NLGN3

Chr XX-linked

neuroligin 3

Also known as: HNL3

NCBI Gene: 54413ENSG00000196338UniProt: Q9NZ94

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]

Primary Disease Associations & Inheritance

{Autism susceptibility, X-linked 1}MIM #300425
X-linked
UniProtAutism, X-linked 1
1
Active trials
53
Pathogenic / LP
251
ClinVar variants
16
Pubs (1 yr)
4.2
Missense Z· constrained
0.31
LOEUF· LoF intolerant
Clinical Summary— NLGN3
🧬
Gene-Disease Validity (ClinGen)
X-linked complex neurodevelopmental disorder · XLModerate

Moderate evidence — consider for supplementary testing

⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.98). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
53 Pathogenic / Likely Pathogenic· 161 VUS of 251 total submissions
💊
Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available
📖
GeneReview available — NLGN3
Authoritative clinical overview · Recommended first read
Open GeneReview ↗
Some data sources returned errors (1)

pubtator: TimeoutError: The operation was aborted due to timeout

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Dual constrained — LoF & missense intolerant
LoF Constraint
0.31LOEUF
pLI 0.976
Z-score 3.77
OE 0.10 (0.04–0.31)
Highly constrained

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

Missense Constraint
4.21Z-score
OE missense 0.39 (0.34–0.45)
151 obs / 382.5 exp
Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios
LoF OE0.10 (0.04–0.31)
0≤0.351.4
Missense OE0.39 (0.34–0.45)
0≤0.61.4
Synonymous OE0.93
0≤1.21.6
LoF obs/exp: 2 / 20.3Missense obs/exp: 151 / 382.5Syn Z: 0.67
LOF
DN
0.3892th %ile
GOF
0.5661th %ile
LOF
0.65top 25%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · LOEUF 0.31

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

251 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic45
Likely Pathogenic8
VUS161
Likely Benign33
Benign3
Conflicting1
45
Pathogenic
8
Likely Pathogenic
161
VUS
33
Likely Benign
3
Benign
1
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
1
2
42
0
45
Likely Pathogenic
3
4
1
0
8
VUS
3
133
21
4
161
Likely Benign
0
3
6
24
33
Benign
0
0
1
2
3
Conflicting
—1
Total71427130251

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

View in ClinVar →

NLGN3 · protein map & ClinVar variants

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

Gene2Phenotype Curations

NLGN3-related autism spectrum disorders

strong
Monoallelic X HemizygousLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

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

Clinical Literature
Landmark / reviewRecent case evidence
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
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