Hereditary spastic paraplegia 53

Summary

Hereditary spastic paraplegia 53 (MONDO:0013962) is a disease with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 2
• ClinVar variants: 157
• Phenotypes (HPO): 16

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		9	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

16 HPO clinical features (Orphanet curated; top 16 by frequency):

HPO ID	Term	Frequency
HP:0002169	Clonus	Very frequent (80-99%)
HP:0007350	Hyperreflexia in upper limbs	Very frequent (80-99%)
HP:0000750	Delayed speech and language development	Frequent (30-79%)
HP:0000768	Pectus carinatum	Frequent (30-79%)
HP:0001382	Joint hypermobility	Frequent (30-79%)
HP:0002808	Kyphosis	Frequent (30-79%)
HP:0200049	Upper limb hypertonia	Frequent (30-79%)
HP:0000365	Hearing impairment	Occasional (5-29%)
HP:0002451	Limb dystonia	Occasional (5-29%)
HP:0002495	Impaired vibratory sensation	Occasional (5-29%)
HP:0000252	Microcephaly	Very rare (<1-4%)
HP:0000372	Abnormality of the auditory canal	Very rare (<1-4%)
HP:0001508	Failure to thrive	Very rare (<1-4%)
HP:0002119	Ventriculomegaly	Very rare (<1-4%)
HP:0002539	Cortical dysplasia	Very rare (<1-4%)
HP:0010831	Impaired proprioception	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	hereditary spastic paraplegia 53
Mondo ID	MONDO:0013962
OMIM	614898
Orphanet	319199
DOID	DOID:0110805
SNOMED CT	723823004
UMLS	C3539494
MedGen	761340
GARD	0017445
Is cancer (heuristic)	no

Also known as: autosomal recessive complex spastic paraplegia caused by mutation in VPS37A · autosomal recessive spastic paraplegia type 53 · hereditary spastic paraplegia 53 · hereditary spastic paraplegia type 53 · spastic paraplegia 53, autosomal recessive · SPG53 · VPS37A autosomal recessive complex spastic paraplegia

Data availability: 157 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › complex hereditary spastic paraplegia › hereditary spastic paraplegia 53

Related subtypes (49): hereditary sensory and autonomic neuropathy with spastic paraplegia, hereditary spastic paraplegia 15, hereditary spastic paraplegia 23, spastic paraplegia-glaucoma-intellectual disability syndrome, Troyer syndrome, MASA syndrome, hereditary spastic paraplegia 11, hereditary spastic paraplegia 24, hereditary spastic paraplegia 25, hereditary spastic paraplegia 27, hereditary spastic paraplegia 26, spastic paraplegia, optic atropy, and neuropathy, hereditary spastic paraplegia 18, hereditary spastic paraplegia 32, spastic ataxia 2, hereditary spastic paraplegia 39, hereditary spastic paraplegia 45, hereditary spastic paraplegia 44, hereditary spastic paraplegia 46, hereditary spastic paraplegia 49, hereditary spastic paraplegia 54, hereditary spastic paraplegia 55, hereditary spastic paraplegia 43, hereditary spastic paraplegia 57, hereditary spastic paraplegia 64, hereditary spastic paraplegia 61, hereditary spastic paraplegia 63, glutamate pyruvate transaminase 2 deficiency, hereditary spastic paraplegia 74, autosomal recessive complex spastic paraplegia type 9B, hereditary spastic paraplegia 75, spastic paraplegia-severe developmental delay-epilepsy syndrome, autosomal recessive spastic paraplegia type 76, autosomal recessive spastic paraplegia type 78, autosomal dominant complex spastic paraplegia, maternally-inherited spastic paraplegia, fatty acid hydroxylase-associated neurodegeneration, autosomal recessive spastic paraplegia type 59, autosomal recessive spastic paraplegia type 60, autosomal recessive spastic paraplegia type 66, autosomal recessive spastic paraplegia type 67, autosomal recessive spastic paraplegia type 68, autosomal recessive spastic paraplegia type 69, autosomal recessive spastic paraplegia type 70, spastic paraplegia 84, autosomal recessive, spastic paraplegia 85, autosomal recessive, spastic paraplegia 86, autosomal recessive, kyphoscoliosis-lateral tongue atrophy-hereditary spastic paraplegia syndrome, autosomal recessive complex spastic paraplegia due to kennedy pathway dysfunction

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

157 retrieved; paginated sample, class counts are floors:

78 uncertain significance, 59 likely benign, 9 benign, 6 benign/likely benign, 4 conflicting classifications of pathogenicity, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
39741	NM_152415.3(VPS37A):c.1146A>T (p.Lys382Asn)	VPS37A	Pathogenic	no assertion criteria provided
1107859	NM_152415.3(VPS37A):c.642+10G>A	VPS37A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1806028	NM_152415.3(VPS37A):c.1157C>T (p.Ala386Val)	VPS37A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
500376	NM_152415.3(VPS37A):c.99C>A (p.Ile33=)	VPS37A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
522587	NM_152415.3(VPS37A):c.700C>A (p.Leu234Ile)	VPS37A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1377072	NC_000008.10:g.(?16850399)(20112692_?)dup	ASAH1-AS1	Uncertain significance	criteria provided, single submitter
1011549	NM_152415.3(VPS37A):c.424A>G (p.Ser142Gly)	VPS37A	Uncertain significance	criteria provided, multiple submitters, no conflicts
1029198	NM_152415.3(VPS37A):c.215A>T (p.Gln72Leu)	VPS37A	Uncertain significance	criteria provided, single submitter
1035635	NM_152415.3(VPS37A):c.642G>A (p.Pro214=)	VPS37A	Uncertain significance	criteria provided, single submitter
1036357	NM_152415.3(VPS37A):c.451G>T (p.Ala151Ser)	VPS37A	Uncertain significance	criteria provided, single submitter
1041314	NM_152415.3(VPS37A):c.745G>A (p.Glu249Lys)	VPS37A	Uncertain significance	criteria provided, multiple submitters, no conflicts
1044520	NM_152415.3(VPS37A):c.812A>G (p.Asp271Gly)	VPS37A	Uncertain significance	criteria provided, multiple submitters, no conflicts
1344175	NM_152415.3(VPS37A):c.648C>A (p.Ser216Arg)	VPS37A	Uncertain significance	criteria provided, multiple submitters, no conflicts
1348945	NM_152415.3(VPS37A):c.791A>G (p.Gln264Arg)	VPS37A	Uncertain significance	criteria provided, single submitter
1416573	NM_152415.3(VPS37A):c.892T>A (p.Leu298Ile)	VPS37A	Uncertain significance	criteria provided, multiple submitters, no conflicts
1442811	NM_152415.3(VPS37A):c.417-2A>G	VPS37A	Uncertain significance	criteria provided, single submitter
1472602	NM_152415.3(VPS37A):c.560C>T (p.Thr187Ile)	VPS37A	Uncertain significance	criteria provided, single submitter
1516806	NM_152415.3(VPS37A):c.874G>T (p.Ala292Ser)	VPS37A	Uncertain significance	criteria provided, single submitter
1523443	NM_152415.3(VPS37A):c.802G>A (p.Asp268Asn)	VPS37A	Uncertain significance	criteria provided, multiple submitters, no conflicts
1721265	NM_152415.3(VPS37A):c.904G>A (p.Glu302Lys)	VPS37A	Uncertain significance	criteria provided, multiple submitters, no conflicts
1908094	NM_152415.3(VPS37A):c.31G>T (p.Ala11Ser)	VPS37A	Uncertain significance	criteria provided, single submitter
1934058	NM_152415.3(VPS37A):c.735G>A (p.Met245Ile)	VPS37A	Uncertain significance	criteria provided, single submitter
1977806	NM_152415.3(VPS37A):c.642+7A>G	VPS37A	Uncertain significance	criteria provided, single submitter
2062391	NM_152415.3(VPS37A):c.404C>T (p.Thr135Ile)	VPS37A	Uncertain significance	criteria provided, single submitter
2073574	NM_152415.3(VPS37A):c.821A>G (p.Lys274Arg)	VPS37A	Uncertain significance	criteria provided, multiple submitters, no conflicts
2117026	NM_152415.3(VPS37A):c.126-1G>C	VPS37A	Uncertain significance	criteria provided, single submitter
2159244	NM_152415.3(VPS37A):c.644C>G (p.Thr215Arg)	VPS37A	Uncertain significance	criteria provided, single submitter
2166324	NM_152415.3(VPS37A):c.215A>G (p.Gln72Arg)	VPS37A	Uncertain significance	criteria provided, single submitter
2171850	NM_152415.3(VPS37A):c.751G>A (p.Val251Ile)	VPS37A	Uncertain significance	criteria provided, single submitter
2180040	NM_152415.3(VPS37A):c.32C>G (p.Ala11Gly)	VPS37A	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · 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
VPS37A	Moderate	Autosomal recessive	hereditary spastic paraplegia 53	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
VPS37A	Orphanet:319199	Autosomal recessive spastic paraplegia type 53

Cohort genes → proteins

2 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
VPS37A	HGNC:24928	ENSG00000155975	Q8NEZ2	Vacuolar protein sorting-associated protein 37A	gencc,clinvar
ASAH1-AS1	HGNC:55603	ENSG00000245281		ASAH1 antisense RNA 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
VPS37A	Vacuolar protein sorting-associated protein 37A	Component of the ESCRT-I complex, a regulator of vesicular trafficking process.

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)
VPS37A	Other/Unknown	no		Mod_r, UBQ-conjugating_enzyme/RWD, Helix_hairpin_bin_sf
ASAH1-AS1	Other/Unknown	no

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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
adrenal tissue	1
gastrocnemius	1
islet of Langerhans	1
bone marrow cell	1
cortical plate	1
male germ line stem cell (sensu Vertebrata) in testis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
VPS37A	255	ubiquitous	marker	islet of Langerhans, gastrocnemius, adrenal tissue
ASAH1-AS1	134		yes	male germ line stem cell (sensu Vertebrata) in testis, cortical plate, bone marrow cell

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
VPS37A	1,000
ASAH1-AS1	0

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
VPS37A	Q8NEZ2	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 5. Enrichment computed across 2 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	VPS37A
Budding and maturation of HIV virion	1	407.9×	0.004	VPS37A
Endosomal Sorting Complex Required For Transport (ESCRT)	1	368.4×	0.004	VPS37A
Late endosomal microautophagy	1	326.3×	0.004	VPS37A
HCMV Late Events	1	98.5×	0.010	VPS37A

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 targeting to vacuole	1	1296.3×	0.003	VPS37A
protein transport to vacuole involved in ubiquitin-dependent protein catabolic process via the multivesicular body sorting pathway	1	1053.2×	0.003	VPS37A
viral budding via host ESCRT complex	1	802.5×	0.003	VPS37A
ubiquitin-dependent protein catabolic process via the multivesicular body sorting pathway	1	543.6×	0.003	VPS37A
multivesicular body assembly	1	526.6×	0.003	VPS37A
membrane fission	1	411.0×	0.003	VPS37A
protein targeting to membrane	1	295.6×	0.004	VPS37A
macroautophagy	1	240.7×	0.004	VPS37A

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
VPS37A	0	0
ASAH1-AS1	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	2	VPS37A, ASAH1-AS1

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)
VPS37A	0	—
ASAH1-AS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.