T (p.Arg270Ter)	Pathogenic
379825	NM_003632.3(CNTNAP1):c.1282C>T (p.Arg428Ter)	Pathogenic
3895870	NM_003632.3(CNTNAP1):c.1312C>T (p.Arg438Ter)	Pathogenic
4072047	NM_003632.3(CNTNAP1):c.530del (p.Phe177fs)	Pathogenic
430068	NM_003632.3(CNTNAP1):c.3475-2A>C	Pathogenic
4734614	NM_003632.3(CNTNAP1):c.180del (p.Trp61fs)	Pathogenic
4737661	NM_003632.3(CNTNAP1):c.1861C>T (p.Arg621Ter)	Pathogenic
560980	NM_003632.3(CNTNAP1):c.2015G>A (p.Trp672Ter)	Pathogenic
590912	NM_003632.3(CNTNAP1):c.635T>C (p.Leu212Pro)	Pathogenic
590913	NM_003632.3(CNTNAP1):c.2011C>T (p.Gln671Ter)	Pathogenic
590918	NM_003632.3(CNTNAP1):c.1677G>A (p.Trp559Ter)	Pathogenic
692016	NM_003632.3(CNTNAP1):c.2668C>T (p.Arg890Ter)	Pathogenic
692274	NM_003632.3(CNTNAP1):c.69C>G (p.Tyr23Ter)	Pathogenic
817524	NM_003632.3(CNTNAP1):c.2344C>T (p.Arg782Ter)	Pathogenic
984430	GRCh37/hg19 17q21.2(chr17:40842168-40846218)x1	Pathogenic

SpliceAI

3473 predictions. Top by Δscore:

Variant	Effect	Δscore
17:42683814:A:AG	acceptor_gain	1.0000
17:42683815:CCCTA:C	acceptor_loss	1.0000
17:42683816:CCTA:C	acceptor_loss	1.0000
17:42683817:CTA:C	acceptor_loss	1.0000
17:42683818:TA:T	acceptor_loss	1.0000
17:42683819:A:AG	acceptor_gain	1.0000
17:42683819:AGAC:A	acceptor_gain	1.0000
17:42683819:AGACG:A	acceptor_gain	1.0000
17:42683820:G:GG	acceptor_gain	1.0000
17:42683820:GA:G	acceptor_gain	1.0000
17:42683820:GAC:G	acceptor_gain	1.0000
17:42683820:GACG:G	acceptor_gain	1.0000
17:42683820:GACGG:G	acceptor_gain	1.0000
17:42684985:CCGCA:C	acceptor_loss	1.0000
17:42684986:CGCAG:C	acceptor_loss	1.0000
17:42684987:GCA:G	acceptor_loss	1.0000
17:42684988:CA:C	acceptor_loss	1.0000
17:42684989:A:AG	acceptor_gain	1.0000
17:42684989:A:AT	acceptor_loss	1.0000
17:42684990:G:GG	acceptor_gain	1.0000
17:42684990:GA:G	acceptor_gain	1.0000
17:42684990:GAC:G	acceptor_gain	1.0000
17:42684990:GACC:G	acceptor_gain	1.0000
17:42684990:GACCT:G	acceptor_gain	1.0000
17:42685139:G:GG	donor_gain	1.0000
17:42686139:GAG:G	donor_gain	1.0000
17:42686140:AGG:A	donor_loss	1.0000
17:42686141:GGTG:G	donor_loss	1.0000
17:42686142:G:GG	donor_gain	1.0000
17:42686142:GT:G	donor_loss	1.0000

AlphaMissense

8982 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:42685067:G:C	R147P	1.000
17:42687844:G:C	R390P	1.000
17:42688487:G:C	W444C	1.000
17:42688487:G:T	W444C	1.000
17:42688927:T:G	F503C	1.000
17:42688932:G:T	G505C	1.000
17:42689537:T:A	C549S	1.000
17:42689538:G:C	C549S	1.000
17:42689539:T:G	C549W	1.000
17:42689555:T:A	C555S	1.000
17:42689556:G:C	C555S	1.000
17:42689584:C:G	C564W	1.000
17:42689618:T:A	C576S	1.000
17:42689618:T:C	C576R	1.000
17:42689619:G:A	C576Y	1.000
17:42689619:G:C	C576S	1.000
17:42689620:C:G	C576W	1.000
17:42691192:G:C	W705C	1.000
17:42691192:G:T	W705C	1.000
17:42691816:G:C	W785C	1.000
17:42691816:G:T	W785C	1.000
17:42691899:T:C	F813S	1.000
17:42691926:T:C	F822S	1.000
17:42692591:T:A	W875R	1.000
17:42692591:T:C	W875R	1.000
17:42692593:G:C	W875C	1.000
17:42692593:G:T	W875C	1.000
17:42692594:C:G	H876D	1.000
17:42692634:T:C	L889P	1.000
17:42693324:T:G	F927C	1.000

dbSNP variants (sampled 300 via entrez): RS1000043400 (17:42686643 C>A), RS1000105463 (17:42693066 C>T), RS1000238170 (17:42692424 A>G,T), RS1000445530 (17:42686559 T>G), RS1000472563 (17:42697631 A>G), RS1000630094 (17:42691301 G>A,C,T), RS1001082990 (17:42691640 A>G), RS1001097202 (17:42680678 G>A), RS1001304871 (17:42694058 A>C,G), RS1001405246 (17:42687667 G>A), RS1001653002 (17:42693815 A>G), RS1001980689 (17:42688410 C>T), RS1002061748 (17:42689878 C>T), RS1002097313 (17:42698957 G>A), RS1002441864 (17:42694264 C>T)

Disease associations

OMIM: gene MIM:602346 | disease phenotypes: MIM:616286, MIM:618186, MIM:605253, MIM:108120, MIM:617468, MIM:208150

GenCC curated gene-disease

Disease	Classification	Inheritance
lethal congenital contracture syndrome 7	Strong	Autosomal recessive
hypomyelination neuropathy-arthrogryposis syndrome	Supportive	Autosomal recessive

Mondo (7): lethal congenital contracture syndrome 7 (MONDO:0014569), neuropathy, congenital hypomyelinating, 3 (MONDO:0020766), Charcot-Marie-Tooth disease type 4E (MONDO:0011527), arthrogryposis, distal, type 1A (MONDO:0007157), arthrogryposis multiplex congenita (MONDO:0015168), fetal akinesia deformation sequence 1 (MONDO:0100101), (MONDO:0017049)

Orphanet (4): Charcot-Marie-Tooth disease type 4E (Orphanet:99951), Distal arthrogryposis type 1 (Orphanet:1146), Arthrogryposis multiplex congenita (Orphanet:1037), Fetal akinesia deformation sequence (Orphanet:994)

HPO phenotypes

58 total (30 of 58 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000189	Narrow palate
HP:0000212	Gingival overgrowth
HP:0000218	High palate
HP:0000252	Microcephaly
HP:0000268	Dolichocephaly
HP:0000278	Retrognathia
HP:0000286	Epicanthus
HP:0000338	Hypomimic face
HP:0000347	Micrognathia
HP:0000365	Hearing impairment
HP:0000369	Low-set ears
HP:0000505	Visual impairment
HP:0000508	Ptosis
HP:0000817	Reduced eye contact
HP:0001188	Hand clenching
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001257	Spasticity
HP:0001265	Hyporeflexia
HP:0001272	Cerebellar atrophy
HP:0001284	Areflexia
HP:0001290	Generalized hypotonia
HP:0001315	Reduced tendon reflexes
HP:0001332	Dystonia
HP:0001347	Hyperreflexia
HP:0001349	Facial diplegia
HP:0001371	Flexion contracture
HP:0001376	Limitation of joint mobility
HP:0001558	Decreased fetal movement

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST004580_1	Body mass index (recreational physical activity interaction)	1.000000e-06
GCST004988_444	Breast cancer	5.000000e-09
GCST005547_13	Major depressive disorder	1.000000e-06
GCST90020025_1443	Waist-to-hip ratio adjusted for BMI	9.000000e-09
GCST90020027_415	Waist-hip index	1.000000e-08

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004340	body mass index
EFO:0008002	physical activity measurement
EFO:0007788	BMI-adjusted waist-hip ratio

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C535301	Charcot-Marie-Tooth disease, Type 4E (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Arsenic Trioxide	affects cotreatment, increases expression, decreases expression	2
Benzo(a)pyrene	affects methylation, decreases methylation	2
Tobacco Smoke Pollution	decreases expression, decreases methylation	2
Valproic Acid	affects expression, decreases expression	2
Cadmium Chloride	decreases expression, increases expression	2
aristolochic acid I	increases expression	1
dicrotophos	increases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	increases abundance, affects cotreatment, increases oxidation	1
bisphenol A	increases methylation	1
arsenite	increases methylation	1
sulforaphane	decreases expression	1
sodium arsenite	decreases expression, increases abundance	1
pyrrolidine dithiocarbamic acid	increases expression, affects cotreatment	1
perfluorooctanoic acid	increases expression	1
bathocuproine sulfonate	affects cotreatment, increases expression	1
nickel sulfate	decreases expression	1
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	1
di-n-butylphosphoric acid	affects expression	1
clothianidin	decreases expression	1
ICG 001	decreases expression	1
incobotulinumtoxinA	increases expression	1
Decitabine	affects expression	1
Sunitinib	decreases expression	1
Zoledronic Acid	increases expression	1
Acrolein	increases abundance, affects cotreatment, increases oxidation	1
Air Pollutants	affects cotreatment, increases abundance, increases oxidation	1
Arsenic	decreases expression, increases abundance	1
Ascorbic Acid	affects cotreatment, increases expression	1
Carmustine	increases expression	1

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_D1RZ	Abcam U-87MG CNTNAP1 KO	Cancer cell line	Male
CVCL_SJ46	HAP1 CNTNAP1 (-) 1	Cancer cell line	Male
CVCL_XM91	HAP1 CNTNAP1 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05902351	Not specified	RECRUITING	Natural History Study for Charcot Marie Tooth Disease
NCT01144741	Not specified	TERMINATED	Survey Study and Records Review of Treatment Outcomes in Freeman-Sheldon Syndrome
NCT05393375	Not specified	COMPLETED	Arthrogryposis Multiplex Congenita in Pediatric Age: Correlation Between MUScular MRI and Functional Evaluation
NCT05673265	Not specified	UNKNOWN	Pediatric and Adult Registry for Patients With ARThrogryposis
NCT06130592	Not specified	UNKNOWN	Technical Feasibility Study of Ultrasound Muscle Imaging in Antenatal Ultrasound
NCT07360574	Not specified	NOT_YET_RECRUITING	Piezo2-related Arthrogryposis & physiopathOLOgy 3