RTN2

Chr 19ARAD

reticulon 2

NCBI Gene: 6253ENSG00000125744UniProt: O75298

Inhibits amyloid precursor protein processing, probably by blocking BACE1 activity (PubMed:15286784). Enhances trafficking of the glutamate transporter SLC1A1/EAAC1 from the endoplasmic reticulum to the cell surface (By similarity). Plays a role in the translocation of SLC2A4/GLUT4 from intracellular membranes to the cell membrane which facilitates the uptake of glucose into the cell (By similarity)

Primary Disease Associations & Inheritance

Neuronopathy, distal hereditary motor, autosomal recessive 11, with spasticityMIM #620854
AR
Spastic paraplegia 12, autosomal dominantMIM #604805
AD
195
ClinVar variants
8
Pathogenic / LP
0.42
pLI score
0
Active trials
Clinical Summary— RTN2
⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.22) despite low pLI — interpret in context.
📋
ClinVar Variants
8 Pathogenic / Likely Pathogenic· 117 VUS of 195 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.42LOEUF
pLI 0.416
Z-score 4.05
OE 0.22 (0.13–0.42)
Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
0.70Z-score
OE missense 0.89 (0.81–0.98)
306 obs / 342.5 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.22 (0.13–0.42)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.89 (0.81–0.98)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.93
0≤1.21.6
LoF obs/exp: 7 / 31.5Missense obs/exp: 306 / 342.5Syn Z: 0.72

ClinVar Variant Classifications

195 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic5
Likely Pathogenic3
VUS117
Likely Benign61
Benign3
Conflicting6
5
Pathogenic
3
Likely Pathogenic
117
VUS
61
Likely Benign
3
Benign
6
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
2
0
3
0
5
Likely Pathogenic
2
0
1
0
3
VUS
4
107
5
1
117
Likely Benign
0
6
14
41
61
Benign
0
0
1
2
3
Conflicting
—6
Total81132444195

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

RTN2 · protein map & ClinVar variants

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
RETICULON 2; RTN2
MIM #603183 · *

Neuronopathy, distal hereditary motor, autosomal recessive 11, with spasticity

MIM #620854

Molecular basis of disorder known

Autosomal recessive

Spastic paraplegia 12, autosomal dominant

MIM #604805

Molecular basis of disorder known

Autosomal dominant
📖
GeneReview available — RTN2
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
RTN2 deficiency results in an autosomal recessive distal motor neuropathy with lower limb spasticity.
Maroofian R et al.·Brain
2024
New phenotype of RTN2-related spectrum: Complicated form of spastic paraplegia-12.
Tian W et al.·Ann Clin Transl Neurol
2022
[Autosomal dominant spastic paraplegias].
Rudenskaya GE et al.·Zh Nevrol Psikhiatr Im S S Korsakova
2021
Amyotrophic lateral sclerosis with primary progressive aphasia: a case report and literature review.
Zhang A et al.·Neuro Endocrinol Lett
2022Case report
Mutations in the ER-shaping protein reticulon 2 cause the axon-degenerative disorder hereditary spastic paraplegia type 12.
Montenegro G et al.·J Clin Invest
2012
In silico development and clinical validation of novel 8 gene signature based on lipid metabolism related genes in colon adenocarcinoma.
Jiang C et al.·Pharmacol Res
2021
Identification of lncRNA and mRNA Biomarkers in Osteoarthritic Degenerative Meniscus by Weighted Gene Coexpression Network and Competing Endogenous RNA Network Analysis.
Zhao J et al.·Biomed Res Int
2020
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools