Hereditary spastic paraplegia 31

Summary

Hereditary spastic paraplegia 31 (MONDO:0012453) is a disease caused by REEP1 (GenCC Definitive), with 2 cohort genes.

At a glance

• Prevalence: Unknown (Worldwide)
• Causal gene: REEP1 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 373
• Phenotypes (HPO): 18

Clinical features

Signs & symptoms

Clinical features (HPO)

18 HPO clinical features (Orphanet curated; top 18 by frequency):

HPO ID	Term	Frequency
HP:0001348	Brisk reflexes	Very frequent (80-99%)
HP:0002064	Spastic gait	Very frequent (80-99%)
HP:0008994	Proximal muscle weakness in lower limbs	Very frequent (80-99%)
HP:0001288	Gait disturbance	Frequent (30-79%)
HP:0001276	Hypertonia	Frequent (30-79%)
HP:0001761	Pes cavus	Frequent (30-79%)
HP:0002395	Lower limb hyperreflexia	Frequent (30-79%)
HP:0002936	Distal sensory impairment	Frequent (30-79%)
HP:0007350	Hyperreflexia in upper limbs	Frequent (30-79%)
HP:0008956	Proximal lower limb amyotrophy	Frequent (30-79%)
HP:0009046	Difficulty running	Frequent (30-79%)
HP:0010831	Impaired proprioception	Frequent (30-79%)
HP:0001260	Dysarthria	Occasional (5-29%)
HP:0001285	Spastic tetraparesis	Occasional (5-29%)
HP:0002015	Dysphagia	Occasional (5-29%)
HP:0002483	Bulbar signs	Occasional (5-29%)
HP:0030237	Hand muscle weakness	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	hereditary spastic paraplegia 31
Mondo ID	MONDO:0012453
MeSH	C565210
OMIM	610250
Orphanet	101011
DOID	DOID:0110782
SNOMED CT	763068005
UMLS	C1853247
MedGen	377858
GARD	0010817
Is cancer (heuristic)	no

Also known as: autosomal dominant spastic paraplegia type 31 · hereditary spastic paraplegia caused by mutation in REEP1 · hereditary spastic paraplegia type 31 · REEP1 hereditary spastic paraplegia · spastic paraplegia 31 · spastic paraplegia 31, autosomal dominant · SPG31

Data availability: 373 ClinVar variants · 4 GenCC gene-disease records · 3 cell lines.

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 › hereditary spastic paraplegia 31

Related subtypes (44): hereditary spastic paraplegia 3A, hereditary spastic paraplegia 4, mast syndrome, hereditary spastic paraplegia 5A, hereditary spastic paraplegia 16, hereditary spastic paraplegia 2, macrocephaly-spastic paraplegia-dysmorphism syndrome, Charcot-Marie-Tooth disease type 5, hereditary spastic paraplegia 6, hereditary spastic paraplegia 10, hereditary spastic paraplegia 14, hereditary spastic paraplegia 13, hereditary spastic paraplegia 7, hereditary spastic paraplegia 33, hereditary spastic paraplegia 30, hereditary spastic paraplegia 35, hereditary spastic paraplegia 50, hereditary spastic paraplegia 48, hereditary spastic paraplegia 51, hereditary spastic paraplegia 47, hereditary spastic paraplegia 52, hereditary spastic paraplegia 56, early-onset progressive neurodegeneration-blindness-ataxia-spasticity syndrome, hereditary spastic paraplegia 77, pure hereditary spastic paraplegia, complex hereditary spastic paraplegia, pure or complex hereditary spastic paraplegia, spastic paraplegia 87, autosomal recessive, spastic paraplegia 80, autosomal dominant, spastic paraplegia 81, autosomal recessive, spastic paraplegia 82, autosomal recessive, spastic paraplegia 83, autosomal recessive, spastic paraplegia 88, autosomal dominant, spastic paraplegia 79A, autosomal dominant, with ataxia, spastic paraplegia 89, autosomal recessive, spastic paraplegia 90A, autosomal dominant, spastic paraplegia 90B, autosomal recessive, spastic paraplegia 91, autosomal dominant, with or without cerebellar ataxia, spastic paraplegia 72b, autosomal recessive, spastic paraplegia 92, autosomal recessive, spastic paraplegia 93, autosomal recessive, IFIH1-related hereditary spastic paraplegia, RNASEH2B-related hereditary spastic paraplegia, ADAR-related hereditary spastic paraplegia

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

373 retrieved; paginated sample, class counts are floors:

160 uncertain significance, 85 likely benign, 49 pathogenic, 22 benign, 21 likely pathogenic, 18 conflicting classifications of pathogenicity, 10 benign/likely benign, 8 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
989231	NC_000002.11:g.(?86565200)(86481816_86479194)del		Pathogenic	criteria provided, single submitter
2426780	NC_000002.11:g.(?85766411)(86564633_?)del	MRPL35	Pathogenic	criteria provided, single submitter
1069793	NM_001371279.1(REEP1):c.417+1G>C	REEP1	Pathogenic	criteria provided, single submitter
1071529	NC_000002.11:g.(?86444152)(86564643_?)del	REEP1	Pathogenic	criteria provided, single submitter
1073769	NM_001371279.1(REEP1):c.417+1G>A	REEP1	Pathogenic	criteria provided, multiple submitters, no conflicts
1073869	NM_001371279.1(REEP1):c.224G>A (p.Trp75Ter)	REEP1	Pathogenic	criteria provided, single submitter
1076331	NM_001371279.1(REEP1):c.345C>G (p.Tyr115Ter)	REEP1	Pathogenic	criteria provided, single submitter
1452761	NM_001371279.1(REEP1):c.460C>T (p.Gln154Ter)	REEP1	Pathogenic	criteria provided, single submitter
1459865	NC_000002.11:g.(?86509273)(86564633_?)del	REEP1	Pathogenic	criteria provided, single submitter
1694461	NM_001164730.2(REEP1):c.40dup (p.Arg14fs)	REEP1	Pathogenic	criteria provided, single submitter
1703490	NM_022912.2(REEP1):c.106delG	REEP1	Pathogenic	criteria provided, single submitter
1703514	NM_001371279.1(REEP1):c.124T>C (p.Trp42Arg)	REEP1	Pathogenic	no assertion criteria provided
1859	NM_001371279.1(REEP1):c.512del (p.Pro171fs)	REEP1	Pathogenic	criteria provided, multiple submitters, no conflicts
1860	NM_001371279.1(REEP1):c.183-2A>G	REEP1	Pathogenic	criteria provided, single submitter
1862	NM_001371279.1(REEP1):c.59C>A (p.Ala20Glu)	REEP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1863	NM_001371279.1(REEP1):c.337C>T (p.Arg113Ter)	REEP1	Pathogenic	criteria provided, multiple submitters, no conflicts
188118	NM_001371279.1(REEP1):c.415A>T (p.Lys139Ter)	REEP1	Pathogenic	criteria provided, single submitter
1996533	NM_001371279.1(REEP1):c.57del (p.Ala20fs)	REEP1	Pathogenic	criteria provided, single submitter
2036306	NM_001371279.1(REEP1):c.304-1G>C	REEP1	Pathogenic	criteria provided, single submitter
2100758	NM_001371279.1(REEP1):c.417+1del	REEP1	Pathogenic	criteria provided, single submitter
2118484	NM_001371279.1(REEP1):c.128_138dup (p.Phe48fs)	REEP1	Pathogenic	criteria provided, single submitter
224884	NM_001371279.1(REEP1):c.595+1G>A	REEP1	Pathogenic	no assertion criteria provided
2426782	NC_000002.11:g.(?86479060)(86481957_?)del	REEP1	Pathogenic	criteria provided, single submitter
2702392	NM_001371279.1(REEP1):c.72C>A (p.Tyr24Ter)	REEP1	Pathogenic	criteria provided, single submitter
2766778	NM_001371279.1(REEP1):c.250_253dup (p.Ser85fs)	REEP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3650738	NM_001371279.1(REEP1):c.106-1G>A	REEP1	Pathogenic	criteria provided, single submitter
3720351	NM_001371279.1(REEP1):c.104_105del (p.Tyr35fs)	REEP1	Pathogenic	criteria provided, single submitter
3723170	NM_001371279.1(REEP1):c.208dup (p.Ile70fs)	REEP1	Pathogenic	criteria provided, single submitter
3764746	NM_001371279.1(REEP1):c.418-597_595+409del	REEP1	Pathogenic	no assertion criteria provided
4075378	NM_001371279.1(REEP1):c.225G>A (p.Trp75Ter)	REEP1	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 11 · Orphanet: 2 · 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
REEP1	Definitive	Autosomal dominant	hereditary spastic paraplegia 31	11

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
REEP1	Orphanet:101011	Autosomal dominant spastic paraplegia type 31
REEP1	Orphanet:139536	Distal hereditary motor neuropathy type 5

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
REEP1	HGNC:25786	ENSG00000068615	Q9H902	Receptor expression-enhancing protein 1	gencc,clinvar
MRPL35	HGNC:14489	ENSG00000132313	Q9NZE8	Large ribosomal subunit protein bL35m	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
REEP1	Receptor expression-enhancing protein 1	Required for endoplasmic reticulum (ER) network formation, shaping and remodeling; it links ER tubules to the cytoskeleton.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · 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	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
REEP1	Other/Unknown	no		TB2_DP1_HVA22
MRPL35	Other/Unknown	no		Ribosomal_bL35m, Ribosomal_bL35-like, Ribosomal_bL35_sf

Expression context

Cohort genes with no expression data: 0.

2 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cortical plate	1
dorsal root ganglion	1
middle temporal gyrus	1
heart left ventricle	1
mucosa of transverse colon	1
rectum	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
REEP1	284	broad	marker	dorsal root ganglion, middle temporal gyrus, cortical plate
MRPL35	283	ubiquitous	marker	rectum, heart left ventricle, mucosa of transverse colon

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MRPL35	1,668
REEP1	1,295

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MRPL35	Q9NZE8	85

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
REEP1	Q9H902	67.91

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 8. Enrichment computed across 2 evidence-associated genes (2 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Mitochondrial translation	1	68.8×	0.029	MRPL35
Mitochondrial translation initiation	1	63.4×	0.029	MRPL35
Mitochondrial translation elongation	1	63.4×	0.029	MRPL35
Mitochondrial ribosome-associated quality control	1	61.4×	0.029	MRPL35
Mitochondrial translation termination	1	54.9×	0.029	MRPL35
Translation	1	31.0×	0.043	MRPL35
Expression and translocation of olfactory receptors	1	14.1×	0.080	REEP1
Metabolism of proteins	1	6.2×	0.155	MRPL35

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
protein insertion into membrane	1	1053.2×	0.004	REEP1
endoplasmic reticulum tubular network organization	1	561.7×	0.004	REEP1
mitochondrial translation	1	86.9×	0.015	MRPL35
translation	1	51.4×	0.019	MRPL35

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 0 of 2 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
REEP1	0	0
MRPL35	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; 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	2	REEP1, MRPL35

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
REEP1	0	—
MRPL35	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.