CNTN4

Chr 3

contactin 4

Also known as: AXCAM, BIG-2

NCBI Gene: 152330ENSG00000144619UniProt: Q8IWV2

The protein is a glycosylphosphatidylinositol-anchored neuronal membrane protein that mediates cell surface interactions during nervous system development and promotes neurite outgrowth. Mutations cause 3p deletion syndrome and are associated with autism spectrum disorders, with autosomal dominant inheritance. The gene is highly intolerant to loss-of-function variants, indicating that complete protein loss is likely incompatible with normal development.

ResearchSummary from RefSeq, UniProt
MultiplemechanismLOEUF 0.52
Clinical Summary— CNTN4
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Gene-Disease Validity (ClinGen)
complex neurodevelopmental disorder · ADDisputed

Disputed — evidence questions this relationship

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Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
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ClinVar Variants
22 unique Pathogenic / Likely Pathogenic· 234 VUS of 400 total submissions
Explore recent and relevant literature in Research Assistant →
Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
LoF Constraint
0.52LOEUF
pLI 0.000
Z-score 4.46
OE 0.36 (0.25–0.52)
Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint
0.57Z-score
OE missense 0.93 (0.87–1.00)
524 obs / 562.1 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios
LoF OE0.36 (0.25–0.52)
0≤0.351.4
Missense OE0.93 (0.87–1.00)
0≤0.61.4
Synonymous OE1.21
0≤1.21.6
LoF obs/exp: 20 / 56.0Missense obs/exp: 524 / 562.1Syn Z: -2.37
DN
0.76top 25%
GOF
0.6834th %ile
LOF
0.3259th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median
GOFprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

400 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic20
Likely Pathogenic2
VUS234
Likely Benign22
Benign101
Conflicting2
20
Pathogenic
2
Likely Pathogenic
234
VUS
22
Likely Benign
101
Benign
2
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
20
0
20
Likely Pathogenic
0
0
2
0
2
VUS
1
147
86
0
234
Likely Benign
0
5
1
16
22
Benign
0
4
85
12
101
Conflicting
—2
Total115619428381

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

CNTN4 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

3D Protein StructureAlphaFold

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →
Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Genetic variants in PPARGC1B and CNTN4 are associated with thromboxane A(2) formation and with cardiovascular event free survival in the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT).
McCarthy NS et al.·Atherosclerosis
2018
Clinicopathological characteristics of pheochromocytoma/paraganglioma and screening of prognostic markers.
Lei J et al.·J Surg Oncol
2023
Clinical significance of germline telomere length and associated genetic factors in patients with neuroblastoma.
Bae JS et al.·Sci Rep
2022Cohort
Genetic Alterations in a Large Population of Italian Patients Affected by Neurodevelopmental Disorders.
Ranieri A et al.·Genes (Basel)
2024Cohort
Aberrant calcium signaling and neuronal activity in the L271H CACNA1D (Cav1.3) iPSC model of neurodevelopmental disease.
Tisch M et al.·Mol Psychiatry
2026Functional
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Cntn4 Gene Deficiency Promotes Autism-Like Phenotypes Associated with Gut Microbiota Perturbations and Gut-Brain Axis Metabolomic Alterations in Mice.
Wang M et al.·Mol Neurobiol
2025
CNTN4 modulates neural elongation through interplay with APP.
Bamford RA et al.·Open Biol
2024Open Access
MiR-148a-3p attenuates apoptosis and inflammation by targeting CNTN4 in atherosclerosis.
Wang K et al.·Ann Transl Med
2022Open Access
Erratum: Effect of the Minor C Allele of CNTN4 rs2619566 on Medial Hypothalamic Connectivity in Early-Stage Patients of Chinese Han Ancestry with Sporadic Amyotrophic Lateral Sclerosis [Corrigendum].
·Neuropsychiatr Dis Treat
2022Open AccessCohort
Effect of the Minor C Allele of CNTN4 rs2619566 on Medial Hypothalamic Connectivity in Early-Stage Patients of Chinese Han Ancestry with Sporadic Amyotrophic Lateral Sclerosis.
Wang Y et al.·Neuropsychiatr Dis Treat
2022Open AccessCohort
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients