RELN

reelin

5 disorders 2 untyped 1 causative 1 susceptibility 1 no genetic record 7q22.1 gene with protein product

HGNC:9957 Monarch NCBI Gene 5649 ENSG00000189056 UniProt P78509 OMIM 600514

Aliases: RL, PRO1598.

Normal function · from ai-gene-review (P78509, commit 79fe13b38970) · AI-generated, not KB evidence

RELN encodes reelin, a large secreted extracellular-matrix glycoprotein that assembles into signaling-competent multimers. Reelin binds the lipoprotein-family receptors VLDLR and LRP8/ApoER2, inducing receptor-associated DAB1 phosphorylation and downstream signaling that coordinates neuronal polarization, positioning, and layer formation during brain development and modulates synaptic maturation and plasticity later in life. Biallelic loss-of-function variants cause lissencephaly with cerebellar hypoplasia in humans. An intrinsic serine peptidase activity has been reported but remains disputed and is not considered an established core activity.

Secreted reelin assembles into covalent homodimers and higher-order multimers that bind the extracellular domains of VLDLR and LRP8/ApoER2. Receptor engagement induces DAB1 phosphorylation and initiates reelin-mediated signaling. This receptor-ligand activity is the core molecular function; neuronal migration, layer formation, differentiation, behavior, and synaptic phenotypes are context-dependent downstream outcomes. Intrinsic serine peptidase activity is excluded from the core function because direct studies conflict.

molecular function: lipoprotein particle receptor binding · directly involved in: reelin-mediated signaling pathway · locations: extracellular matrix · in complex: reelin complex

In the knowledge base · computed from kb/ at build time

Disorders

Relationship is the entry's genetic[].relationship_type. untyped means the entry has a genetic record for the gene but does not type it; its free-text association is shown instead.

Disorder	Relationship	Where the gene appears
Autosomal Dominant Epilepsy with Auditory Features	causative germline
Otosclerosis	susceptibility germline
Lissencephaly Spectrum Disorders	untyped Loss of function	mechanism: Reelin Signaling Deficiency subtype: RELN-related scoped to subtype: RELN-related
Schizophrenia	untyped Risk Factor	mechanism: Abnormality of GABAergic Signaling
Reelin Pathway Lissencephaly	no genetic record	mechanism: Cajal-Retzius Reelin Ligand Deficiency; VLDLR-ApoER2-DAB1 Signal Transduction Failure

ClinGen gene–disease validity · snapshot 2026-10-03 · matched to entries by MONDO

An entry matches when ClinGen's MONDO disease is the entry's own disease term, a subtype term, or an exact-match mapping. An amber status marks an entry ClinGen supports the gene for (Definitive, Strong or Moderate) whose own record does not type it. A Limited, Disputed or Refuted tier on such an entry is not a gap.

ClinGen disease	MOI	Classification	dismech entry
lissencephaly with cerebellar hypoplasia MONDO:0019450	AR	Definitive 2023-12-04	Lissencephaly Spectrum Disorders untyped Reelin Pathway Lissencephaly no genetic record
complex neurodevelopmental disorder MONDO:0100038	AD	Disputed 2023-07-19	no dismech entry

Mechanism modules · computed from kb/

reelin_terminal_translocation_lamination_failure via Reelin Pathway Lissencephaly named in the module itself

Identity from HGNC (snapshot 2026-10-01). Page layers are described in the gene pages documentation.