NRXN2

Chr 11

neurexin 2

NCBI Gene: 9379 ENSG00000110076 UniProt: P58401 OMIM: 600566

Neurexin-2 functions as a neuronal cell surface adhesion molecule and receptor that mediates cell recognition and adhesion in the nervous system. Mutations cause neurodevelopmental disorders including autism spectrum disorder, intellectual disability, and seizures. The gene follows autosomal dominant inheritance and is highly constrained against loss-of-function variants.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a member of the neurexin gene family. The products of these genes function as cell adhesion molecules and receptors in the vertebrate nervous system. These genes utilize two promoters. The majority of transcripts are produced from the upstream promoter and encode alpha-neurexin isoforms while a smaller number of transcripts are produced from the downstream promoter and encode beta-neuresin isoforms. The alpha-neurexins contain epidermal growth factor-like (EGF-like) sequences and laminin G domains, and have been shown to interact with neurexophilins. The beta-neurexins lack EGF-like sequences and contain fewer laminin G domains than alpha-neurexins. Alternative splicing and the use of alternative promoters may generate thousands of transcript variants (PMID: 12036300, PMID: 11944992).[provided by RefSeq, Jun 2010]

OMIM ResearchGenerating clinical summary…

Clinical highlights

Gene–disease validity (ClinGen)

Limited · complex neurodevelopmental disorder · AD · ClinGen 2025

not for standalone diagnostic reporting

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype) and the gene is intolerant of it in the population — truncating, frameshift and canonical splice variants carry more prior weight here than missense.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.26

LOEUF· LoF intol.

LOF

Mechanism· G2P

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.26LOEUF

pLI 0.999

Z-score 6.16

OE 0.15 (0.09–0.26)

Highly constrained

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

Missense Constraint?

4.02Z-score

OE missense 0.64 (0.60–0.69)

646 obs / 1004.9 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.15 (0.09–0.26)

0≤0.351.4

Missense OE?0.64 (0.60–0.69)

0≤0.61.4

Synonymous OE?0.99

0≤1.21.6

LoF obs/exp: 9 / 60.8Missense obs/exp: 646 / 1004.9Syn Z: 0.23

Background carrier burden — how many people carry a rare variant somewhere in NRXN2?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 35

2,174 rare PASS variants

Rare truncating (LoF)

1 in 1,200

128 rare PASS variants

Rare synonymous (reference)

1 in 48

1,231 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for NRXN2. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 38	1 in 1,600
South Asian	~43k	1 in 32	1 in 1,400
Remaining (unassigned)	~30k	1 in 27	1 in 1,300
European (Finnish)	~27k	1 in 71	1 in 900
Admixed American	~22k	1 in 32	1 in 760
African / African American	~21k	1 in 36	1 in 1,400
East Asian	~20k	1 in 27	1 in 1,000
Ashkenazi Jewish	~13k	1 in 86	1 in 2,500
Middle Eastern	~2,884	1 in 32	≈ 1 in 2,900

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 20 of 22 coding exons well covered in gnomAD exomes; exons 2, 7 marginal. Genomes: 21 of 22 (exon 7 below).? see exons ↓