NLGN2

Chr 17

neuroligin 2

NCBI Gene: 57555 ENSG00000169992 UniProt: Q8NFZ4

This gene encodes neuroligin-2, a transmembrane scaffolding protein that clusters postsynaptic GABA receptors and modulates inhibitory synaptic signaling. Mutations cause autism spectrum disorder and intellectual disability with autosomal recessive inheritance. The gene is highly constrained against loss-of-function variants, indicating that complete loss of neuroligin-2 function has severe developmental consequences.

ResearchSummary from RefSeq, UniProt

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. [provided by RefSeq, Jul 2008]

ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.13

Clinical Summary— NLGN2

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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.

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ClinVar Variants

1 unique Pathogenic / Likely Pathogenic· 162 VUS of 268 total submissions

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Clinical Trials

2 active or recruiting trials — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.13LOEUF

pLI 1.000

Z-score 4.50

OE 0.00 (0.00–0.13)

Highly constrained

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

Missense Constraint?

4.47Z-score

OE missense 0.44 (0.40–0.49)

225 obs / 508.5 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.00 (0.00–0.13)

0≤0.351.4

Missense OE?0.44 (0.40–0.49)

0≤0.61.4

Synonymous OE?0.98

0≤1.21.6

LoF obs/exp: 0 / 23.6Missense obs/exp: 225 / 508.5Syn Z: 0.28

This gene — mechanism propensity

0.3395th %ile

GOF

0.5758th %ile

LOF

0.69top 10%

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

LOFprediction above median · LOEUF 0.13

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

268 submitted variants in ClinVar

ClinVar

Classification Summary

Likely Pathogenic1

VUS162

Likely Benign75

Benign18

Conflicting1

Likely Pathogenic

162

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0	0
Likely Pathogenic	0	1	0	0	1
VUS	10	146	5	1	162
Likely Benign	0	3	9	63	75
Benign	0	1	4	13	18
Conflicting	—				1
Total	10	151	18	77	257

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

View in ClinVar →

28 pathogenic / likely-pathogenic (of 34) ClinVar copy-number / structural variants overlap NLGN2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →