NRXN3

Chr 14

neurexin 3

Also known as: C14orf60

NCBI Gene: 9369ENSG00000021645UniProt: Q9HDB5

This gene encodes a member of a family of proteins that function in the nervous system as receptors and cell adhesion molecules. Extensive alternative splicing and the use of alternative promoters results in multiple transcript variants and protein isoforms for this gene, but the full-length nature of many of these variants has not been determined. Transcripts that initiate from an upstream promoter encode alpha isoforms, which contain epidermal growth factor-like (EGF-like) sequences and laminin G domains. Transcripts initiating from the downstream promoter encode beta isoforms, which lack EGF-like sequences. Genetic variation at this locus has been associated with a range of behavioral phenotypes, including alcohol dependence and autism spectrum disorder. [provided by RefSeq, Dec 2012]

203
ClinVar variants
11
Pathogenic / LP
1.00
pLI score· haploinsufficient
0
Active trials
Clinical Summary— NRXN3
⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
11 Pathogenic / Likely Pathogenic· 136 VUS of 203 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Dual constrained — LoF & missense intolerant
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.11LOEUF
pLI 1.000
Z-score 5.90
OE 0.02 (0.01–0.11)
Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
3.44Z-score
OE missense 0.62 (0.57–0.68)
409 obs / 657.0 exp
Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.02 (0.01–0.11)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.62 (0.57–0.68)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.95
0≤1.21.6
LoF obs/exp: 1 / 42.5Missense obs/exp: 409 / 657.0Syn Z: 0.57

ClinVar Variant Classifications

203 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic7
Likely Pathogenic4
VUS136
Likely Benign44
Benign12
7
Pathogenic
4
Likely Pathogenic
136
VUS
44
Likely Benign
12
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
1
6
0
7
Likely Pathogenic
0
0
4
0
4
VUS
1
128
7
0
136
Likely Benign
1
5
7
31
44
Benign
0
1
5
6
12
Total21352937203

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

View in ClinVar →

Protein Context — Lollipop Plot

NRXN3 · protein map & ClinVar variants

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

Gene2Phenotype Curations

NRXN3-related autism

limited
ADLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
NEUREXIN III; NRXN3
MIM #600567 · *
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Fibromyalgia: Genetics and epigenetics insights may provide the basis for the development of diagnostic biomarkers.
D'Agnelli S et al.·Mol Pain
2019Review
Case Report-An Inherited Loss-of-Function NRXN3 Variant Potentially Causes a Neurodevelopmental Disorder with Autism Consistent with Previously Described 14q24.3-31.1 Deletions.
Feichtinger RG et al.·Genes (Basel)
2023Case report
Fibromyalgia: A Review of Related Polymorphisms and Clinical Relevance.
Janssen LP et al.·An Acad Bras Cienc
2021Review
Rare heterozygous genetic variants of NRXN and NLGN gene families involved in synaptic function and their association with neurodevelopmental disorders.
Gerik-Celebi HB et al.·Dev Neurobiol
2024
Evaluation of clinical and genetic factors in obstructive sleep apnoea.
de Lourdes Rabelo Guimarães M et al.·Acta Otorhinolaryngol Ital
2023
Locus and gene-based GWAS meta-analysis identifies new diabetic nephropathy genes.
Saeed M·Immunogenetics
2018Meta-analysis
Differential Expression of the Synapse Regulatory Proteins Neurexins in Early Diabetic Retinal Disease.
Unlu EK et al.·Invest Ophthalmol Vis Sci
2025
Evidence for reduced synaptic protein SNAP-25 in cerebrospinal fluid in major depressive disorder and schizophrenia.
Steinacker P et al.·BMJ Ment Health
2025
A rare exonic NRXN3 deletion segregating with neurodevelopmental and neuropsychiatric conditions in a three-generation Chinese family.
Yuan H et al.·Am J Med Genet B Neuropsychiatr Genet
2018Case report
A Multicenter Analysis of Abnormal Chromosomal Microarray Findings in Congenital Heart Disease.
Landis BJ et al.·J Am Heart Assoc
2023
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools