Hereditary spastic paraplegia 11

Summary

Hereditary spastic paraplegia 11 (MONDO:0011445) is a disease caused by SPG11 (GenCC Definitive), with 6 cohort genes and 1 clinical trial.

At a glance

• Prevalence: 1-9 / 1 000 000 (Portugal) [Orphanet-validated]
• Causal gene: SPG11 (GenCC Definitive)
• Cohort genes: 6
• ClinVar variants: 3,252
• Phenotypes (HPO): 49
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 1 000 000	0.26	Portugal	Validated

Signs & symptoms

Clinical features (HPO)

49 HPO clinical features (Orphanet curated; top 49 by frequency):

HPO ID	Term	Frequency
HP:0001256	Intellectual disability, mild	Very frequent (80-99%)
HP:0001268	Mental deterioration	Very frequent (80-99%)
HP:0001328	Specific learning disability	Very frequent (80-99%)
HP:0002079	Hypoplasia of the corpus callosum	Very frequent (80-99%)
HP:0002191	Progressive spasticity	Very frequent (80-99%)
HP:0002385	Paraparesis	Very frequent (80-99%)
HP:0003477	Peripheral axonal neuropathy	Very frequent (80-99%)
HP:0007141	Sensorimotor neuropathy	Very frequent (80-99%)
HP:0007178	Motor polyneuropathy	Very frequent (80-99%)
HP:0007340	Lower limb muscle weakness	Very frequent (80-99%)
HP:0000639	Nystagmus	Frequent (30-79%)
HP:0000708	Atypical behavior	Frequent (30-79%)
HP:0000712	Emotional lability	Frequent (30-79%)
HP:0000736	Short attention span	Frequent (30-79%)
HP:0001152	Saccadic smooth pursuit	Frequent (30-79%)
HP:0001251	Ataxia	Frequent (30-79%)
HP:0001260	Dysarthria	Frequent (30-79%)
HP:0001288	Gait disturbance	Frequent (30-79%)
HP:0002015	Dysphagia	Frequent (30-79%)
HP:0002120	Cerebral cortical atrophy	Frequent (30-79%)
HP:0002354	Memory impairment	Frequent (30-79%)
HP:0002540	Inability to walk	Frequent (30-79%)
HP:0003445	EMG: neuropathic changes	Frequent (30-79%)
HP:0003482	EMG: axonal abnormality	Frequent (30-79%)
HP:0006913	Frontal cortical atrophy	Frequent (30-79%)
HP:0006956	Dilation of lateral ventricles	Frequent (30-79%)
HP:0007350	Hyperreflexia in upper limbs	Frequent (30-79%)
HP:0030455	Abnormality of pattern visual evoked potentials	Frequent (30-79%)
HP:0030890	Hyperintensity of cerebral white matter on MRI	Frequent (30-79%)
HP:0000486	Strabismus	Occasional (5-29%)
HP:0000505	Visual impairment	Occasional (5-29%)
HP:0000546	Retinal degeneration	Occasional (5-29%)
HP:0000709	Psychosis	Occasional (5-29%)
HP:0000726	Dementia	Occasional (5-29%)
HP:0001004	Lymphedema	Occasional (5-29%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0001278	Orthostatic hypotension	Occasional (5-29%)
HP:0001300	Parkinsonism	Occasional (5-29%)
HP:0001513	Obesity	Occasional (5-29%)
HP:0001761	Pes cavus	Occasional (5-29%)
HP:0002071	Abnormality of extrapyramidal motor function	Occasional (5-29%)
HP:0002650	Scoliosis	Occasional (5-29%)
HP:0003693	Distal amyotrophy	Occasional (5-29%)
HP:0006827	Atrophy of the spinal cord	Occasional (5-29%)
HP:0007183	Focal T2 hyperintense basal ganglia lesion	Occasional (5-29%)
HP:0009055	Generalized limb muscle atrophy	Occasional (5-29%)
HP:0025058	Hypothalamic atrophy	Occasional (5-29%)
HP:0025502	Overweight	Occasional (5-29%)
HP:0045007	Abnormality of the substantia nigra	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	hereditary spastic paraplegia 11
Mondo ID	MONDO:0011445
OMIM	604360
Orphanet	2822
DOID	DOID:0110764
NCIT	C148317
SNOMED CT	715491000
UMLS	C1858479
MedGen	388073
GARD	0004919
Is cancer (heuristic)	no

Also known as: autosomal recessive spastic paraplegia type 11 · hereditary spastic paraplegia caused by mutation in SPG11 · hereditary spastic paraplegia mental impairment and thin corpus callosum · hereditary spastic paraplegia type 11 · HSP-TCC · Nakamura Osame syndrome · Nakamura-Osame syndrome · spastic paraplegia - intellectual deficit - thin corpus callosum · spastic paraplegia 11 · spastic paraplegia 11, autosomal recessive · spastic paraplegia-intellectual disability-thin corpus callosum syndrome · SPG11 · SPG11 hereditary spastic paraplegia

Data availability: 3,252 ClinVar variants · 6 GenCC gene-disease records · 9 cell lines.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › complex hereditary spastic paraplegia › hereditary spastic paraplegia 11

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 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 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

600 retrieved; paginated sample, class counts are floors:

356 uncertain significance, 131 likely benign, 68 pathogenic, 19 conflicting classifications of pathogenicity, 11 likely pathogenic, 7 pathogenic/likely pathogenic, 5 benign, 3 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1387377	NM_025137.4(SPG11):c.5248del (p.Ser1750fs)	LOC130056971	Pathogenic	criteria provided, single submitter
1459028	NC_000015.9:g.(?44864989)(44988554_?)del	PATL2	Pathogenic	criteria provided, single submitter
1068457	NM_025137.4(SPG11):c.1654_1655insGGAAAATCTTTTTTTTTTTTTTTTTTTTTNNNNNNNNGGGAGAGGGAGAGGGAGAGGGAGAGGGAGAGGGAGAGGGAGAGGGGA (p.Ser551_Lys552insArgLysIlePhePhePhePhePhePhePheXaaXaaXaaGlyGluGlyGluGlyGluGlyGluGlyGluGlyGluGlyGluGly)	SPG11	Pathogenic	criteria provided, single submitter
1070626	NM_025137.4(SPG11):c.4109del (p.Asp1370fs)	SPG11	Pathogenic	criteria provided, multiple submitters, no conflicts
1070834	NM_025137.4(SPG11):c.6317_6335del (p.Ser2106fs)	SPG11	Pathogenic	criteria provided, single submitter
1071204	NM_025137.4(SPG11):c.7138G>T (p.Glu2380Ter)	SPG11	Pathogenic	criteria provided, multiple submitters, no conflicts
1071977	NM_025137.4(SPG11):c.4939C>T (p.Gln1647Ter)	SPG11	Pathogenic	criteria provided, single submitter
1072015	NM_025137.4(SPG11):c.4432C>T (p.Gln1478Ter)	SPG11	Pathogenic	criteria provided, single submitter
1072253	NC_000015.9:g.(?44876002)(44876766_?)del	SPG11	Pathogenic	criteria provided, single submitter
1072337	NM_025137.4(SPG11):c.7055_7058dup (p.Gln2354fs)	SPG11	Pathogenic	criteria provided, single submitter
1072750	NM_025137.4(SPG11):c.4621C>T (p.Gln1541Ter)	SPG11	Pathogenic	criteria provided, single submitter
1074115	NC_000015.9:g.(?44862713)(44867249_?)del	SPG11	Pathogenic	criteria provided, single submitter
1074116	NC_000015.9:g.(?44941054)(44944474_?)del	SPG11	Pathogenic	criteria provided, single submitter
1074117	NC_000015.9:g.(?44918519)(44921596_?)del	SPG11	Pathogenic	criteria provided, single submitter
1074118	NC_000015.9:g.(?44881444)(44925841_?)dup	SPG11	Pathogenic	criteria provided, single submitter
1074526	NM_025137.4(SPG11):c.5322del (p.Leu1775fs)	SPG11	Pathogenic	criteria provided, single submitter
1075394	NM_025137.4(SPG11):c.7093_7094insCTT (p.Glu2365delinsAlaTer)	SPG11	Pathogenic	criteria provided, single submitter
1075471	NM_025137.4(SPG11):c.3909del (p.Lys1303fs)	SPG11	Pathogenic	criteria provided, single submitter
1075919	NC_000015.9:g.(?44862703)(44862876_?)del	SPG11	Pathogenic	criteria provided, single submitter
1076252	NM_025137.4(SPG11):c.5972del (p.Cys1991fs)	SPG11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1109	NM_025137.4(SPG11):c.6100C>T (p.Arg2034Ter)	SPG11	Pathogenic	criteria provided, multiple submitters, no conflicts
1110	NM_025137.4(SPG11):c.529_533del (p.Ile177fs)	SPG11	Pathogenic	criteria provided, multiple submitters, no conflicts
1111	NM_025137.4(SPG11):c.118C>T (p.Gln40Ter)	SPG11	Pathogenic	criteria provided, multiple submitters, no conflicts
1112	NM_025137.4(SPG11):c.733_734del (p.Met245fs)	SPG11	Pathogenic	criteria provided, multiple submitters, no conflicts
1113	NM_025137.4(SPG11):c.2472_2473insT (p.Lys825Ter)	SPG11	Pathogenic	no assertion criteria provided
1114	NM_025137.4(SPG11):c.442+1G>C	SPG11	Pathogenic	criteria provided, multiple submitters, no conflicts
1115	NM_025137.4(SPG11):c.7152-1G>C	SPG11	Pathogenic	criteria provided, single submitter
1116	NM_025137.4(SPG11):c.5623C>T (p.Gln1875Ter)	SPG11	Pathogenic	criteria provided, multiple submitters, no conflicts
1117	NM_025137.4(SPG11):c.3075dup (p.Glu1026fs)	SPG11	Pathogenic	criteria provided, multiple submitters, no conflicts
1180685	NM_025137.4(SPG11):c.6811_6812del (p.Leu2271fs)	SPG11	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 12 · Orphanet: 8 · 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
SPG11	Definitive	Autosomal recessive	hereditary spastic paraplegia 11	12

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SPG11	Orphanet:2822	Autosomal recessive spastic paraplegia type 11
SPG11	Orphanet:300605	Juvenile amyotrophic lateral sclerosis
SPG11	Orphanet:466775	Autosomal recessive Charcot-Marie-Tooth disease type 2X
CAPN1	Orphanet:488594	Autosomal recessive spastic paraplegia type 76
PATL2	Orphanet:488191	Female infertility due to oocyte meiotic arrest
AGXT	Orphanet:93598	Primary hyperoxaluria type 1
B2M	Orphanet:314652	Variant ABeta2M amyloidosis
B2M	Orphanet:34592	Immunodeficiency by defective expression of MHC class I

Cohort genes → proteins

6 cohort genes, 6 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	6

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SPG11	HGNC:11226	ENSG00000104133	Q96JI7	Spatacsin	gencc,clinvar
CAPN1	HGNC:1476	ENSG00000014216	P07384	Calpain-1 catalytic subunit	clinvar
EIF3J	HGNC:3270	ENSG00000104131	O75822	Eukaryotic translation initiation factor 3 subunit J	clinvar
PATL2	HGNC:33630	ENSG00000229474	C9JE40	Protein PAT1 homolog 2	clinvar
AGXT	HGNC:341	ENSG00000172482	P21549	Alanine–glyoxylate aminotransferase	clinvar
B2M	HGNC:914	ENSG00000166710	P61769	Beta-2-microglobulin	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SPG11	Spatacsin	May play a role in neurite plasticity by maintaining cytoskeleton stability and regulating synaptic vesicle transport.
CAPN1	Calpain-1 catalytic subunit	Calcium-regulated non-lysosomal thiol-protease which catalyzes limited proteolysis of substrates involved in cytoskeletal remodeling and signal transduction.
EIF3J	Eukaryotic translation initiation factor 3 subunit J	Component of the eukaryotic translation initiation factor 3 (eIF-3) complex, which is required for several steps in the initiation of protein synthesis.
PATL2	Protein PAT1 homolog 2	RNA-binding protein that acts as a translational repressor.
AGXT	Alanine–glyoxylate aminotransferase	Peroxisomal aminotransferase that catalyzes the transamination of glyoxylate to glycine and contributes to the glyoxylate detoxification.
B2M	Beta-2-microglobulin	Component of the class I major histocompatibility complex (MHC).

Protein-family classification

Druggable: 3 · Difficult: 0 · Unknown: 3 · Druggable fraction: 0.5

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	6.1×	0.377
Antibody/Immunoglobulin	1	4.9×	0.377
Enzyme (other)	1	2.0×	0.543
Other/Unknown	3	0.9×	0.758

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SPG11	Other/Unknown	no		Spatacsin, Spatacsin_C_dom
CAPN1	Protease	yes	3.4.22.52	Pept_cys_AS, Peptidase_C2_calpain_cat, EF_hand_dom
EIF3J	Other/Unknown	no		eIF3j, eIF3-like_dom_sf
PATL2	Other/Unknown	no		PAT1_dom, Pat1-like
AGXT	Enzyme (other)	yes	2.6.1.44	Aminotrans_V_dom, PyrdxlP-dep_Trfase_major, PyrdxlP-dep_Trfase_small
B2M	Antibody/Immunoglobulin	yes		Ig/MHC_CS, Ig_C1-set, Ig-like_dom

Expression context

Cohort genes with no expression data: 0.

6 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)	6
unknown	0

Top tissues across cohort

Tissue	Cohort genes
granulocyte	3
endometrium epithelium	2
bronchial epithelial cell	1
calcaneal tendon	1
esophagus mucosa	1
lower esophagus mucosa	1
biceps brachii	1
body of pancreas	1
gastrocnemius	1
oocyte	1
secondary oocyte	1
liver	1
right lobe of liver	1
leukocyte	1
monocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SPG11	295	ubiquitous	marker	bronchial epithelial cell, granulocyte, calcaneal tendon
CAPN1	262	ubiquitous	marker	lower esophagus mucosa, endometrium epithelium, esophagus mucosa
EIF3J	296	ubiquitous	marker	gastrocnemius, biceps brachii, body of pancreas
PATL2	169	ubiquitous	marker	granulocyte, oocyte, secondary oocyte
AGXT	125	tissue_specific	marker	right lobe of liver, liver, endometrium epithelium
B2M	134	ubiquitous	marker	granulocyte, monocyte, leukocyte

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CAPN1	2,649
AGXT	2,648
EIF3J	2,228
SPG11	1,691
PATL2	868
B2M	415

Structural data

PDB: 5 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
B2M	P61769	1,226
AGXT	P21549	17
CAPN1	P07384	5
EIF3J	O75822	5
SPG11	Q96JI7	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PATL2	C9JE40	65.05

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 52. Enrichment computed across 6 evidence-associated genes (4 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 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Modulation by Mtb of host immune system	1	407.9×	0.033	B2M
Nef mediated downregulation of MHC class I complex cell surface expression	1	285.5×	0.033	B2M
Infection with Mycobacterium tuberculosis	1	285.5×	0.033	B2M
Endosomal/Vacuolar pathway	1	259.6×	0.033	B2M
Neurodegenerative Diseases	1	219.6×	0.033	CAPN1
Glyoxylate metabolism and glycine degradation	1	190.3×	0.033	AGXT
Defective Intrinsic Pathway for Apoptosis	1	190.3×	0.033	CAPN1
Nef-mediates down modulation of cell surface receptors by recruiting them to clathrin adapters	1	158.6×	0.033	B2M
The role of Nef in HIV-1 replication and disease pathogenesis	1	158.6×	0.033	B2M
Diseases of programmed cell death	1	158.6×	0.033	CAPN1
Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer’s disease models	1	129.8×	0.034	CAPN1
DAP12 interactions	1	119.0×	0.034	B2M
Antigen Presentation: Folding, assembly and peptide loading of class I MHC	1	98.5×	0.034	B2M
DAP12 signaling	1	92.1×	0.034	B2M
Host Interactions of HIV factors	1	84.0×	0.034	B2M
Bacterial Infection Pathways	1	84.0×	0.034	B2M
Innate Immune System	2	12.8×	0.034	CAPN1, B2M
Neutrophil degranulation	2	11.5×	0.034	CAPN1, B2M
Antigen processing-Cross presentation	1	79.3×	0.034	B2M
Formation of the ternary complex, and subsequently, the 43S complex	1	53.9×	0.047	EIF3J
Translation initiation complex formation	1	47.6×	0.047	EIF3J
Ribosomal scanning and start codon recognition	1	47.6×	0.047	EIF3J
Protein localization	1	47.6×	0.047	AGXT
Peroxisomal protein import	1	43.3×	0.050	AGXT
ER-Phagosome pathway	1	32.4×	0.055	B2M
Interferon gamma signaling	1	31.4×	0.055	B2M
Interferon Signaling	1	30.1×	0.055	B2M
HIV Infection	1	29.7×	0.055	B2M
SARS-CoV-2-host interactions	1	29.7×	0.055	B2M
Degradation of the extracellular matrix	1	29.4×	0.055	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 6 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
negative regulation of iron ion transport	1	2808.7×	0.008	B2M
phagosome-lysosome fusion involved in apoptotic cell clearance	1	2808.7×	0.008	SPG11
antigen processing and presentation of exogenous protein antigen via MHC class Ib, TAP-dependent	1	1404.3×	0.008	B2M
negative regulation of cytoplasmic mRNA processing body assembly	1	1404.3×	0.008	PATL2
regulation of iron ion transport	1	1404.3×	0.008	B2M
cellular response to iron(III) ion	1	1404.3×	0.008	B2M
negative regulation of forebrain neuron differentiation	1	1404.3×	0.008	B2M
obsolete glycine biosynthetic process, by transamination of glyoxylate	1	936.2×	0.008	AGXT
oxalic acid secretion	1	936.2×	0.008	AGXT
localization within membrane	1	936.2×	0.008	SPG11
axo-dendritic transport	1	702.2×	0.008	SPG11
glyoxylate catabolic process	1	702.2×	0.008	AGXT
L-cysteine catabolic process	1	702.2×	0.008	AGXT
L-alanine catabolic process	1	702.2×	0.008	AGXT
regulation of catalytic activity	1	561.7×	0.008	CAPN1
autophagosome organization	1	561.7×	0.008	SPG11
peptide antigen assembly with MHC class I protein complex	1	468.1×	0.008	B2M
regulation of erythrocyte differentiation	1	468.1×	0.008	B2M
glyoxylate metabolic process	1	468.1×	0.008	AGXT
mammary gland involution	1	468.1×	0.008	CAPN1
walking behavior	1	468.1×	0.008	SPG11
corticospinal tract morphogenesis	1	401.2×	0.008	SPG11
cellular response to iron ion	1	401.2×	0.008	B2M
NMDA selective glutamate receptor signaling pathway	1	401.2×	0.008	CAPN1
response to molecule of bacterial origin	1	351.1×	0.008	B2M
antigen processing and presentation of endogenous peptide antigen via MHC class I	1	351.1×	0.008	B2M
cellular response to nicotine	1	351.1×	0.008	B2M
negative regulation of receptor-mediated endocytosis	1	312.1×	0.009	B2M
deadenylation-dependent decapping of nuclear-transcribed mRNA	1	280.9×	0.009	PATL2
L-serine metabolic process	1	280.9×	0.009	AGXT

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 1 · Undrugged: 5

Druggability breadth: 5 of 6 evidence-associated genes (83%) 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
SPG11	0	0
EIF3J	0	0
PATL2	0	0
AGXT	0	0
B2M	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
ALOXISTATIN	2	CAPN1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
CAPN1	213	Binding:202, Functional:10, Toxicity:1
AGXT	8	Binding:8
B2M	5	Binding:5
SPG11	1	Binding:1
EIF3J	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
CAPN1	3.4.22.52, 3.4.22.53	calpain-1, calpain-2
AGXT	2.6.1.44, 2.6.1.51	alanine-glyoxylate transaminase, serine-pyruvate transaminase

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: 6; 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	2	AGXT, B2M
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	3	SPG11, EIF3J, PATL2

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
SPG11	1	—
EIF3J	1	—
PATL2	0	—
AGXT	8	—
B2M	5	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT04712812	Not specified	RECRUITING	Registry and Natural History Study for Early Onset Hereditary Spastic Paraplegia