CBLN2

Chr 18

cerebellin 2 precursor

NCBI Gene: 147381 ENSG00000141668 UniProt: Q8IUK8 OMIM: 600433

The CBLN2 protein acts as a synaptic organizer that is essential for long-term maintenance of excitatory synapses, functioning in trans-synaptic complexes with neurexins and GRID1 to regulate NMDA and AMPA receptor activity at hippocampal synapses. Mutations in CBLN2 cause neurodevelopmental disorders with intellectual disability and seizures, inherited in an autosomal recessive pattern. The gene shows relatively low constraint to loss-of-function variation (pLI 0.12, LOEUF 1.17).

OMIM ResearchSummary from RefSeq, UniProt

Contributes to signaling receptor regulator activity. Involved in trans-synaptic signaling by trans-synaptic complex, modulating synaptic transmission. Is active in synapse. [provided by Alliance of Genome Resources, Jun 2026]

OMIM ResearchGenerating clinical summary…

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.17

LOEUF

Multiple*

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.17LOEUF

pLI 0.122

Z-score 1.35

OE 0.37 (0.15–1.17)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

1.87Z-score

OE missense 0.52 (0.42–0.64)

62 obs / 119.4 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.37 (0.15–1.17)

0≤0.351.4

Missense OE?0.52 (0.42–0.64)

0≤0.61.4

Synonymous OE?1.13

0≤1.21.6

LoF obs/exp: 2 / 5.4Missense obs/exp: 62 / 119.4Syn Z: -0.78

Background carrier burden — how many people carry a rare variant somewhere in CBLN2?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 220

269 rare PASS variants

Rare truncating (LoF)

1 in 2,000

26 rare PASS variants

Rare synonymous (reference)

1 in 310

157 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for CBLN2. 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 580	1 in 1,200
South Asian	~43k	1 in 550	1 in 370
Remaining (unassigned)	~30k	1 in 200	1 in 570
European (Finnish)	~27k	1 in 1,500	≈ 1 in 5,600
Admixed American	~22k	1 in 460	1 in 3,500
African / African American	~21k	1 in 420	1 in 2,500
East Asian	~20k	1 in 270	none seen
Ashkenazi Jewish	~13k	1 in 550	none seen
Middle Eastern	~2,884	1 in 150	none seen

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): All 3 coding exons well covered in gnomAD exomes and genomes.? see exons ↓