DCLK1

Chr 13

doublecortin like kinase 1

Also known as: CL1, CLICK1, DCAMKL1, DCDC3A, DCLK

NCBI Gene: 9201 ENSG00000133083 UniProt: O15075

The protein is a serine/threonine kinase containing doublecortin domains that bind microtubules and regulate microtubule polymerization, functioning in neuronal migration, retrograde transport, and neurogenesis in the developing and mature nervous system. Mutations cause autosomal dominant epileptic encephalopathy with intellectual disability and developmental delay, typically presenting in early childhood. This gene is extremely intolerant to loss-of-function mutations, indicating that even single functional copies may be insufficient for normal development.

ResearchSummary from RefSeq, UniProt

This gene encodes a member of the protein kinase superfamily and the doublecortin family. The protein encoded by this gene contains two N-terminal doublecortin domains, which bind microtubules and regulate microtubule polymerization, a C-terminal serine/threonine protein kinase domain, which shows substantial homology to Ca2+/calmodulin-dependent protein kinase, and a serine/proline-rich domain in between the doublecortin and the protein kinase domains, which mediates multiple protein-protein interactions. The microtubule-polymerizing activity of the encoded protein is independent of its protein kinase activity. The encoded protein is involved in several different cellular processes, including neuronal migration, retrograde transport, neuronal apoptosis and neurogenesis. This gene is up-regulated by brain-derived neurotrophic factor and associated with memory and general cognitive abilities. Multiple transcript variants generated by two alternative promoter usage and alternative splicing have been reported, but the full-length nature and biological validity of some variants have not been defined. These variants encode different isoforms, which are differentially expressed and have different kinase activities.[provided by RefSeq, Sep 2010]

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)

—

P/LP submissions

—

P/LP missense

0.23

LOEUF· LoF intol.

LOF

Mechanism· predicted

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?

0.23LOEUF

pLI 1.000

Z-score 5.30

OE 0.10 (0.05–0.23)

Highly constrained

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

Missense Constraint?

4.40Z-score

OE missense 0.41 (0.36–0.46)

177 obs / 435.7 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.10 (0.05–0.23)

0≤0.351.4

Missense OE?0.41 (0.36–0.46)

0≤0.61.4

Synonymous OE?0.85

0≤1.21.6

LoF obs/exp: 4 / 40.4Missense obs/exp: 177 / 435.7Syn Z: 1.59

Background carrier burden — how many people carry a rare variant somewhere in DCLK1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 150

680 rare PASS variants

Rare truncating (LoF)

1 in 4,000

53 rare PASS variants

Rare synonymous (reference)

1 in 82

400 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for DCLK1. 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 220	1 in 8,100
South Asian	~43k	1 in 130	1 in 6,000
Remaining (unassigned)	~30k	1 in 110	1 in 5,000
European (Finnish)	~27k	1 in 460	1 in 3,000
Admixed American	~22k	1 in 140	1 in 3,200
African / African American	~21k	1 in 290	1 in 3,500
East Asian	~20k	1 in 180	1 in 2,300
Ashkenazi Jewish	~13k	1 in 330	none seen
Middle Eastern	~2,884	1 in 170	≈ 1 in 1,400

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 16 coding exons well covered in gnomAD exomes and genomes.? see exons ↓