Hereditary spastic paraplegia 12

Summary

Hereditary spastic paraplegia 12 (MONDO:0011489) is a disease caused by RTN2 (GenCC Strong), with 3 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: RTN2 (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 37
• Phenotypes (HPO): 26

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		27	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

26 HPO clinical features (Orphanet curated; top 26 by frequency):

HPO ID	Term	Frequency
HP:0001288	Gait disturbance	Very frequent (80-99%)
HP:0001347	Hyperreflexia	Very frequent (80-99%)
HP:0002061	Lower limb spasticity	Very frequent (80-99%)
HP:0002314	Degeneration of the lateral corticospinal tracts	Very frequent (80-99%)
HP:0007020	Progressive spastic paraplegia	Very frequent (80-99%)
HP:0007340	Lower limb muscle weakness	Very frequent (80-99%)
HP:0001761	Pes cavus	Frequent (30-79%)
HP:0040307	Male sexual dysfunction	Frequent (30-79%)
HP:0100561	Spinal cord lesion	Frequent (30-79%)
HP:0000012	Urinary urgency	Frequent (30-79%)
HP:0000020	Urinary incontinence	Frequent (30-79%)
HP:0002064	Spastic gait	Frequent (30-79%)
HP:0002070	Limb ataxia	Frequent (30-79%)
HP:0002166	Impaired vibration sensation in the lower limbs	Frequent (30-79%)
HP:0002169	Clonus	Frequent (30-79%)
HP:0003394	Muscle spasm	Frequent (30-79%)
HP:0003487	Babinski sign	Frequent (30-79%)
HP:0007210	Lower limb amyotrophy	Frequent (30-79%)
HP:0010831	Impaired proprioception	Frequent (30-79%)
HP:0030014	Female sexual dysfunction	Frequent (30-79%)
HP:0002607	Bowel incontinence	Occasional (5-29%)
HP:0007350	Hyperreflexia in upper limbs	Occasional (5-29%)
HP:0001250	Seizure	Excluded (0%)
HP:0002921	Abnormality of the cerebrospinal fluid	Excluded (0%)
HP:0003457	EMG abnormality	Excluded (0%)
HP:0012898	Abnormal lower-limb motor evoked potentials	Excluded (0%)

Identifiers

Disease identifiers

Field	Value
Canonical name	hereditary spastic paraplegia 12
Mondo ID	MONDO:0011489
MeSH	C537484
OMIM	604805
Orphanet	100993
DOID	DOID:0110765
SNOMED CT	763374004
UMLS	C1858106
MedGen	347618
GARD	0009586
Is cancer (heuristic)	no

Also known as: autosomal dominant spastic paraplegia type 12 · hereditary spastic paraplegia caused by mutation in RTN2 · hereditary spastic paraplegia type 12 · RTN2 hereditary spastic paraplegia · spastic paraplegia 12 · spastic paraplegia 12, autosomal dominant · SPG12

Data availability: 37 ClinVar variants · 4 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 12

Related subtypes (11): hereditary spastic paraplegia 34, hereditary spastic paraplegia 8, hereditary spastic paraplegia 19, hereditary spastic paraplegia 28, hereditary spastic paraplegia 37, hereditary spastic paraplegia 42, hereditary spastic paraplegia 41, hereditary spastic paraplegia 72, 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

37 retrieved; paginated sample, class counts are floors:

21 uncertain significance, 6 conflicting classifications of pathogenicity, 3 pathogenic/likely pathogenic, 3 pathogenic, 3 likely benign, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1070023	NM_005619.5(RTN2):c.148G>T (p.Glu50Ter)	RTN2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2433038	NM_005619.5(RTN2):c.926del (p.Gly309fs)	RTN2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
30324	NM_005619.5(RTN2):c.178dup (p.Arg60fs)	RTN2	Pathogenic	no assertion criteria provided
30325	NC_000019.10:g.(?45485294_45497047?)del	RTN2	Pathogenic	no assertion criteria provided
3248640	NM_005619.5(RTN2):c.103C>T (p.Arg35Ter)	RTN2	Pathogenic	no assertion criteria provided
933606	NM_005619.5(RTN2):c.170del (p.Gly57fs)	RTN2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2442171	NM_005619.5(RTN2):c.198C>A (p.Tyr66Ter)	RTN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
329550	NM_005619.5(RTN2):c.986G>A (p.Ser329Asn)	RTN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
378054	NM_005619.5(RTN2):c.939del (p.Thr314fs)	RTN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
548603	NM_005619.5(RTN2):c.938dup (p.Thr314fs)	RTN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
633397	NM_005619.4(RTN2):c.818_828del	RTN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
653220	NM_005619.5(RTN2):c.1630G>A (p.Ala544Thr)	RTN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3255562	NM_005619.5(RTN2):c.1216dup (p.Arg406fs)	PPM1N	Uncertain significance	criteria provided, single submitter
1028922	NM_005619.5(RTN2):c.943C>A (p.Pro315Thr)	RTN2	Uncertain significance	criteria provided, single submitter
1445728	NM_005619.5(RTN2):c.1340G>A (p.Arg447Gln)	RTN2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1707642	NM_005619.5(RTN2):c.212G>T (p.Gly71Val)	RTN2	Uncertain significance	criteria provided, single submitter
2310046	NM_005619.5(RTN2):c.1453G>A (p.Val485Met)	RTN2	Uncertain significance	criteria provided, multiple submitters, no conflicts
2435489	NM_005619.5(RTN2):c.847C>T (p.Leu283Phe)	RTN2	Uncertain significance	criteria provided, single submitter
2435490	NM_005619.5(RTN2):c.1192C>G (p.Arg398Gly)	RTN2	Uncertain significance	criteria provided, single submitter
329541	NM_005619.5(RTN2):c.*344C>T	RTN2	Uncertain significance	criteria provided, single submitter
329542	NM_005619.5(RTN2):c.*300G>C	RTN2	Uncertain significance	criteria provided, single submitter
329543	NM_005619.5(RTN2):c.*270C>T	RTN2	Uncertain significance	criteria provided, single submitter
329545	NM_005619.5(RTN2):c.*148G>A	RTN2	Uncertain significance	criteria provided, single submitter
4076392	NM_005619.5(RTN2):c.1170C>T (p.Gly390=)	RTN2	Uncertain significance	criteria provided, single submitter
458237	NM_005619.5(RTN2):c.1411G>A (p.Val471Met)	RTN2	Uncertain significance	criteria provided, multiple submitters, no conflicts
841510	NM_005619.5(RTN2):c.1618T>C (p.Ser540Pro)	RTN2	Uncertain significance	criteria provided, multiple submitters, no conflicts
893521	NM_005619.5(RTN2):c.1497+3G>A	RTN2	Uncertain significance	criteria provided, multiple submitters, no conflicts
893522	NM_005619.5(RTN2):c.1421T>C (p.Ile474Thr)	RTN2	Uncertain significance	criteria provided, single submitter
893523	NM_005619.5(RTN2):c.1339C>T (p.Arg447Trp)	RTN2	Uncertain significance	criteria provided, single submitter
893524	NM_005619.5(RTN2):c.1241+3G>A	RTN2	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 11 · Orphanet: 3 · 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
RTN2	Strong	Autosomal dominant	hereditary spastic paraplegia 12	5
UBAP1	Strong	Autosomal dominant	spastic paraplegia 80, autosomal dominant	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
RTN2	Orphanet:100993	Autosomal dominant spastic paraplegia type 12
UBAP1	Orphanet:100993	Autosomal dominant spastic paraplegia type 12
UBAP1	Orphanet:631068	Autosomal dominant spastic paraplegia type 80

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
RTN2	HGNC:10468	ENSG00000125744	O75298	Reticulon-2	gencc,clinvar
UBAP1	HGNC:12461	ENSG00000165006	Q9NZ09	Ubiquitin-associated protein 1	gencc
PPM1N	HGNC:26845	ENSG00000213889	Q8N819	Probable protein phosphatase 1N	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
RTN2	Reticulon-2	Inhibits amyloid precursor protein processing, probably by blocking BACE1 activity.
UBAP1	Ubiquitin-associated protein 1	Component of the ESCRT-I complex, a regulator of vesicular trafficking process.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.33

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
Phosphatase	1	28.0×	0.071
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
RTN2	Other/Unknown	no		Reticulon, RTN1-4
UBAP1	Other/Unknown	no		UBA-like_sf, UBA, UMA
PPM1N	Phosphatase	yes		PPM-type_phosphatase-like_dom, PP2C_C, PP2C

Expression context

Cohort genes with no expression data: 0.

3 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
gastrocnemius	2
hindlimb stylopod muscle	1
skeletal muscle tissue of rectus abdominis	1
lower esophagus mucosa	1
muscle of leg	1
male germ line stem cell (sensu Vertebrata) in testis	1
monocyte	1
primordial germ cell in gonad	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RTN2	271	ubiquitous	marker	skeletal muscle tissue of rectus abdominis, hindlimb stylopod muscle, gastrocnemius
UBAP1	288	ubiquitous	marker	lower esophagus mucosa, gastrocnemius, muscle of leg
PPM1N	159	broad	marker	male germ line stem cell (sensu Vertebrata) in testis, primordial germ cell in gonad, monocyte

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PPM1N	1,459
RTN2	1,343
UBAP1	894

Structural data

PDB: 1 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
UBAP1	Q9NZ09	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PPM1N	Q8N819	87.36
RTN2	O75298	50.99

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 5. Enrichment computed across 3 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Membrane binding and targetting of GAG proteins	1	815.7×	0.004	UBAP1
Budding and maturation of HIV virion	1	407.9×	0.004	UBAP1
Endosomal Sorting Complex Required For Transport (ESCRT)	1	368.4×	0.004	UBAP1
Late endosomal microautophagy	1	326.3×	0.004	UBAP1
HCMV Late Events	1	98.5×	0.010	UBAP1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
intracellular protein transmembrane transport	1	1872.4×	0.005	RTN2
endoplasmic reticulum tubular network formation	1	936.2×	0.005	RTN2
regulation of D-glucose import across plasma membrane	1	702.2×	0.005	RTN2
endoplasmic reticulum tubular network membrane organization	1	702.2×	0.005	RTN2
protein transport to vacuole involved in ubiquitin-dependent protein catabolic process via the multivesicular body sorting pathway	1	351.1×	0.008	UBAP1
negative regulation of amyloid-beta formation	1	295.6×	0.008	RTN2
ubiquitin-dependent protein catabolic process via the multivesicular body sorting pathway	1	181.2×	0.010	UBAP1
multivesicular body assembly	1	175.5×	0.010	UBAP1
regulation of canonical NF-kappaB signal transduction	1	160.5×	0.010	PPM1N
membrane fission	1	137.0×	0.010	UBAP1
positive regulation of canonical Wnt signaling pathway	1	51.5×	0.025	PPM1N
neuron differentiation	1	33.4×	0.035	RTN2
gene expression	1	26.6×	0.037	RTN2
brain development	1	26.5×	0.037	RTN2

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 3 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
RTN2	0	0
UBAP1	0	0
PPM1N	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; 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	1	PPM1N
E	Difficult family or no structure, no drug	2	RTN2, UBAP1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
RTN2	0	—
UBAP1	0	—
PPM1N	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.