CLSTN1

Chr 1

calsyntenin 1

ENSG00000171603 UniProt: O94985 OMIM: 611321

The encoded protein functions as a postsynaptic adhesion molecule that binds to presynaptic neurexins to mediate synapse formation and also serves as a molecular adapter promoting axonal anterograde transport of vesicles. Mutations in this gene cause autosomal dominant developmental and epileptic encephalopathy with onset in infancy or early childhood. This gene is highly constrained against loss-of-function variants, indicating that such mutations are likely to be pathogenic.

OMIM ResearchSummary from RefSeq, UniProt

Postsynaptic adhesion molecule that binds to presynaptic neurexins to mediate both excitatory and inhibitory synapse formation (By similarity). Promotes synapse development by acting as a cell adhesion molecule at the postsynaptic membrane, which associates with neurexin-alpha at the presynaptic membrane (By similarity). Also functions as a cargo in axonal anterograde transport by acting as a molecular adapter that promotes KLC1 association with vesicles (PubMed:21385839). Complex formation with APBA2 and APP, stabilizes APP metabolism and enhances APBA2-mediated suppression of beta-APP40 secretion, due to the retardation of intracellular APP maturation (PubMed:12972431)

OMIM ResearchGenerating clinical summary…

Clinical highlights

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

Pubs (1 yr)

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P/LP submissions

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P/LP missense

0.31

LOEUF· LoF intol.

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Mechanism

Some data sources returned errors (1)

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.31LOEUF

pLI 0.978

Z-score 5.27

OE 0.17 (0.10–0.31)

Highly constrained

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

Missense Constraint?

1.02Z-score

OE missense 0.88 (0.82–0.95)

525 obs / 595.2 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.17 (0.10–0.31)

0≤0.351.4

Missense OE?0.88 (0.82–0.95)

0≤0.61.4

Synonymous OE?1.06

0≤1.21.6

LoF obs/exp: 8 / 46.9Missense obs/exp: 525 / 595.2Syn Z: -0.81

Background carrier burden — how many people carry a rare variant somewhere in CLSTN1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 50

1,247 rare PASS variants

Rare truncating (LoF)

1 in 4,100

83 rare PASS variants

Rare synonymous (reference)

1 in 55

554 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for CLSTN1. 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 56	1 in 6,300
South Asian	~43k	1 in 43	1 in 1,800
Remaining (unassigned)	~30k	1 in 39	1 in 6,000
European (Finnish)	~27k	1 in 130	1 in 1,700
Admixed American	~22k	1 in 46	≈ 1 in 22,000
African / African American	~21k	1 in 49	≈ 1 in 6,400
East Asian	~20k	1 in 48	1 in 980
Ashkenazi Jewish	~13k	1 in 180	≈ 1 in 13,000
Middle Eastern	~2,884	1 in 43	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): 18 of 19 coding exons well covered in gnomAD exomes; exon 1 marginal. Genomes: all 19.? see exons ↓