NRXN1

Chr 2AR

neurexin 1

Also known as: Hs.22998, PTHSL2, SCZD17

NCBI Gene: 9378ENSG00000179915UniProt: P58400

This gene encodes a single-pass type I membrane protein that belongs to the neurexin family. Neurexins are cell-surface receptors that bind neuroligins to form Ca(2+)-dependent neurexin/neuroligin complexes at synapses in the central nervous system. This complex is required for efficient neurotransmission and is involved in the formation of synaptic contacts. Three members of this gene family have been studied in detail and are estimated to generate over 3,000 variants through the use of two alternative promoters (alpha and beta) and extensive alternative splicing in each family member. Recently, a third promoter (gamma) was identified for this gene in the 3' region. Mutations in this gene are associated with Pitt-Hopkins-like syndrome-2 and may contribute to susceptibility to schizophrenia. [provided by RefSeq, Aug 2016]

Primary Disease Associations & Inheritance

{Schizophrenia, susceptibility to, 17}MIM #621407
Pitt-Hopkins-like syndrome 2MIM #614325
AR
581
ClinVar variants
60
Pathogenic / LP
1.00
pLI score· haploinsufficient
1
Active trials
Clinical Summary— NRXN1
🧬
Gene-Disease Validity (ClinGen)
complex neurodevelopmental disorder · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
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
60 Pathogenic / Likely Pathogenic· 339 VUS of 581 total submissions
💊
Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
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.
0.25LOEUF
pLI 1.000
Z-score 6.44
OE 0.15 (0.09–0.25)
Highly constrained

Highly LoF-intolerant (top ~10% of genes)

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.
2.56Z-score
OE missense 0.76 (0.71–0.81)
681 obs / 897.1 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

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.0.15 (0.09–0.25)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.76 (0.71–0.81)
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.1.22
0≤1.21.6
LoF obs/exp: 10 / 66.8Missense obs/exp: 681 / 897.1Syn Z: -3.35

ClinVar Variant Classifications

581 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic40
Likely Pathogenic20
VUS339
Likely Benign177
Benign5
40
Pathogenic
20
Likely Pathogenic
339
VUS
177
Likely Benign
5
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
5
1
34
0
40
Likely Pathogenic
7
0
13
0
20
VUS
3
289
44
3
339
Likely Benign
0
4
65
108
177
Benign
0
0
5
0
5
Total15294161111581

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

View in ClinVar →

Protein Context — Lollipop Plot

NRXN1 · protein map & ClinVar variants

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

Gene2Phenotype Curations

NRXN1-related Pitt Hopkins-like syndrome

strong
ARLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

NRXN1-related autism

moderate
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 I; NRXN1
MIM #600565 · *

{Schizophrenia, susceptibility to, 17}

MIM #621407

Molecular basis of disorder known

Pitt-Hopkins-like syndrome 2

MIM #614325

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — NRXN1
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
NRXN1 deletion syndrome; phenotypic and penetrance data from 34 families.
Al Shehhi M et al.·Eur J Med Genet
2019
Autism spectrum disorder: neuropathology and animal models.
Varghese M et al.·Acta Neuropathol
2017Review
Clinical phenotypic spectrum of NRXN1 microdeletions and their association with epilepsy: A systematic review and meta-analysis.
Guo X et al.·Epilepsia
2025Meta-analysis
Phenotypic spectrum of NRXN1 mono- and bi-allelic deficiency: A systematic review.
Castronovo P et al.·Clin Genet
2020Review
Molecular and clinical characterization of 25 individuals with exonic deletions of NRXN1 and comprehensive review of the literature.
Béna F et al.·Am J Med Genet B Neuropsychiatr Genet
2013Review
Resequencing and association analysis of coding regions at twenty candidate genes suggest a role for rare risk variation at AKAP9 and protective variation at NRXN1 in schizophrenia susceptibility.
Suárez-Rama JJ et al.·J Psychiatr Res
2015Meta-analysis
The neurodevelopmental spectrum of synaptic vesicle cycling disorders.
John A et al.·J Neurochem
2021Review
Characterization of speech and language phenotype in children with NRXN1 deletions.
Brignell A et al.·Am J Med Genet B Neuropsychiatr Genet
2018
Homozygous exonic and intragenic NRXN1 deletion presenting as either West syndrome or autism spectrum disorder in two siblings.
Aksu Uzunhan T et al.·Clin Neurol Neurosurg
2022
Mutations in NRXN1 and NRXN2 in a patient with early-onset epileptic encephalopathy and respiratory depression.
Rochtus AM et al.·Cold Spring Harb Mol Case Stud
2019Case report
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
16P11.2 Deletion Syndrome16p11.2 Duplications1Q21.1 Deletion

Online Study of People Who Have Genetic Changes and Features of Autism: Simons Searchlight

RECRUITING
NCT01238250Simons SearchlightStarted 2010-10

External Resources

Links to major genomics databases and tools