NLGN4X

Chr XX-linked

neuroligin 4 X-linked

Also known as: ASPGX2, AUTSX2, HLNX, HNL4X, NLGN4

NCBI Gene: 57502ENSG00000146938UniProt: Q8N0W4OMIM: 300427

The protein is a neuronal cell surface protein that mediates cell-cell interactions through binding to neurexin family members, functioning in synapse formation and remodeling. Mutations cause autism spectrum disorders including autism and Asperger syndrome with X-linked inheritance. The gene is highly constrained against loss-of-function variants (pLI 0.99, LOEUF 0.25), indicating that complete loss of protein function is likely not tolerated.

OMIMResearchSummary from RefSeq, UniProt
LOFmechanismX-linkedLOEUF 0.252 OMIM phenotypes
Clinical Summary— NLGN4X
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Gene-Disease Validity (ClinGen)
X-linked complex neurodevelopmental disorder · XLDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.99). One damaged copy is likely sufficient to cause disease.
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ClinVar Variants
136 unique Pathogenic / Likely Pathogenic· 239 VUS of 500 total submissions
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Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available
Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
LoF Constraint
0.25LOEUF
pLI 0.993
Z-score 3.84
OE 0.05 (0.02–0.25)
Highly constrained

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

Missense Constraint
2.70Z-score
OE missense 0.60 (0.54–0.68)
222 obs / 367.7 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios
LoF OE0.05 (0.02–0.25)
0≤0.351.4
Missense OE0.60 (0.54–0.68)
0≤0.61.4
Synonymous OE1.15
0≤1.21.6
LoF obs/exp: 1 / 19.1Missense obs/exp: 222 / 367.7Syn Z: -1.51

ClinVar Variant Classifications

500 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic124
Likely Pathogenic12
VUS239
Likely Benign65
Benign14
Conflicting8
124
Pathogenic
12
Likely Pathogenic
239
VUS
65
Likely Benign
14
Benign
8
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
4
2
118
0
124
Likely Pathogenic
2
0
10
0
12
VUS
6
195
34
4
239
Likely Benign
0
15
2
48
65
Benign
0
0
11
3
14
Conflicting
—8
Total1221217555462

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

View in ClinVar →

Protein Context — Lollipop Plot

NLGN4X · protein map & ClinVar variants

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

3D Protein StructureAlphaFold
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
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