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10 sources retrieved · Most recent: April 2026 · Index updated 15 days ago
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CNTNAP4
contactin associated protein family member 4
Chromosome 16 · 16q23.1
NCBI Gene: 85445Ensembl: ENSG00000152910.19HGNC: HGNC:18747UniProt: A0A087WTA1
31PubMed Papers
20Diseases
0Drugs
0Pathogenic Variants
DATA QUALITY
✓ Experimental GO Evidence✓ Swiss-Prot Reviewed
protein bindingsynapsenervous system developmentregulation of synaptic transmission, dopaminergicmathematical abilitysmoking initiationsubstance-related disordercervical carcinoma
✦AI Summary

CNTNAP4 (contactin-associated protein-like 4) is a presynaptic transmembrane protein belonging to the neurexin superfamily that plays critical roles in neurotransmitter regulation and neural development 1. The protein functions as a key regulator of both dopaminergic and GABAergic synaptic transmission, with deficiency leading to decreased GABA release and increased dopamine release 2. Mechanistically, CNTNAP4 regulates GABAergic signaling through interactions with GABAA receptor β2/3 subunits and GABAA receptor-associated protein (GABARAP), influencing receptor membrane localization without affecting total protein levels 3. The protein also serves as a receptor for neural EGFL-like 1 (Nell-1), mediating osteogenic signaling through Wnt and MAPK pathways 2. CNTNAP4 deficiency is clinically significant across multiple disorders. In Parkinson's disease, reduced CNTNAP4 expression in dopaminergic neurons induces α-synuclein pathology, neurodegeneration, and motor dysfunction through disrupted mitophagy and increased neuroinflammation via astrocyte-microglia C3-C3aR signaling 41. The gene is also implicated in autism spectrum disorders, with knockout mice displaying repetitive behaviors and altered brain-testicular gene expression affecting mitochondrial function and synaptic signaling 5. Additionally, CNTNAP4 expression changes are associated with epilepsy susceptibility and osteosarcoma progression, highlighting its broad pathological relevance 36.

Sources cited
1
CNTNAP4 is a presynaptic protein in the neurexin superfamily that regulates dopaminergic transmission and is linked to Parkinson's disease pathogenesis
PMID: 32194851
2
CNTNAP4 knockout mice show decreased GABA and increased dopamine release, and the protein serves as a receptor for Nell-1 in osteogenic signaling
PMID: 29905970
3
CNTNAP4 regulates GABAergic transmission through interactions with GABAA receptor subunits and affects epilepsy susceptibility
PMID: 28968899
4
CNTNAP4 deficiency exacerbates α-synuclein pathology in Parkinson's disease through astrocyte-microglia C3-C3aR pathway
PMID: 37087484
5
CNTNAP4 deletion affects mitochondrial function and synaptic signaling in autism spectrum disorder, with alterations in both brain and testicular tissues
PMID: 40262286
6
CNTNAP4 regulates osteosarcoma disease progression through MAPK/ERK signaling and interactions with NELL-1
PMID: 36599925
Disease Associationsⓘ20
mathematical abilityOpen Targets
0.40Moderate
smoking initiationOpen Targets
0.35Weak
substance-related disorderOpen Targets
0.35Weak
cervical carcinomaOpen Targets
0.34Weak
male reproductive organ cancerOpen Targets
0.32Weak
type 1 diabetes mellitusOpen Targets
0.30Weak
smoking behaviorOpen Targets
0.30Weak
alcohol drinkingOpen Targets
0.29Weak
brain cancerOpen Targets
0.27Weak
cardiomyopathyOpen Targets
0.25Weak
head and neck malignant neoplasiaOpen Targets
0.25Weak
musculoskeletal system diseaseOpen Targets
0.24Weak
nervous system cancerOpen Targets
0.21Weak
placental retentionOpen Targets
0.20Weak
pituitary gland diseaseOpen Targets
0.16Weak
adolescent idiopathic scoliosisOpen Targets
0.12Weak
Abnormality of limbsOpen Targets
0.10Weak
adrenal gland hyperfunctionOpen Targets
0.10Weak
jaw diseaseOpen Targets
0.10Weak
Parkinson diseaseOpen Targets
0.08Suggestive
Pathogenic Variants
No pathogenic variants reported on ClinVar for this gene.
View on ClinVar ↗
Related Genes
NRCAMProtein interaction89%CNTN5Protein interaction89%APBA1Protein interaction78%CHL1Protein interaction73%TIAM1Protein interaction72%BAIAP3Shared pathway25%
Tissue Expression6 tissues
Brain
100%
Liver
1%
Bone Marrow
0%
Ovary
0%
Heart
0%
Lung
0%
Gene Interaction Network
Click a node to explore
CNTNAP4NRCAMCNTN5APBA1CHL1TIAM1BAIAP3
PROTEIN STRUCTURE
Preparing viewer…
PDB4NXQ · 2.10 Å · X-ray
View on RCSB ↗
Constraintⓘ
LOEUFⓘ
0.83LoF Tolerant
pLIⓘ
0.00Tolerant
Observed/Expected LoF0.68 [0.56–0.83]
RankingsWhere CNTNAP4 stands among ~20K protein-coding genes
  • #11,688of 20,598
    Most Researched31
  • #7,102of 17,882
    Most Constrained (LOEUF)0.83
Genes detectedCNTNAP4
Sources retrieved10 papers
Response time—
📄 Sources
10▼
1
Cntnap4 partial deficiency exacerbates α-synuclein pathology through astrocyte-microglia C3-C3aR pathway.
PMID: 37087484
Cell Death Dis · 2023
1.00
2
Investigation of the transcriptome and metabolome of the cerebral cortex and testes in Cntnap4-deficient mice.
PMID: 40262286
J Psychiatr Res · 2025
0.90
3
CNTNAP4 signaling regulates osteosarcoma disease progression.
PMID: 36599925
NPJ Precis Oncol · 2023
0.80
4
CNTNAP4 deficiency in dopaminergic neurons initiates parkinsonian phenotypes.
PMID: 32194851
Theranostics · 2020
0.70
5
CNTNAP4 Impacts Epilepsy Through GABAA Receptors Regulation: Evidence From Temporal Lobe Epilepsy Patients and Mouse Models.
PMID: 28968899
Cereb Cortex · 2018
0.60