Hereditary spastic paraplegia 30

Summary

Hereditary spastic paraplegia 30 (MONDO:0012476) is a disease caused by KIF1A (GenCC Strong), with 3 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: KIF1A (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 2,838
• Phenotypes (HPO): 15

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		3	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

15 HPO clinical features (Orphanet curated; top 15 by frequency):

HPO ID	Term	Frequency
HP:0002061	Lower limb spasticity	Very frequent (80-99%)
HP:0002064	Spastic gait	Very frequent (80-99%)
HP:0002317	Unsteady gait	Very frequent (80-99%)
HP:0002395	Lower limb hyperreflexia	Very frequent (80-99%)
HP:0003487	Babinski sign	Very frequent (80-99%)
HP:0007020	Progressive spastic paraplegia	Very frequent (80-99%)
HP:0008969	Leg muscle stiffness	Very frequent (80-99%)
HP:0000570	Abnormal saccadic eye movements	Frequent (30-79%)
HP:0001251	Ataxia	Frequent (30-79%)
HP:0002936	Distal sensory impairment	Frequent (30-79%)
HP:0003474	Somatic sensory dysfunction	Frequent (30-79%)
HP:0003693	Distal amyotrophy	Frequent (30-79%)
HP:0007141	Sensorimotor neuropathy	Frequent (30-79%)
HP:0012407	Scissor gait	Frequent (30-79%)
HP:0100275	Diffuse cerebellar atrophy	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	hereditary spastic paraplegia 30
Mondo ID	MONDO:0012476
MeSH	C563677
Orphanet	101010
DOID	DOID:0110781
SNOMED CT	763377006
UMLS	C5235139
MedGen	1710020
GARD	0016942
Is cancer (heuristic)	no

Also known as: autosomal spastic paraplegia type 30 · hereditary spastic paraplegia caused by mutation in KIF1A · hereditary spastic paraplegia type 30 · KIF1A hereditary spastic paraplegia · spastic paraplegia 30, autosomal dominant · SPG30

Data availability: 2,838 ClinVar variants · 5 GenCC gene-disease records · 1 cell line.

Disease family

An umbrella term covering 2 Mondo subtypes.

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 30

Related subtypes (44): hereditary spastic paraplegia 3A, hereditary spastic paraplegia 4, 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 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

Subtypes (2): spastic paraplegia 30A, autosomal dominant, spastic paraplegia 30B, autosomal recessive

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:

248 likely benign, 234 uncertain significance, 67 conflicting classifications of pathogenicity, 19 benign, 15 pathogenic, 11 likely pathogenic, 6 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1411455	NC_000002.11:g.(?238233417)(242801596_?)del	ATG4B	Pathogenic	criteria provided, single submitter
1004912	NM_001244008.2(KIF1A):c.934A>C (p.Thr312Pro)	KIF1A	Pathogenic	criteria provided, single submitter
1058331	NM_001244008.2(KIF1A):c.467A>T (p.Asp156Val)	KIF1A	Pathogenic	criteria provided, single submitter
1076894	NC_000002.11:g.(?_241656771)_241759735del	KIF1A	Pathogenic	criteria provided, single submitter
1349128	NM_001244008.2(KIF1A):c.173C>G (p.Ser58Trp)	KIF1A	Pathogenic	criteria provided, single submitter
1395436	NM_001244008.2(KIF1A):c.785_798+1del	KIF1A	Pathogenic	criteria provided, single submitter
1413300	NM_001244008.2(KIF1A):c.361C>T (p.Gln121Ter)	KIF1A	Pathogenic	criteria provided, single submitter
1439490	NM_001244008.2(KIF1A):c.4529del (p.Pro1510fs)	KIF1A	Pathogenic	criteria provided, single submitter
1451452	NM_001244008.2(KIF1A):c.2389G>T (p.Glu797Ter)	KIF1A	Pathogenic	criteria provided, single submitter
1451736	NM_001244008.2(KIF1A):c.864+1del	KIF1A	Pathogenic	criteria provided, single submitter
1452132	NM_001244008.2(KIF1A):c.1031C>T (p.Thr344Met)	KIF1A	Pathogenic	criteria provided, multiple submitters, no conflicts
1454352	NM_001244008.2(KIF1A):c.919C>T (p.Arg307Ter)	KIF1A	Pathogenic	criteria provided, single submitter
1456633	NM_001244008.2(KIF1A):c.2270_2271del (p.Gln757fs)	KIF1A	Pathogenic	criteria provided, single submitter
1459290	NM_001244008.2(KIF1A):c.4624del (p.Leu1542fs)	KIF1A	Pathogenic	criteria provided, single submitter
1460332	NC_000002.11:g.(?241676460)(241686758_?)del	KIF1A	Pathogenic	criteria provided, single submitter
1001813	NM_001244008.2(KIF1A):c.32G>T (p.Arg11Leu)	KIF1A	Likely pathogenic	criteria provided, single submitter
1023002	NM_001244008.2(KIF1A):c.748G>T (p.Ala250Ser)	KIF1A	Likely pathogenic	criteria provided, single submitter
1027416	NM_001244008.2(KIF1A):c.609_610delinsAAAAG (p.Thr204delinsLysAla)	KIF1A	Likely pathogenic	criteria provided, single submitter
1467822	NM_001244008.2(KIF1A):c.1037+1G>C	KIF1A	Likely pathogenic	criteria provided, single submitter
1472010	NM_001244008.2(KIF1A):c.958+1G>C	KIF1A	Likely pathogenic	criteria provided, single submitter
1477424	NM_001244008.2(KIF1A):c.760C>G (p.Arg254Gly)	KIF1A	Likely pathogenic	criteria provided, single submitter
1486265	NM_001244008.2(KIF1A):c.759G>C (p.Glu253Asp)	KIF1A	Likely pathogenic	criteria provided, single submitter
1505292	NM_001244008.2(KIF1A):c.79A>T (p.Ile27Phe)	KIF1A	Likely pathogenic	criteria provided, single submitter
1507070	NM_001244008.2(KIF1A):c.773C>A (p.Thr258Lys)	KIF1A	Likely pathogenic	criteria provided, single submitter
1513283	NM_001244008.2(KIF1A):c.3374+2T>G	KIF1A	Likely pathogenic	criteria provided, single submitter
1524644	NM_001244008.2(KIF1A):c.1578-2A>G	KIF1A	Likely pathogenic	criteria provided, single submitter
1003221	NM_001244008.2(KIF1A):c.4391G>T (p.Gly1464Val)	KIF1A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1005458	NM_001244008.2(KIF1A):c.3776G>A (p.Arg1259His)	KIF1A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1009584	NM_001244008.2(KIF1A):c.2341G>A (p.Ala781Thr)	KIF1A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1010452	NM_001244008.2(KIF1A):c.4999G>A (p.Asp1667Asn)	KIF1A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 19 · Orphanet: 4 · 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
KIF1A	Strong	Autosomal dominant	hereditary spastic paraplegia 30	19

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
KIF1A	Orphanet:101010	Autosomal spastic paraplegia type 30
KIF1A	Orphanet:662367	NESCAV syndrome
KIF1A	Orphanet:970	Hereditary sensory and autonomic neuropathy type 2
AGXT	Orphanet:93598	Primary hyperoxaluria type 1

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
KIF1A	HGNC:888	ENSG00000130294	Q12756	Kinesin-like protein KIF1A	gencc,clinvar
ATG4B	HGNC:20790	ENSG00000168397	Q9Y4P1	Cysteine protease ATG4B	clinvar
AGXT	HGNC:341	ENSG00000172482	P21549	Alanine–glyoxylate aminotransferase	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
KIF1A	Kinesin-like protein KIF1A	Kinesin motor with a plus-end-directed microtubule motor activity.
ATG4B	Cysteine protease ATG4B	Cysteine protease that plays a key role in autophagy by mediating both proteolytic activation and delipidation of ATG8 family proteins.
AGXT	Alanine–glyoxylate aminotransferase	Peroxisomal aminotransferase that catalyzes the transamination of glyoxylate to glycine and contributes to the glyoxylate detoxification.

Protein-family classification

Druggable: 2 · Difficult: 1 · Unknown: 0 · Druggable fraction: 0.67

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	12.2×	0.230
Scaffold/PPI	1	5.8×	0.230
Enzyme (other)	1	4.0×	0.230

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
KIF1A	Scaffold/PPI	no	5.6.1.3	FHA_dom, Kinesin_motor_dom, PH_domain
ATG4B	Protease	yes		Peptidase_C54, Papain-like_cys_pep_sf, Peptidase_C54_cat
AGXT	Enzyme (other)	yes	2.6.1.44	Aminotrans_V_dom, PyrdxlP-dep_Trfase_major, PyrdxlP-dep_Trfase_small

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
parietal lobe	1
postcentral gyrus	1
right frontal lobe	1
cerebellar cortex	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1
endometrium epithelium	1
liver	1
right lobe of liver	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
KIF1A	198	broad	marker	right frontal lobe, postcentral gyrus, parietal lobe
ATG4B	289	ubiquitous	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
AGXT	125	tissue_specific	marker	right lobe of liver, liver, endometrium epithelium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
KIF1A	2,833
AGXT	2,648
ATG4B	2,076

Structural data

PDB: 3 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
KIF1A	Q12756	21
AGXT	P21549	17
ATG4B	Q9Y4P1	7

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 15. Enrichment computed across 3 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Glyoxylate metabolism and glycine degradation	1	253.8×	0.047	AGXT
Protein localization	1	63.4×	0.047	AGXT
Kinesins	1	59.5×	0.047	KIF1A
Peroxisomal protein import	1	57.7×	0.047	AGXT
Autophagy	1	49.4×	0.047	ATG4B
Golgi-to-ER retrograde transport	1	44.3×	0.047	KIF1A
Macroautophagy	1	38.5×	0.047	ATG4B
COPI-dependent Golgi-to-ER retrograde traffic	1	37.0×	0.047	KIF1A
Intra-Golgi and retrograde Golgi-to-ER traffic	1	34.9×	0.047	KIF1A
Metabolism of amino acids and derivatives	1	22.5×	0.061	AGXT
Factors involved in megakaryocyte development and platelet production	1	22.1×	0.061	KIF1A
Membrane Trafficking	1	12.4×	0.090	KIF1A
Hemostasis	1	12.0×	0.090	KIF1A
Vesicle-mediated transport	1	11.6×	0.090	KIF1A
Metabolism	1	3.9×	0.237	AGXT

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
otolith mineralization completed early in development	1	5617.3×	0.002	ATG4B
microautophagy	1	1872.4×	0.002	ATG4B
obsolete glycine biosynthetic process, by transamination of glyoxylate	1	1872.4×	0.002	AGXT
oxalic acid secretion	1	1872.4×	0.002	AGXT
glyoxylate catabolic process	1	1404.3×	0.002	AGXT
L-cysteine catabolic process	1	1404.3×	0.002	AGXT
L-alanine catabolic process	1	1404.3×	0.002	AGXT
dense core granule cytoskeletal transport	1	1404.3×	0.002	KIF1A
anterograde neuronal dense core vesicle transport	1	1404.3×	0.002	KIF1A
protein delipidation	1	1123.5×	0.002	ATG4B
retrograde neuronal dense core vesicle transport	1	1123.5×	0.002	KIF1A
glyoxylate metabolic process	1	936.2×	0.002	AGXT
L-serine metabolic process	1	561.7×	0.003	AGXT
aggrephagy	1	561.7×	0.003	ATG4B
regulation of dendritic spine development	1	561.7×	0.003	KIF1A
protein localization to phagophore assembly site	1	330.4×	0.005	ATG4B
piecemeal microautophagy of the nucleus	1	312.1×	0.005	ATG4B
regulation of dendritic spine morphogenesis	1	280.9×	0.006	KIF1A
anterograde axonal transport	1	193.7×	0.008	KIF1A
mitophagy	1	106.0×	0.013	ATG4B
macroautophagy	1	80.2×	0.017	ATG4B
autophagosome assembly	1	74.9×	0.017	ATG4B
protein processing	1	56.7×	0.021	ATG4B
Notch signaling pathway	1	47.2×	0.025	AGXT
autophagy	1	36.7×	0.030	ATG4B
vesicle-mediated transport	1	32.1×	0.033	KIF1A
protein transport	1	14.6×	0.069	ATG4B
proteolysis	1	11.4×	0.085	ATG4B

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 2

Druggability breadth: 3 of 3 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
ATG4B	TIOCONAZOLE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ATG4B	7	4
KIF1A	0	0
AGXT	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
TIOCONAZOLE	4	ATG4B
BIFONAZOLE	4	ATG4B
HYPERICIN	3	ATG4B
EBSELEN	3	ATG4B
TOLFENAMIC ACID	2	ATG4B
FENTICLOR	2	ATG4B
ELLAGIC ACID	2	ATG4B

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
ATG4B	63	Binding:61, Functional:2
AGXT	8	Binding:8
KIF1A	2	Binding:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
KIF1A	5.6.1.3	plus-end-directed kinesin ATPase
AGXT	2.6.1.44, 2.6.1.51	alanine-glyoxylate transaminase, serine-pyruvate transaminase

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

7 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)
TIOCONAZOLE	4	ATG4B
BIFONAZOLE	4	ATG4B
HYPERICIN	3	ATG4B
EBSELEN	3	ATG4B
TOLFENAMIC ACID	2	ATG4B
FENTICLOR	2	ATG4B
ELLAGIC ACID	2	ATG4B

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	ATG4B
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	AGXT
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	KIF1A

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)
KIF1A	2	—
AGXT	8	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.