CLSTN1

Chr 1

calsyntenin 1

Also known as: ALC-ALPHA, CDHR12, CST-1, CSTN1, XB31alpha, alcalpha1, alcalpha2

NCBI Gene: 22883 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

This gene is a member of the calsyntenin family, a subset of the cadherin superfamily. The encoded transmembrane protein, also known as alcadein-alpha, is thought to bind to kinesin-1 motors to mediate the axonal anterograde transport of certain types of vesicle. Amyloid precursor protein (APP) is trafficked via these vesicles and so this protein is being investigated to see how it might contribute to the mechanisms underlying Alzheimer's disease. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2014]

OMIM ResearchGenerating clinical summary…

LOEUF 0.31

Clinical Summary— CLSTN1

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.98). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

144 VUS of 185 total submissions

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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

ClinVar Variant Classifications

185 submitted variants in ClinVar

ClinVar

Classification Summary

VUS144

Likely Benign8

Benign3

144

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0
Likely Pathogenic	0	0	0	0
VUS	144	0	0	144
Likely Benign	5	1	2	8
Benign	1	0	2	3
Total	150	1	4	155

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

View in ClinVar →

35 pathogenic / likely-pathogenic (of 47) ClinVar copy-number / structural variants overlap CLSTN1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →