RELN

Chr 7ADAR

reelin

NCBI Gene: 5649 ENSG00000189056 UniProt: P78509 OMIM: 600514

The protein is a large secreted extracellular matrix protein that controls cell positioning and neuronal migration during brain development. Mutations cause autosomal recessive lissencephaly type 2 (Norman-Roberts type) with cerebellar hypoplasia and autosomal dominant familial temporal lobe epilepsy type 7. The pathogenic mechanism involves loss of function, disrupting normal neuronal migration patterns.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

Extracellular matrix serine protease secreted by pioneer neurons that plays a role in layering of neurons in the cerebral cortex and cerebellum by coordinating cell positioning during neurodevelopment. Regulates microtubule function in neurons and neuronal migration. Binding to the extracellular domains of lipoprotein receptors VLDLR and LRP8/APOER2 induces tyrosine phosphorylation of DAB1 and modulation of TAU phosphorylation. Affects migration of sympathetic preganglionic neurons in the spinal cord, where it seems to act as a barrier to neuronal migration. Enzymatic activity is important for the modulation of cell adhesion

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

{Epilepsy, familial temporal lobe, 7}MIM #616436

Lissencephaly 2 (Norman-Roberts type)MIM #257320

Clinical highlights

Gene–disease validity (ClinGen · GenCC)

Definitive · lissencephaly with cerebellar hypoplasia · AR · ClinGen 2023
Definitive · Norman-Roberts syndrome · AR · Illumina
Strong · familial temporal lobe epilepsy 7 · AD · Labcorp Genetics (formerly Invitae)
Limited · ankylosing spondylitis · AD · Ambry Genetics — not for standalone diagnostic reporting
Disputed · complex neurodevelopmental disorder · AD · ClinGen 2023 — evidence questions this relationship

+1 more curated pair

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype) and the gene is intolerant of it in the population — truncating, frameshift and canonical splice variants carry more prior weight here than missense.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.18

LOEUF· LoF intol.

LOF

Mechanism· G2P

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.18LOEUF

pLI 1.000

Z-score 11.05

OE 0.12 (0.09–0.18)

Highly constrained

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

Missense Constraint?

2.25Z-score

OE missense 0.85 (0.82–0.89)

1577 obs / 1849.2 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.12 (0.09–0.18)

0≤0.351.4

Missense OE?0.85 (0.82–0.89)

0≤0.61.4

Synonymous OE?1.05

0≤1.21.6

LoF obs/exp: 23 / 185.3Missense obs/exp: 1577 / 1849.2Syn Z: -1.09

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

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 15

4,052 rare PASS variants

Rare truncating (LoF)

1 in 1,400

205 rare PASS variants

Rare synonymous (reference)

1 in 29

1,611 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for RELN. 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 20	1 in 1,600
South Asian	~43k	1 in 14	1 in 1,300
Remaining (unassigned)	~30k	1 in 13	1 in 450
European (Finnish)	~27k	1 in 41	1 in 1,300
Admixed American	~22k	1 in 15	1 in 950
African / African American	~21k	1 in 14	1 in 1,100
East Asian	~20k	1 in 16	1 in 1,200
Ashkenazi Jewish	~13k	1 in 65	≈ 1 in 3,300
Middle Eastern	~2,884	1 in 16	≈ 1 in 960

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): 49 of 65 coding exons well covered in gnomAD exomes; exons 8, 37, 64 poorly covered; exons 2, 6, 9, 13, 18 and 8 more marginal. Genomes: 64 of 65 (exon 35 below).? see exons ↓