Hereditary spastic paraplegia 4

Summary

Hereditary spastic paraplegia 4 (MONDO:0008438) is a disease caused by SPAST (GenCC Definitive), with 11 cohort genes and 3 clinical trials.

At a glance

• Prevalence: 1-9 / 1 000 000 (Portugal) [Orphanet-validated]
• Causal gene: SPAST (GenCC Definitive)
• Cohort genes: 11
• ClinVar variants: 1,233
• Phenotypes (HPO): 19
• Clinical trials: 3

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 1 000 000	0.91	Portugal	Validated

Signs & symptoms

Clinical features (HPO)

19 HPO clinical features (Orphanet curated; top 19 by frequency):

HPO ID	Term	Frequency
HP:0000012	Urinary urgency	Frequent (30-79%)
HP:0001257	Spasticity	Frequent (30-79%)
HP:0001348	Brisk reflexes	Frequent (30-79%)
HP:0002061	Lower limb spasticity	Frequent (30-79%)
HP:0003487	Babinski sign	Frequent (30-79%)
HP:0004302	Functional motor deficit	Frequent (30-79%)
HP:0006938	Impaired vibration sensation at ankles	Frequent (30-79%)
HP:0007340	Lower limb muscle weakness	Frequent (30-79%)
HP:0008969	Leg muscle stiffness	Frequent (30-79%)
HP:0011448	Ankle clonus	Frequent (30-79%)
HP:0001260	Dysarthria	Occasional (5-29%)
HP:0001761	Pes cavus	Occasional (5-29%)
HP:0002839	Urinary bladder sphincter dysfunction	Occasional (5-29%)
HP:0003693	Distal amyotrophy	Occasional (5-29%)
HP:0007350	Hyperreflexia in upper limbs	Occasional (5-29%)
HP:0100543	Cognitive impairment	Occasional (5-29%)
HP:0001249	Intellectual disability	Very rare (<1-4%)
HP:0001250	Seizure	Very rare (<1-4%)
HP:0001251	Ataxia	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	hereditary spastic paraplegia 4
Mondo ID	MONDO:0008438
MeSH	C536865
OMIM	182601
Orphanet	100985
DOID	DOID:0110792
NCIT	C129981
SNOMED CT	723820001
UMLS	C1866855
MedGen	401097
GARD	0004925
Is cancer (heuristic)	no

Also known as: autosomal dominant spastic paraplegia type 4 · familial spastic paraplegia autosomal dominant 2 · FSP2 · hereditary spastic paraplegia 4 · hereditary spastic paraplegia caused by mutation in SPAST · hereditary spastic paraplegia type 4 · SPAST hereditary spastic paraplegia · spastic paraplegia 4 · spastic paraplegia 4, autosomal dominant · SPG4

Data availability: 1,233 ClinVar variants · 6 GenCC gene-disease records · 6 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 4

Related subtypes (44): hereditary spastic paraplegia 3A, 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 31, 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

600 retrieved; paginated sample, class counts are floors:

203 pathogenic, 169 uncertain significance, 134 likely benign, 36 likely pathogenic, 26 pathogenic/likely pathogenic, 18 conflicting classifications of pathogenicity, 7 benign/likely benign, 6 benign, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
219057	Single allele	BIRC6	Pathogenic	criteria provided, single submitter
219060	Single allele	BIRC6	Pathogenic	criteria provided, single submitter
219087	Single allele	BIRC6	Pathogenic	criteria provided, single submitter
219058	Single allele	DPY30	Pathogenic	criteria provided, single submitter
219095	Single allele	DPY30	Pathogenic	criteria provided, single submitter
2572634	NM_021870.3(FGG):c.1201C>T (p.Arg401Trp)	FGG	Pathogenic	criteria provided, multiple submitters, no conflicts
15932	NM_000516.7(GNAS):c.493C>T (p.Arg165Cys)	GNAS	Pathogenic	criteria provided, multiple submitters, no conflicts
219064	Single allele	LOC129388840	Pathogenic	criteria provided, single submitter
219093	Single allele	LOC129388840	Pathogenic	criteria provided, single submitter
219063	Single allele	LOC129933454	Pathogenic	criteria provided, single submitter
219071	Single allele	LOC129933454	Pathogenic	criteria provided, single submitter
219074	NC_000002.12:g.32063148_32067182del	LOC129933454	Pathogenic	criteria provided, single submitter
219076	Single allele	LOC129933454	Pathogenic	criteria provided, single submitter
219086	Single allele	LOC129933455	Pathogenic	criteria provided, single submitter
267324	NC_000002.12:g.(?32063826)(32087584_?)del	LOC129933455	Pathogenic	criteria provided, single submitter
11510	NM_001011658.4(TRAPPC2):c.271_275del (p.Gln91fs)	OFD1	Pathogenic	criteria provided, multiple submitters, no conflicts
11068	NM_001015877.2(PHF6):c.2T>C (p.Met1Thr)	PHF6	Pathogenic	criteria provided, multiple submitters, no conflicts
219052	Single allele	SLC30A6	Pathogenic	criteria provided, single submitter
219054	Single allele	SLC30A6	Pathogenic	criteria provided, single submitter
219055	Single allele	SLC30A6	Pathogenic	criteria provided, single submitter
219061	Single allele	SLC30A6	Pathogenic	criteria provided, single submitter
219062	Single allele	SLC30A6	Pathogenic	criteria provided, single submitter
219077	Single allele	SLC30A6	Pathogenic	criteria provided, single submitter
219078	Single allele	SLC30A6	Pathogenic	criteria provided, single submitter
219085	Single allele	SLC30A6	Pathogenic	criteria provided, single submitter
219083	Single allele	SLC30A6-DT	Pathogenic	criteria provided, single submitter
1013407	NM_014946.4(SPAST):c.1210_1212del (p.Phe404del)	SPAST	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1038129	NM_014946.4(SPAST):c.1349G>A (p.Arg450Lys)	SPAST	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1065986	NM_014946.4(SPAST):c.1724_1725insGCCGGGCGCGGTGGCTCACGCCTGTAATCCCAGCACTTTGGGAGGCCGAGGCGGGCGGATCACGAGGTCANNNNNNNNNNNNAAAAAAAAAAAAAAAAAAGAATATGTCTGCCAG (p.Ser575fs)	SPAST	Pathogenic	criteria provided, single submitter
1066782	NM_014946.4(SPAST):c.1492A>G (p.Arg498Gly)	SPAST	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · Orphanet: 30 · 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
SPAST	Definitive	Autosomal dominant	hereditary spastic paraplegia 4	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SPAST	Orphanet:100985	Autosomal dominant spastic paraplegia type 4
TCF4	Orphanet:171	Primary sclerosing cholangitis
TCF4	Orphanet:178469	Autosomal dominant non-syndromic intellectual disability
TCF4	Orphanet:2896	Pitt-Hopkins syndrome
TCF4	Orphanet:98974	Fuchs endothelial corneal dystrophy
PHF6	Orphanet:127	Borjeson-Forssman-Lehmann syndrome
COL3A1	Orphanet:231160	Familial cerebral saccular aneurysm
COL3A1	Orphanet:2500	Acrogeria
COL3A1	Orphanet:286	Vascular Ehlers-Danlos syndrome
COL3A1	Orphanet:636941	Vascular Ehlers-Danlos-polymicrogyria syndrome
COL3A1	Orphanet:86	Familial abdominal aortic aneurysm
OFD1	Orphanet:244	Primary ciliary dyskinesia
OFD1	Orphanet:2750	Orofaciodigital syndrome type 1
OFD1	Orphanet:2754	Orofaciodigital syndrome type 6
OFD1	Orphanet:475	Isolated Joubert syndrome
OFD1	Orphanet:791	Retinitis pigmentosa
FGG	Orphanet:101041	Familial hypofibrinogenemia
FGG	Orphanet:248408	Familial hypodysfibrinogenemia
FGG	Orphanet:98880	Familial afibrinogenemia
FGG	Orphanet:98881	Familial dysfibrinogenemia
GNAS	Orphanet:189427	Cushing syndrome due to bilateral macronodular adrenocortical disease
GNAS	Orphanet:2762	Progressive osseous heteroplasia
GNAS	Orphanet:562	McCune-Albright syndrome
GNAS	Orphanet:57782	Mazabraud syndrome
GNAS	Orphanet:79443	Pseudohypoparathyroidism type 1A
GNAS	Orphanet:79444	Pseudohypoparathyroidism type 1C
GNAS	Orphanet:79445	Pseudopseudohypoparathyroidism
GNAS	Orphanet:93276	Polyostotic fibrous dysplasia
GNAS	Orphanet:93277	Monostotic fibrous dysplasia
GNAS	Orphanet:94089	Pseudohypoparathyroidism type 1B

Cohort genes → proteins

11 cohort genes, 10 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	11

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SPAST	HGNC:11233	ENSG00000021574	Q9UBP0	Spastin	gencc,clinvar
TCF4	HGNC:11634	ENSG00000196628	P15884	Transcription factor 4	clinvar
BIRC6	HGNC:13516	ENSG00000115760	Q9NR09	Dual E2 ubiquitin-conjugating enzyme/E3 ubiquitin-protein ligase BIRC6	clinvar
PHF6	HGNC:18145	ENSG00000156531	Q8IWS0	PHD finger protein 6	clinvar
SLC30A6	HGNC:19305	ENSG00000152683	Q6NXT4	Zinc transporter 6	clinvar
COL3A1	HGNC:2201	ENSG00000168542	P02461	Collagen alpha-1(III) chain	clinvar
DPY30	HGNC:24590	ENSG00000162961	Q9C005	Protein dpy-30 homolog	clinvar
OFD1	HGNC:2567	ENSG00000046651	O75665	Centriole and centriolar satellite protein OFD1	clinvar
FGG	HGNC:3694	ENSG00000171557	P02679	Fibrinogen gamma chain	clinvar
GNAS	HGNC:4392	ENSG00000087460	O95467	Neuroendocrine secretory protein 55	clinvar
SLC30A6-DT	HGNC:55203	ENSG00000272716		SLC30A6 divergent transcript	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SPAST	Spastin	ATP-dependent microtubule severing protein that specifically recognizes and cuts microtubules that are polyglutamylated.
TCF4	Transcription factor 4	Transcription factor that binds to the immunoglobulin enhancer Mu-E5/KE5-motif.
BIRC6	Dual E2 ubiquitin-conjugating enzyme/E3 ubiquitin-protein ligase BIRC6	Anti-apoptotic protein known as inhibitor of apoptosis (IAP) which can regulate cell death by controlling caspases and by acting as an E3 ubiquitin-protein ligase.
PHF6	PHD finger protein 6	Transcriptional regulator that associates with ribosomal RNA promoters and suppresses ribosomal RNA (rRNA) transcription.
SLC30A6	Zinc transporter 6	Has probably no intrinsic transporter activity but together with SLC30A5 forms a functional zinc ion:proton antiporter heterodimer, mediating zinc entry into the lumen of organelles along the secretory pathway.
COL3A1	Collagen alpha-1(III) chain	Collagen type III occurs in most soft connective tissues along with type I collagen.
DPY30	Protein dpy-30 homolog	As part of the MLL1/MLL complex, involved in the methylation of histone H3 at ‘Lys-4’, particularly trimethylation.
OFD1	Centriole and centriolar satellite protein OFD1	Component of the centrioles controlling mother and daughter centrioles length.
FGG	Fibrinogen gamma chain	Together with fibrinogen alpha (FGA) and fibrinogen beta (FGB), polymerizes to form an insoluble fibrin matrix.

Protein-family classification

Druggable: 1 · Difficult: 2 · Unknown: 8 · Druggable fraction: 0.09

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
Transcription factor	2	1.5×	0.588
Other/Unknown	8	1.3×	0.588
Enzyme (other)	1	1.1×	0.616

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SPAST	Enzyme (other)	yes	5.6.1.1	AAA+_ATPase, ATPase_AAA_core, ATPase_AAA_CS
TCF4	Transcription factor	no	7.6.2.3	bHLH_dom, HLH_DNA-bd_sf, NeuroDiff_E-box_TFs
BIRC6	Other/Unknown	no		UBC, BIR_rpt, UBQ-conjugating_enzyme/RWD
PHF6	Transcription factor	no		Znf_PHD, Znf_RING/FYVE/PHD, EPHD
SLC30A6	Other/Unknown	no		Cation_efflux, Cation_efflux_TMD_sf, CDF_SLC30A
COL3A1	Other/Unknown	no		Fib_collagen_C, VWF_dom, Collagen
DPY30	Other/Unknown	no		Dpy-30_motif, Sdc1/DPY30, DPY30_SDC1_DD
OFD1	Other/Unknown	no		LisH, OFD1
FGG	Other/Unknown	no		Fibrinogen_a/b/g_C_dom, Fibrinogen_a/b/g_coil_dom, Fibrinogen_a/b/g_C_1
GNAS	Other/Unknown	no		NESP55, Gprotein_alpha_S, Gprotein_alpha_su
SLC30A6-DT	Other/Unknown	no

Expression context

Cohort genes with no expression data: 0.

10 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)	11
unknown	0

Top tissues across cohort

Tissue	Cohort genes
oocyte	2
endothelial cell	2
skin of hip	2
bronchial epithelial cell	2
type B pancreatic cell	2
cortical plate	1
secondary oocyte	1
pericardium	1
calcaneal tendon	1
epithelial cell of pancreas	1
oviduct epithelium	1
corpus epididymis	1
ileal mucosa	1
left ventricle myocardium	1
tibialis anterior	1
parietal pleura	1
visceral pleura	1
bronchus	1
olfactory segment of nasal mucosa	1
cervix squamous epithelium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SPAST	284	ubiquitous	marker	cortical plate, oocyte, secondary oocyte
TCF4	292	ubiquitous	marker	endothelial cell, skin of hip, pericardium
BIRC6	256	ubiquitous	marker	epithelial cell of pancreas, oviduct epithelium, calcaneal tendon
PHF6	254	ubiquitous	marker	corpus epididymis, oocyte, endothelial cell
SLC30A6	247	ubiquitous	marker	left ventricle myocardium, tibialis anterior, ileal mucosa
COL3A1	281	ubiquitous	marker	skin of hip, parietal pleura, visceral pleura
DPY30	256	ubiquitous	marker	bronchial epithelial cell, bronchus, olfactory segment of nasal mucosa
OFD1	288	ubiquitous	marker	sperm, bronchial epithelial cell, cervix squamous epithelium
FGG	157	broad	marker	right lobe of liver, liver, type B pancreatic cell
GNAS	312	ubiquitous	marker	type B pancreatic cell, postcentral gyrus, Brodmann (1909) area 46
SLC30A6-DT	129	broad	yes	male germ line stem cell (sensu Vertebrata) in testis, primordial germ cell in gonad, bone marrow cell

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
BIRC6	5,905
DPY30	3,894
COL3A1	3,629
SPAST	3,393
TCF4	3,342
PHF6	2,999
OFD1	2,878
FGG	2,018
SLC30A6	1,732
GNAS	410

Structural data

PDB: 8 · AlphaFold-only: 2 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GNAS	O95467	490
FGG	P02679	47
BIRC6	Q9NR09	22
DPY30	Q9C005	12
COL3A1	P02461	11
SPAST	Q9UBP0	7
TCF4	P15884	5
PHF6	Q8IWS0	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SLC30A6	Q6NXT4	71.44
OFD1	O75665	68.41

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 86. Enrichment computed across 11 evidence-associated genes (9 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 9 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Aggregated β-amyloid interacts with fibrinogen	1	317.2×	0.068	FGG
Loss of Function of KMT2D in MLL4 Complex Formation in Kabuki Syndrome	1	253.8×	0.068	DPY30
Hedgehog ‘off’ state	2	39.6×	0.068	OFD1, GNAS
Integrin cell surface interactions	2	29.9×	0.068	COL3A1, FGG
Formation of the beta-catenin:TCF transactivating complex	2	26.7×	0.068	TCF4, DPY30
ALK mutants bind TKIs	1	105.7×	0.075	BIRC6
Fibrin formation	1	97.6×	0.075	FGG
p130Cas linkage to MAPK signaling for integrins	1	84.6×	0.075	FGG
GRB2:SOS provides linkage to MAPK signaling for Integrins	1	79.3×	0.075	FGG
PKA activation in glucagon signalling	1	74.6×	0.075	GNAS
Scavenging by Class A Receptors	1	66.8×	0.075	COL3A1
Prostacyclin signalling through prostacyclin receptor	1	66.8×	0.075	GNAS
MyD88 deficiency (TLR2/4)	1	66.8×	0.075	FGG
Fibronectin matrix formation	1	63.4×	0.075	COL3A1
IRAK4 deficiency (TLR2/4)	1	63.4×	0.075	FGG
Regulation of TLR by endogenous ligand	1	55.2×	0.075	FGG
TGFBR3 expression	1	50.8×	0.075	TCF4
Syndecan interactions	1	47.0×	0.075	COL3A1
Integrin signaling	1	47.0×	0.075	FGG
Myogenesis	1	42.3×	0.075	TCF4
MET activates PTK2 signaling	1	42.3×	0.075	COL3A1
Signaling by TGFBR3	1	40.9×	0.075	TCF4
Glucagon signaling in metabolic regulation	1	38.5×	0.075	GNAS
Glucagon-type ligand receptors	1	38.5×	0.075	GNAS
Sealing of the nuclear envelope (NE) by ESCRT-III	1	38.5×	0.075	SPAST
Signaling by high-kinase activity BRAF mutants	1	35.2×	0.075	FGG
Nuclear Envelope (NE) Reassembly	1	32.5×	0.075	SPAST
MAP2K and MAPK activation	1	31.7×	0.075	FGG
Signaling by RAF1 mutants	1	30.9×	0.075	FGG
Signaling by ALK in cancer	1	30.2×	0.075	BIRC6

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 10 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 zinc ion transport	1	1685.2×	0.019	SLC30A6
obsolete negative regulation of fibroblast growth factor receptor signaling pathway involved in neural plate anterior/posterior pattern formation	1	842.6×	0.019	OFD1
cytokinetic process	1	561.7×	0.019	SPAST
transforming growth factor beta1 production	1	561.7×	0.019	COL3A1
limb joint morphogenesis	1	561.7×	0.019	COL3A1
adenylate cyclase-activating G protein-coupled bile acid receptor signaling pathway	1	561.7×	0.019	GNAS
mitotic spindle disassembly	1	561.7×	0.019	SPAST
protein-DNA complex assembly	1	561.7×	0.019	TCF4
zinc ion import into Golgi lumen	1	561.7×	0.019	SLC30A6
platelet aggregation	2	67.4×	0.019	FGG, GNAS
protein secretion	2	52.7×	0.019	FGG, GNAS
cell-matrix adhesion	2	32.7×	0.019	COL3A1, FGG
endochondral bone morphogenesis	1	421.3×	0.020	COL3A1
aorta smooth muscle tissue morphogenesis	1	421.3×	0.020	COL3A1
response to parathyroid hormone	1	421.3×	0.020	GNAS
adenylate cyclase-activating serotonin receptor signaling pathway	1	337.0×	0.021	GNAS
positive regulation of microtubule depolymerization	1	337.0×	0.021	SPAST
hair follicle placode formation	1	337.0×	0.021	GNAS
regulation of skeletal muscle contraction	1	280.9×	0.024	GNAS
cellular response to catecholamine stimulus	1	240.7×	0.025	GNAS
embryonic body morphogenesis	1	210.7×	0.025	OFD1
labyrinthine layer development	1	210.7×	0.025	BIRC6
central nervous system neuron axonogenesis	1	187.2×	0.025	SPAST
response to angiotensin	1	187.2×	0.025	COL3A1
mitotic nuclear membrane reassembly	1	168.5×	0.025	SPAST
blood coagulation, fibrin clot formation	1	168.5×	0.025	FGG
zinc ion transport	1	153.2×	0.025	SLC30A6
adenylate cyclase-activating dopamine receptor signaling pathway	1	153.2×	0.025	GNAS
intracellular transport	1	153.2×	0.025	GNAS
elastic fiber assembly	1	153.2×	0.025	COL3A1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 1 · Undrugged: 10

Druggability breadth: 8 of 11 evidence-associated genes (73%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TCF4	1	2
SPAST	0	0
BIRC6	0	0
PHF6	0	0
SLC30A6	0	0
COL3A1	0	0
DPY30	0	0
OFD1	0	0
FGG	0	0
GNAS	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
SALINOMYCIN	2	TCF4

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
TCF4	31	Binding:31
PHF6	4	Binding:4
DPY30	3	Binding:3
SPAST	1	Binding:1
SLC30A6	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
SPAST	5.6.1.1	microtubule-severing ATPase
TCF4	7.6.2.3	ABC-type glutathione-S-conjugate transporter

Pharmacogenomics

Cohort genes with a PharmGKB record: 10; 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)
SALINOMYCIN	2	TCF4

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	TCF4
C	Druggable family + PDB, no drug	1	SPAST
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	9	BIRC6, PHF6, SLC30A6, COL3A1, DPY30, OFD1, FGG, GNAS, SLC30A6-DT

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
SPAST	1	—
BIRC6	0	—
PHF6	4	—
SLC30A6	1	—
COL3A1	0	—
DPY30	3	—
OFD1	0	—
FGG	0	—
GNAS	0	—
SLC30A6-DT	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 3.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	3

Top trials by phase / activity

NCT	Phase	Status	Title
NCT04712812	Not specified	RECRUITING	Registry and Natural History Study for Early Onset Hereditary Spastic Paraplegia
NCT06553976	Not specified	RECRUITING	Spastic Paraplegia - Centers of Excellence Research Network
NCT03204773	Not specified	COMPLETED	Studying Non-motor Symptoms in HSP