Autosomal recessive spastic paraplegia type 76

Summary

Autosomal recessive spastic paraplegia type 76 (MONDO:0014827) is a disease caused by CAPN1 (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: CAPN1 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 47
• Phenotypes (HPO): 17

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		7	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

17 HPO clinical features (Orphanet curated; top 17 by frequency):

HPO ID	Term	Frequency
HP:0002061	Lower limb spasticity	Very frequent (80-99%)
HP:0002395	Lower limb hyperreflexia	Very frequent (80-99%)
HP:0003487	Babinski sign	Very frequent (80-99%)
HP:0001251	Ataxia	Frequent (30-79%)
HP:0001260	Dysarthria	Frequent (30-79%)
HP:0001761	Pes cavus	Frequent (30-79%)
HP:0002066	Gait ataxia	Frequent (30-79%)
HP:0003202	Skeletal muscle atrophy	Frequent (30-79%)
HP:0007340	Lower limb muscle weakness	Frequent (30-79%)
HP:0007350	Hyperreflexia in upper limbs	Frequent (30-79%)
HP:0009830	Peripheral neuropathy	Frequent (30-79%)
HP:0000009	Functional abnormality of the bladder	Occasional (5-29%)
HP:0000496	Abnormality of eye movement	Occasional (5-29%)
HP:0002070	Limb ataxia	Occasional (5-29%)
HP:0002650	Scoliosis	Occasional (5-29%)
HP:0008081	Pes valgus	Occasional (5-29%)
HP:0011448	Ankle clonus	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	autosomal recessive spastic paraplegia type 76
Mondo ID	MONDO:0014827
OMIM	616907
Orphanet	488594
DOID	DOID:0110821
UMLS	C5567483
MedGen	1798906
GARD	0017892
Is cancer (heuristic)	no

Also known as: autosomal recessive complex spastic paraplegia caused by mutation in CAPN1 · CAPN1 autosomal recessive complex spastic paraplegia · hereditary spastic paraplegia type 76 · spastic paraplegia 76, autosomal recessive · SPG76

Data availability: 47 ClinVar variants · 2 GenCC gene-disease records · 1 cell line.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › complex hereditary spastic paraplegia › autosomal recessive spastic paraplegia type 76

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 53, 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 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

47 retrieved; paginated sample, class counts are floors:

18 pathogenic, 8 uncertain significance, 7 pathogenic/likely pathogenic, 6 likely pathogenic, 6 benign, 1 benign/likely benign, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
1325392	NM_005186.4(CAPN1):c.267+2T>C	CAPN1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1338393	NM_005186.4(CAPN1):c.843+1G>C	CAPN1	Pathogenic	criteria provided, multiple submitters, no conflicts
1802257	NM_005186.4(CAPN1):c.181_182insC (p.Phe61fs)	CAPN1	Pathogenic	criteria provided, single submitter
225765	NM_005186.4(CAPN1):c.884G>C (p.Arg295Pro)	CAPN1	Pathogenic	no assertion criteria provided
225766	NM_005186.4(CAPN1):c.1579C>T (p.Gln527Ter)	CAPN1	Pathogenic	no assertion criteria provided
225767	NM_005186.4(CAPN1):c.407del (p.Pro136fs)	CAPN1	Pathogenic	no assertion criteria provided
225768	NM_005186.4(CAPN1):c.1605+5G>A	CAPN1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2691341	NC_000011.9:g.(64956218_64972153)_(64974291_64975525)del	CAPN1	Pathogenic	criteria provided, single submitter
4294014	NM_005186.4(CAPN1):c.268-1G>T	CAPN1	Pathogenic	criteria provided, single submitter
4847518	NC_000011.9:g.(64955512_64955884)_(64956218_64972153)del	CAPN1	Pathogenic	criteria provided, single submitter
489121	NM_005186.4(CAPN1):c.853C>T (p.Arg285Ter)	CAPN1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
489122	NM_005186.4(CAPN1):c.1153C>T (p.Arg385Ter)	CAPN1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
617483	NM_005186.4(CAPN1):c.338-1G>A	CAPN1	Pathogenic	criteria provided, multiple submitters, no conflicts
802686	NM_005186.4(CAPN1):c.618_619del (p.Gly208fs)	CAPN1	Pathogenic	criteria provided, multiple submitters, no conflicts
802687	NM_005186.4(CAPN1):c.1176G>A (p.Trp392Ter)	CAPN1	Pathogenic	criteria provided, multiple submitters, no conflicts
817644	NM_005186.4(CAPN1):c.188dup (p.Val64fs)	CAPN1	Pathogenic	criteria provided, multiple submitters, no conflicts
986744	NM_005186.4(CAPN1):c.254G>A (p.Trp85Ter)	CAPN1	Pathogenic	criteria provided, single submitter
986745	NM_005186.4(CAPN1):c.623G>A (p.Gly208Asp)	CAPN1	Pathogenic	criteria provided, single submitter
986746	NM_005186.4(CAPN1):c.1005G>A (p.Trp335Ter)	CAPN1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
986747	NM_005186.4(CAPN1):c.1129_1133del (p.Arg377fs)	CAPN1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
986748	NM_005186.4(CAPN1):c.1165+1G>A	CAPN1	Pathogenic	criteria provided, single submitter
986749	NM_005186.4(CAPN1):c.1341G>C (p.Glu447Asp)	CAPN1	Pathogenic	criteria provided, single submitter
986750	NM_005186.4(CAPN1):c.1418_1419del (p.Arg473fs)	CAPN1	Pathogenic	criteria provided, single submitter
986751	NM_005186.4(CAPN1):c.1697dup (p.Leu566fs)	CAPN1	Pathogenic	criteria provided, single submitter
986752	NM_005186.4(CAPN1):c.1969G>T (p.Glu657Ter)	CAPN1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1029241	NM_005186.4(CAPN1):c.929+2T>A	CAPN1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1325391	NM_005186.4(CAPN1):c.1010C>A (p.Ser337Ter)	CAPN1	Likely pathogenic	criteria provided, single submitter
2584813	NM_005186.4(CAPN1):c.667G>T (p.Glu223Ter)	CAPN1	Likely pathogenic	criteria provided, single submitter
4081225	NM_005186.4(CAPN1):c.1943-1G>C	CAPN1	Likely pathogenic	criteria provided, single submitter
4537454	NM_005186.4(CAPN1):c.1697T>A (p.Leu566Ter)	CAPN1	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 2 · 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
CAPN1	Strong	Autosomal recessive	autosomal recessive spastic paraplegia type 76	2

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CAPN1	Orphanet:488594	Autosomal recessive spastic paraplegia type 76

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
CAPN1	HGNC:1476	ENSG00000014216	P07384	Calpain-1 catalytic subunit	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CAPN1	Calpain-1 catalytic subunit	Calcium-regulated non-lysosomal thiol-protease which catalyzes limited proteolysis of substrates involved in cytoskeletal remodeling and signal transduction.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Protease	1	36.6×	0.027

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CAPN1	Protease	yes	3.4.22.52	Pept_cys_AS, Peptidase_C2_calpain_cat, EF_hand_dom

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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
endometrium epithelium	1
esophagus mucosa	1
lower esophagus mucosa	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CAPN1	262	ubiquitous	marker	lower esophagus mucosa, endometrium epithelium, esophagus mucosa

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CAPN1	2,649

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CAPN1	P07384	5

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 13. Enrichment computed across 1 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
Neurodegenerative Diseases	1	878.5×	0.006	CAPN1
Defective Intrinsic Pathway for Apoptosis	1	761.3×	0.006	CAPN1
Diseases of programmed cell death	1	634.4×	0.006	CAPN1
Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer’s disease models	1	519.1×	0.006	CAPN1
Degradation of the extracellular matrix	1	117.7×	0.022	CAPN1
Formation of the cornified envelope	1	87.8×	0.025	CAPN1
Extracellular matrix organization	1	63.1×	0.029	CAPN1
Keratinization	1	55.7×	0.029	CAPN1
Innate Immune System	1	25.5×	0.056	CAPN1
Neutrophil degranulation	1	23.1×	0.056	CAPN1
Developmental Biology	1	14.5×	0.077	CAPN1
Disease	1	13.1×	0.077	CAPN1
Immune System	1	13.0×	0.077	CAPN1

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
regulation of catalytic activity	1	3370.4×	0.001	CAPN1
mammary gland involution	1	2808.7×	0.001	CAPN1
NMDA selective glutamate receptor signaling pathway	1	2407.4×	0.001	CAPN1
self proteolysis	1	1532.0×	0.001	CAPN1
receptor catabolic process	1	1123.5×	0.001	CAPN1
regulation of macroautophagy	1	295.6×	0.005	CAPN1
proteolysis	1	34.2×	0.030	CAPN1
positive regulation of cell population proliferation	1	33.6×	0.030	CAPN1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CAPN1	1	2

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
ALOXISTATIN	2	CAPN1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
CAPN1	213	Binding:202, Functional:10, Toxicity:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
CAPN1	3.4.22.52, 3.4.22.53	calpain-1, calpain-2

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
CAPN1	213

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

1 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.

Compound	Max phase	Cohort target (bioactivity)
ALOXISTATIN	2	CAPN1

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	1	CAPN1
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.