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.

Summary from RefSeq, UniProt
Research Assistant →
0
Active trials
9
Pubs (1 yr)
74
P/LP submissions
0%
P/LP missense
0.52
LOEUF
Multiple*
Mechanism· predicted
Clinical Summary— CNTN4
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Gene-Disease Validity (ClinGen)
complex neurodevelopmental disorder · ADDisputed

Disputed — evidence questions this relationship

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
74 unique Pathogenic / Likely Pathogenic· 239 VUS of 399 total submissions
Explore recent and relevant literature in Research Assistant →

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

399 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic67
Likely Pathogenic7
VUS239
Likely Benign23
Benign59
Conflicting3
67
Pathogenic
7
Likely Pathogenic
239
VUS
23
Likely Benign
59
Benign
3
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
67
0
67
Likely Pathogenic
0
0
7
0
7
VUS
1
78
160
0
239
Likely Benign
0
3
13
7
23
Benign
0
1
54
4
59
Conflicting
—3
Total18230111398

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.

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
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