REEP1

Chr 2ADAR

receptor accessory protein 1

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

NCBI Gene: 65055 ENSG00000068615 UniProt: Q9H902 OMIM: 609139

The protein is required for endoplasmic reticulum network formation and shaping, linking ER tubules to the cytoskeleton and playing a role in long-term axonal maintenance. Mutations cause autosomal dominant spastic paraplegia 31 and both autosomal dominant and recessive forms of distal hereditary motor neuronopathy. The gene is highly constrained against loss-of-function variants, reflecting its essential cellular role.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

GeneReviews OMIM ResearchGenerating clinical summary…

MultiplemechanismAD/ARLOEUF 0.233 OMIM phenotypes

Clinical Summary— REEP1

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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.

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ClinVar Variants

99 unique Pathogenic / Likely Pathogenic· 192 VUS of 475 total submissions

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GeneReview available — REEP1

Authoritative clinical overview · Recommended first read

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

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?

1.35Z-score

OE missense 0.66 (0.55–0.79)

80 obs / 122.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.00 (0.00–0.23)

0≤0.351.4

Missense OE?0.66 (0.55–0.79)

0≤0.61.4

Synonymous OE?1.06

0≤1.21.6

LoF obs/exp: 0 / 13.0Missense obs/exp: 80 / 122.1Syn Z: -0.33

This gene — mechanism propensity

0.6840th %ile

GOF

0.73top 25%

LOF

0.59top 25%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function, gain-of-function and dominant-negative). 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 · 72% of P/LP variants are LoF · LOEUF 0.23

GOFprediction above median · 1 literature citation

DNprediction above median · 1 literature citation

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

DNIn in vitro functional expression studies, Lim et al. (2015) found that the A20E mutation interfered with the ability of REEP1 to facilitate ER-mitochondria interactions when coexpressed with the wildtype gene, consistent with a dominant-negative effect.1

GOFOur coexpression data, therefore, strongly argue for the association of an interaction-mediated, possibly toxic gain-of-function effect with p.102_139del (with atlastin-1 not necessarily representing the pathologically relevant interactor), but not with p.Ala20Glu.2

LOFWe also establish haploinsufficiency as the main molecular genetic mechanism in SPG31, which should initiate and guide functional studies on REEP1 with a focus on loss-of-function mechanisms. Our results should be valid as a reference for mutation frequency, spectrum of REEP1 mutations, and clinical3

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

References

ClinVar Variant Classifications

475 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic61

Likely Pathogenic38

VUS192

Likely Benign111

Benign51

Conflicting19

Pathogenic

Likely Pathogenic

192

VUS

111

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	46	3	12	0	61
Likely Pathogenic	25	11	2	0	38
VUS	11	123	56	2	192
Likely Benign	1	19	65	26	111
Benign	0	1	49	1	51
Conflicting	—				19
Total	83	157	184	29	472

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

View in ClinVar →

16 pathogenic / likely-pathogenic (of 38) ClinVar copy-number / structural variants overlap REEP1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →