DAB1

Chr 1AD

DAB adaptor protein 1

Also known as: SCA37

NCBI Gene: 1600 ENSG00000173406 UniProt: O75553 OMIM: 603448

DAB1 encodes a signaling adapter protein that mediates reelin signaling to regulate neuronal migration and differentiation during brain development. Mutations cause spinocerebellar ataxia 37, inherited in an autosomal dominant pattern. The gene is highly constrained against loss-of-function variants (pLI 0.999, LOEUF 0.215), indicating that complete loss of function is likely incompatible with normal development.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

The laminar organization of multiple neuronal types in the cerebral cortex is required for normal cognitive function. In mice, the disabled-1 gene plays a central role in brain development, directing the migration of cortical neurons past previously formed neurons to reach their proper layer. This gene is similar to disabled-1, and the protein encoded by this gene is thought to be a signal transducer that interacts with protein kinase pathways to regulate neuronal positioning in the developing brain. [provided by RefSeq, Jan 2017]

OMIM ResearchGenerating clinical summary…

MultiplemechanismADLOEUF 0.211 OMIM phenotype

Clinical Summary— DAB1

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.21LOEUF

pLI 0.999

Z-score 4.67

OE 0.07 (0.03–0.21)

Highly constrained

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

Missense Constraint?

1.52Z-score

OE missense 0.76 (0.69–0.85)

245 obs / 321.6 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.07 (0.03–0.21)

0≤0.351.4

Missense OE?0.76 (0.69–0.85)

0≤0.61.4

Synonymous OE?0.90

0≤1.21.6

LoF obs/exp: 2 / 29.3Missense obs/exp: 245 / 321.6Syn Z: 0.90

This gene — mechanism propensity

0.3395th %ile

GOF

0.4481th %ile

LOF

0.65top 25%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFprediction above median · LOEUF 0.21

GOF1 literature citation

Literature Evidence

GOFIn this regard, our data support that a gain-of-function mutation by upregulation of DAB1 alternate isoforms underlies SCA37 with mislocalization of Purkinje neurons in the cerebellar cortex reflecting improper positioning and selective migration deficits.1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References