RELN

Chr 7ADAR

reelin

Also known as: ETL7, LIS2, PRO1598, RL

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.

OMIMResearchSummary from RefSeq, OMIM, UniProt, Mechanism
LOFmechanismAD/ARLOEUF 0.182 OMIM phenotypes
Clinical SummaryRELN
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Gene-Disease Validity (ClinGen)
lissencephaly with cerebellar hypoplasia · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

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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Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

LoF intolerant — likely haploinsufficient
LoF Constraint
0.18LOEUF
pLI 1.000
Z-score 11.05
OE 0.12 (0.090.18)
Highly constrained

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

Missense Constraint
2.25Z-score
OE missense 0.85 (0.820.89)
1577 obs / 1849.2 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios
LoF OE0.12 (0.090.18)
00.351.4
Missense OE0.85 (0.820.89)
00.61.4
Synonymous OE1.05
01.21.6
LoF obs/exp: 23 / 185.3Missense obs/exp: 1577 / 1849.2Syn Z: -1.09
Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗
definitiveRELN-related lissencephalyLOFAR

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

DN
0.3296th %ile
GOF
0.3887th %ile
LOF
0.71top 10%

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Literature Evidence

DNPreviously reported functional studies demonstrated severe reduction in overall RELN secretion caused by heterozygous missense variants p.Cys539Arg and p.Arg3207Cys associated with lissencephaly suggesting a dominant-negative effect.PMID:35769015

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

ClinVar Variant Classifications

0 submitted variants in ClinVar

Protein Context — Lollipop Plot

RELN · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

3D Protein StructureAlphaFold
Clinical Literature
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