RTN4R

Chr 22AD

reticulon 4 receptor

Also known as: NGR, NOGOR, NgR1

NCBI Gene: 65078 ENSG00000040608 UniProt: Q9BZR6 OMIM: 605566

This gene encodes a receptor for multiple myelin-associated proteins (reticulon 4, oligodendrocyte myelin glycoprotein, and myelin-associated glycoprotein) that mediates axonal growth inhibition and regulates axon regeneration, neuronal plasticity, and synaptic formation in the central nervous system. Mutations cause autosomal dominant susceptibility to schizophrenia. The gene is highly constrained against loss-of-function variants (pLI 0.96, LOEUF 0.3), suggesting that complete loss of function is likely incompatible with normal development.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes the receptor for reticulon 4, oligodendrocyte myelin glycoprotein and myelin-associated glycoprotein. This receptor mediates axonal growth inhibition and may play a role in regulating axonal regeneration and plasticity in the adult central nervous system. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

MultiplemechanismADLOEUF 0.301 OMIM phenotype

Clinical Summary— RTN4R

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.96). 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?

0.30LOEUF

pLI 0.959

Z-score 2.93

OE 0.00 (0.00–0.30)

Highly constrained

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

Missense Constraint?

1.13Z-score

OE missense 0.82 (0.74–0.91)

265 obs / 322.2 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.00 (0.00–0.30)

0≤0.351.4

Missense OE?0.82 (0.74–0.91)

0≤0.61.4

Synonymous OE?0.99

0≤1.21.6

LoF obs/exp: 0 / 10.0Missense obs/exp: 265 / 322.2Syn Z: 0.13

This gene — mechanism propensity

0.4983th %ile

GOF

0.6834th %ile

LOF

0.60top 25%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and gain-of-function). The Badonyi & Marsh model scores gain-of-function highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports loss-of-function (haploinsufficiency). Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOF1 literature citation · LOEUF 0.30

GOFprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

LOFSchizophrenia or schizoaffective disorders are rather common features in patients with DiGeorge/velocardiofacial syndrome (DGS, 188400/VCFS, 192430) as a result of 22q11.2 haploinsufficiency. Sinibaldi et al. (2004) evaluated the RTN4R gene, which maps within the DGS/VCFS critical region, as a poten1

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

References