REEP2

Chr 5

receptor accessory protein 2

Also known as: C5orf19, SGC32445, SPG72, SPG72A, SPG72B, Yip2d

NCBI Gene: 51308 ENSG00000132563 UniProt: Q9BRK0

The REEP2 protein is required for endoplasmic reticulum network formation, shaping and remodeling, and may enhance cell surface expression of odorant receptors. Mutations cause spastic paraplegia 72, which can follow either autosomal dominant or autosomal recessive inheritance patterns. The gene shows moderate constraint against loss-of-function variants (LOEUF 0.549), suggesting some tolerance to protein-truncating mutations.

GeneReviews ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a member of the receptor expression enhancing protein family. Studies of a related gene in mouse suggest that the encoded protein is found in the cell membrane and enhances the function of sweet taste receptors. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2012]

GeneReviews ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.55

Clinical Summary— REEP2

⚡

Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.21) despite low pLI — interpret in context.

📋

ClinVar Variants

7 unique Pathogenic / Likely Pathogenic· 66 VUS of 160 total submissions

Explore recent and relevant literature in Research Assistant →

📖

GeneReview available — REEP2

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.55LOEUF

pLI 0.439

Z-score 2.74

OE 0.21 (0.10–0.55)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.64Z-score

OE missense 0.64 (0.54–0.75)

103 obs / 161.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.21 (0.10–0.55)

0≤0.351.4

Missense OE?0.64 (0.54–0.75)

0≤0.61.4

Synonymous OE?0.92

0≤1.21.6

LoF obs/exp: 3 / 14.1Missense obs/exp: 103 / 161.5Syn Z: 0.52

This gene — mechanism propensity

0.7132th %ile

GOF

0.6833th %ile

LOF

0.4726th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative, gain-of-function and loss-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median · 1 literature citation

GOFprediction above median

LOF43% of P/LP variants are LoF

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 vitro functional expression studies showed that the V36E mutant protein inhibited the normal binding of wildtype REEP2 to cellular membranes, thus acting in a dominant-negative manner.1

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

References

1.PMID 24388663 ↗

ClinVar Variant Classifications

160 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic4

Likely Pathogenic3

VUS66

Likely Benign69

Benign11

Conflicting2

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	3	1	0	4
Likely Pathogenic	3	0	0	0	3
VUS	4	58	4	0	66
Likely Benign	0	0	35	34	69
Benign	0	0	9	2	11
Conflicting	—				2
Total	7	61	49	36	155

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

View in ClinVar →

11 pathogenic / likely-pathogenic (of 18) ClinVar copy-number / structural variants overlap REEP2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →