REEP1

Chr 2

receptor accessory protein 1

Also known as: C2orf23, DSMA6, HMN5B, HMND12, HMNR6, SPG31, Yip2a

NCBI Gene: 65055ENSG00000068615UniProt: Q9H902

This gene encodes a mitochondrial protein that functions to enhance the cell surface expression of odorant receptors. Mutations in this gene cause spastic paraplegia autosomal dominant type 31, a neurodegenerative disorder. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2009]

Primary Disease Associations & Inheritance

UniProtSpastic paraplegia 31, autosomal dominant
UniProtNeuronopathy, distal hereditary motor, autosomal dominant 12
UniProtNeuronopathy, distal hereditary motor, autosomal recessive 6
509
ClinVar variants
97
Pathogenic / LP
0.99
pLI score· haploinsufficient
0
Active trials
Clinical Summary— REEP1
⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.99). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
97 Pathogenic / Likely Pathogenic· 177 VUS of 509 total submissions
Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
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.
0.23LOEUF
pLI 0.986
Z-score 3.34
OE 0.00 (0.00–0.23)
Highly constrained

Highly LoF-intolerant (top ~10% 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.
1.35Z-score
OE missense 0.66 (0.55–0.79)
80 obs / 122.1 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.0.00 (0.00–0.23)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.66 (0.55–0.79)
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.1.06
0≤1.21.6
LoF obs/exp: 0 / 13.0Missense obs/exp: 80 / 122.1Syn Z: -0.33

ClinVar Variant Classifications

509 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic64
Likely Pathogenic33
VUS177
Likely Benign84
Benign36
Conflicting12
64
Pathogenic
33
Likely Pathogenic
177
VUS
84
Likely Benign
36
Benign
12
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
32
3
28
1
64
Likely Pathogenic
14
9
10
0
33
VUS
9
114
52
2
177
Likely Benign
0
16
45
23
84
Benign
0
1
34
1
36
Conflicting
—12
Total5514316927406

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

View in ClinVar →

Protein Context — Lollipop Plot

REEP1 · protein map & ClinVar variants

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

OMIM — Genotype-Phenotype

OMIM

No OMIM entries found.

Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Clinical and genetic spectra of 1550 index patients with hereditary spastic paraplegia.
Méreaux JL et al.·Brain
2022Cohort
Distal hereditary motor neuropathies.
Tazir M et al.·Rev Neurol (Paris)
2024Review
A complete overview of REEP1: old and new insights on its role in hereditary spastic paraplegia and neurodegeneration.
Guglielmi A·Rev Neurosci
2020Review
Clinical and genetic study of a novel mutation in the REEP1 gene.
Liu SG et al.·Synapse
2009
Childhood-Onset Hereditary Spastic Paraplegia (HSP): A Case Series and Review of Literature.
Panwala TF et al.·Pediatr Neurol
2022Review
REEP1 and REEP2 proteins are preferentially expressed in neuronal and neuronal-like exocytotic tissues.
Hurt CM et al.·Brain Res
2014
A clinical and genetic study of SPG31 in Japan.
Hata T et al.·J Hum Genet
2022
REEP1 Accumulation Disrupts ER Integrity and Drives Spinal Motoneuron Degeneration in Distal Hereditary Motor Neuropathy.
Bock A et al.·Adv Sci (Weinh)
2026
Hereditary spastic paraplegia due to a novel mutation of the REEP1 gene: Case report and literature review.
Richard S et al.·Medicine (Baltimore)
2017Review
[Autosomal dominant spastic paraplegias].
Rudenskaya GE et al.·Zh Nevrol Psikhiatr Im S S Korsakova
2021
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