NLGN3
protein-codingneuroligin 3, the group of Neuroligins
Gene summary
This gene encodes a member of a family of neuronal cell surface proteins. Members of this family may act as splice site-specific ligands for beta-neurexins and may be involved in the formation and remodeling of central nervous system synapses. Mutations in this gene may be associated with autism and Asperger syndrome. Multiple transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Oct 2009]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~30.4 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: XL
Disease ID:MONDO:0010321
Submitter: Ambry Genetics
Inheritance Pattern: XL
Disease ID:MONDO:0100148
Submitter: PanelApp Australia
Inheritance Pattern: XL
Disease ID:MONDO:0010321
Submitter: G2P
Inheritance Pattern: XL
Disease ID:MONDO:0100148
Submitter: ClinGen
*NLGN3* was first reported in relation to X-linked complex neurodevelopmental disorder in 2003 (Jamain et al., PMID: 12669065). *NLGN43* encodes a member of the neuroligin family of neuronal cell-adhesion molecules that are localized postsynaptically, interact with presynaptic neurexins, and play a key role in the maturation and function of synapses. *NLGN3* variants have been identified in males with autism, intellectual disability, learning disability, or seizures. Carrier females are unaffected. Variants in *NLGN3* were curated under the disease entity complex neurodevelopmental disorder. A truncating variant reported in an individual with schizophrenia (PMID: 24126926) was not included in this curation. Four variants (nonsense, frameshift, and missense) that have been reported in five probands in four publications (PMIDs: 12669065, 25167861, 25533962, 28263302) are included in this curation. Variants in this gene segregated with disease in two additional family members. The mechanism of pathogenicity is loss of function. This gene-disease relationship is also supported by mouse models and *in vitro* functional studies that underscore a critical role of NLGN3 in synaptic transmission. In summary, there is moderate evidence supporting the relationship between *NLGN3* and X-linked complex neurodevelopmental disorder. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on August 15, 2018 (SOP Version 5). As of October 2025, this record underwent administrative updates to include an evidence summary text and update scoring to be consistent with SOP Version 11. No new evidence was added.
Inheritance Pattern: Unknown
Disease ID:MONDO:0010321
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: XL
Disease ID:MONDO:0100148
Submitter: Illumina
Clinical Genomic Database (CGD)
Manifestation: Neurologic
Intervention: General
Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to NLGN3 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_181303.2. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 16 | 37 | 3 | 56 | ||
| missense | 2 | 5 | 181 | 5 | 193 | |
| nonsense | 1 | 7 | 8 | |||
| start loss | 1 | 1 | ||||
| frameshift | 2 | 1 | 3 | 6 | ||
| splice donor/acceptor (+/-2bp) | 2 | 7 | 9 | |||
| Total | 5 | 8 | 215 | 42 | 3 | 273 |
Highest pathogenic variant AF is 0.0000036427218
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_851820.1 | 7 | MANE Select | |
| Ensembl | ENSP00000351591.4 | 7 | MANE Select | |
| RefSeq | NP_001160132.1 | 5 | Standard | |
| RefSeq | NP_001308205.1 | 6 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Cell adhesion molecules (CAMs) - Homo sapiens (human)
- Neuronal System
- Neurexins and neuroligins
- Protein-protein interactions at synapses
Biological Process
- regulation of respiratory gaseous exchange by neurological system process
- receptor-mediated endocytosis
- neuron cell-cell adhesion
- synapse assembly
- learning
Molecular Function
- protein binding
- signaling receptor activity
- neurexin family protein binding
- cell adhesion molecule binding
- scaffold protein binding
Cellular Component
- plasma membrane
- integral component of plasma membrane
- cell surface
- cell junction
- endocytic vesicle
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000358741
- Coding exons
- 7
- Length
- 26371
- Individuals with no LoFs
- 125591
- Homozygous LoFs
- 1
- Heterozygous LoFs
- 1
- Defined
- 125593
- p
- 0.00000796
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 4.21 | 151 | 382 | 0.395 | 0.0000331 | 5517 |
| Missense (PolyPhen) | 51 | 191.59 | 0.2662 | 2733 | ||
| Synonymous | 0.674 | 157 | 168 | 0.934 | 0.0000153 | 1781 |
| Loss of Function | 3.77 | 2 | 20.3 | 0.0984 | 0.00000151 | 322 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0.00027 | 0.00020 | rare |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0 | 0.0 | absent |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Cell surface protein involved in cell-cell-interactions via its interactions with neurexin family members. Plays a role in synapse function and synaptic signal transmission, and may mediate its effects by clustering other synaptic proteins. May promote the initial formation of synapses, but is not essential for this. May also play a role in glia-glia or glia-neuron interactions in the developing peripheral nervous system (By similarity). {ECO:0000250, ECO:0000269|PubMed:15620359}.;
- Disease
- DISEASE: Asperger syndrome, X-linked, 1 (ASPGX1) [MIM:300494]: A syndrome with features similar to autism. Affected individuals exhibit qualitative impairment in social interaction, as manifest by impairment in the use of non-verbal behaviors such as eye-to- eye gaze, facial expression, body postures, and gestures, failure to develop appropriate peer relationships, and lack of social sharing or reciprocity. Patients also exhibit restricted, repetitive and stereotyped patterns of behavior, interests, and activities, including abnormal preoccupation with certain activities and inflexible adherence to routines or rituals. Asperger syndrome is primarily distinguished from autism by the higher cognitive abilities and a more normal and timely development of language and communicative phrases. {ECO:0000269|PubMed:12669065}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.212
Intolerance Scores
- LoFtool
- 0.165
- RVIS EVS
- -0.54
- RVIS percentile EVS
- 20.54
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.739
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |