Hereditary spastic paraplegia 72

Summary

Hereditary spastic paraplegia 72 (MONDO:0014282) is a disease caused by REEP2 (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: REEP2 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 113
• Phenotypes (HPO): 9

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		14	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

9 HPO clinical features (Orphanet curated; top 9 by frequency):

HPO ID	Term	Frequency
HP:0002063	Rigidity	Very frequent (80-99%)
HP:0002064	Spastic gait	Very frequent (80-99%)
HP:0001761	Pes cavus	Frequent (30-79%)
HP:0002839	Urinary bladder sphincter dysfunction	Frequent (30-79%)
HP:0002174	Postural tremor	Occasional (5-29%)
HP:0002354	Memory impairment	Occasional (5-29%)
HP:0006938	Impaired vibration sensation at ankles	Occasional (5-29%)
HP:0011446	Abnormality of higher mental function	Occasional (5-29%)
HP:0012531	Pain	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	hereditary spastic paraplegia 72
Mondo ID	MONDO:0014282
OMIM	615625
Orphanet	401849
DOID	DOID:0110817
UMLS	C5882669
MedGen	1847422
GARD	0017660
Is cancer (heuristic)	no

Also known as: autosomal spastic paraplegia type 72 · hereditary spastic paraplegia type 72 · pure hereditary spastic paraplegia caused by mutation in REEP2 · REEP2 pure hereditary spastic paraplegia · spastic paraplegia 72, autosomal dominant · spastic paraplegia 72, autosomal recessive · SPG72

Data availability: 113 ClinVar variants · 6 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › palsy › paraplegia › hereditary spastic paraplegia › pure hereditary spastic paraplegia › hereditary spastic paraplegia 72

Related subtypes (11): hereditary spastic paraplegia 34, hereditary spastic paraplegia 8, hereditary spastic paraplegia 12, hereditary spastic paraplegia 19, hereditary spastic paraplegia 28, hereditary spastic paraplegia 37, hereditary spastic paraplegia 42, hereditary spastic paraplegia 41, hereditary spastic paraplegia 62, hereditary spastic paraplegia 73, autosomal recessive spastic paraplegia type 71

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

113 retrieved; paginated sample, class counts are floors:

60 likely benign, 39 uncertain significance, 5 benign, 3 likely pathogenic, 2 benign/likely benign, 2 conflicting classifications of pathogenicity, 2 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
864419	NM_001271803.2(REEP2):c.119T>G (p.Met40Arg)	REEP2	Pathogenic	criteria provided, multiple submitters, no conflicts
97002	NM_001271803.2(REEP2):c.107T>A (p.Val36Glu)	REEP2	Pathogenic	no assertion criteria provided
1029275	NM_001271803.2(REEP2):c.331C>T (p.Arg111Ter)	REEP2	Likely pathogenic	criteria provided, single submitter
1029276	NM_001271803.2(REEP2):c.523C>T (p.Arg175Ter)	REEP2	Likely pathogenic	criteria provided, single submitter
804453	NM_001271803.2(REEP2):c.696+2T>G	REEP2	Likely pathogenic	criteria provided, single submitter
2737956	NM_001271803.2(REEP2):c.739A>G (p.Thr247Ala)	REEP2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
704542	NM_001271803.2(REEP2):c.605C>T (p.Pro202Leu)	REEP2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1060404	NM_001271803.2(REEP2):c.1A>G (p.Met1Val)	LOC129994740	Uncertain significance	criteria provided, single submitter
1180501	NM_001271803.2(REEP2):c.125G>C (p.Trp42Ser)	REEP2	Uncertain significance	criteria provided, single submitter
1339931	NM_001271803.2(REEP2):c.626C>G (p.Ala209Gly)	REEP2	Uncertain significance	criteria provided, single submitter
1387682	NM_001271803.2(REEP2):c.86del (p.Thr29fs)	REEP2	Uncertain significance	criteria provided, single submitter
1405559	NM_001271803.2(REEP2):c.388G>A (p.Ala130Thr)	REEP2	Uncertain significance	criteria provided, single submitter
1418172	NM_001271803.2(REEP2):c.350C>T (p.Thr117Ile)	REEP2	Uncertain significance	criteria provided, single submitter
1493138	NM_001271803.2(REEP2):c.697-3C>T	REEP2	Uncertain significance	criteria provided, single submitter
1495314	NM_001271803.2(REEP2):c.517C>T (p.Arg173Cys)	REEP2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1717111	NM_001271803.2(REEP2):c.331C>G (p.Arg111Gly)	REEP2	Uncertain significance	criteria provided, single submitter
1718985	NM_001271803.2(REEP2):c.100G>A (p.Glu34Lys)	REEP2	Uncertain significance	criteria provided, single submitter
1980399	NM_001271803.2(REEP2):c.683C>T (p.Ala228Val)	REEP2	Uncertain significance	criteria provided, single submitter
1992748	NM_001271803.2(REEP2):c.222A>G (p.Ile74Met)	REEP2	Uncertain significance	criteria provided, single submitter
2003055	NM_001271803.2(REEP2):c.508C>T (p.Pro170Ser)	REEP2	Uncertain significance	criteria provided, single submitter
2048651	NM_001271803.2(REEP2):c.556G>A (p.Glu186Lys)	REEP2	Uncertain significance	criteria provided, single submitter
2051992	NM_001271803.2(REEP2):c.696+6G>C	REEP2	Uncertain significance	criteria provided, single submitter
2052458	NM_001271803.2(REEP2):c.617G>A (p.Arg206Gln)	REEP2	Uncertain significance	criteria provided, multiple submitters, no conflicts
2073637	NM_001271803.2(REEP2):c.514G>A (p.Gly172Ser)	REEP2	Uncertain significance	criteria provided, single submitter
2096268	NM_001271803.2(REEP2):c.393_416dup (p.Ala138_Lys139insAsnAlaAlaValThrAlaAlaAla)	REEP2	Uncertain significance	criteria provided, single submitter
2130714	NM_001271803.2(REEP2):c.691G>A (p.Ala231Thr)	REEP2	Uncertain significance	criteria provided, single submitter
2716397	NM_001271803.2(REEP2):c.484G>A (p.Glu162Lys)	REEP2	Uncertain significance	criteria provided, single submitter
2724335	NM_001271803.2(REEP2):c.574C>T (p.Pro192Ser)	REEP2	Uncertain significance	criteria provided, single submitter
2731323	NM_001271803.2(REEP2):c.483C>G (p.Asp161Glu)	REEP2	Uncertain significance	criteria provided, single submitter
2835687	NM_001271803.2(REEP2):c.223T>C (p.Trp75Arg)	REEP2	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · Orphanet: 1 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
REEP2	Strong	Autosomal dominant	hereditary spastic paraplegia 72	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
REEP2	Orphanet:401849	Autosomal spastic paraplegia type 72

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
REEP2	HGNC:17975	ENSG00000132563	Q9BRK0	Receptor expression-enhancing protein 2	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
REEP2	Receptor expression-enhancing protein 2	Required for endoplasmic reticulum (ER) network formation, shaping and remodeling.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
REEP2	Other/Unknown	no		TB2_DP1_HVA22

Expression context

Cohort genes with no expression data: 0.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cerebellar cortex	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
REEP2	224	ubiquitous	yes	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
REEP2	937

Structural data

PDB: 0 · AlphaFold-only: 1 · No structure: 0

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
REEP2	Q9BRK0	65.05

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 1 evidence-associated genes (0 with Reactome annotation).

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
protein transport into membrane raft	1	8426.0×	5e-04	REEP2
sensory perception of bitter taste	1	2808.7×	6e-04	REEP2
sensory perception of sweet taste	1	2407.4×	6e-04	REEP2
endoplasmic reticulum tubular network organization	1	1123.5×	9e-04	REEP2

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 1

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
REEP2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	REEP2

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
REEP2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.