Hereditary spastic paraplegia 10

Summary

Hereditary spastic paraplegia 10 (MONDO:0011408) is a disease caused by KIF5A (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: KIF5A (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 144
• Phenotypes (HPO): 28

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		10	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

28 HPO clinical features (Orphanet curated; top 28 by frequency):

HPO ID	Term	Frequency
HP:0002061	Lower limb spasticity	Obligate (100%)
HP:0002395	Lower limb hyperreflexia	Very frequent (80-99%)
HP:0008944	Distal lower limb amyotrophy	Very frequent (80-99%)
HP:0003487	Babinski sign	Frequent (30-79%)
HP:0000510	Rod-cone dystrophy	Frequent (30-79%)
HP:0002936	Distal sensory impairment	Frequent (30-79%)
HP:0003477	Peripheral axonal neuropathy	Frequent (30-79%)
HP:0031958	Spastic paraparetic gait	Frequent (30-79%)
HP:0002493	Upper motor neuron dysfunction	Frequent (30-79%)
HP:0006886	Impaired distal vibration sensation	Frequent (30-79%)
HP:0007350	Hyperreflexia in upper limbs	Frequent (30-79%)
HP:0000012	Urinary urgency	Frequent (30-79%)
HP:0008969	Leg muscle stiffness	Frequent (30-79%)
HP:0007340	Lower limb muscle weakness	Frequent (30-79%)
HP:0005340	Spastic/hyperactive bladder	Frequent (30-79%)
HP:0001761	Pes cavus	Occasional (5-29%)
HP:0007141	Sensorimotor neuropathy	Occasional (5-29%)
HP:0009129	Upper limb amyotrophy	Occasional (5-29%)
HP:0002342	Intellectual disability, moderate	Occasional (5-29%)
HP:0003401	Paresthesia	Occasional (5-29%)
HP:0002619	Varicose veins	Occasional (5-29%)
HP:0005679	Dupuytren contracture	Occasional (5-29%)
HP:0001300	Parkinsonism	Very rare (<1-4%)
HP:0000365	Hearing impairment	Very rare (<1-4%)
HP:0100543	Cognitive impairment	Very rare (<1-4%)
HP:0011448	Ankle clonus	Very rare (<1-4%)
HP:0006986	Upper limb spasticity	Very rare (<1-4%)
HP:0002650	Scoliosis	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	hereditary spastic paraplegia 10
Mondo ID	MONDO:0011408
MeSH	C537482
OMIM	604187
Orphanet	100991
DOID	DOID:0110763
SNOMED CT	732948003
UMLS	C1858712
MedGen	349003
GARD	0009590
Is cancer (heuristic)	no

Also known as: autosomal dominant spastic paraplegia · autosomal dominant spastic paraplegia type 10 · hereditary spastic paraplegia caused by mutation in KIF5A · hereditary spastic paraplegia type 10 · KIF5A hereditary spastic paraplegia · spastic paraplegia 10 · spastic paraplegia 10, autosomal dominant · SPG10

Data availability: 144 ClinVar variants · 5 GenCC gene-disease records · 7 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 10

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 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

144 retrieved; paginated sample, class counts are floors:

48 uncertain significance, 39 conflicting classifications of pathogenicity, 12 benign/likely benign, 11 pathogenic, 9 likely pathogenic, 9 pathogenic/likely pathogenic, 8 likely benign, 7 benign, 1 uncertain significance/vus-mid

ClinVar	Variant (HGVS)	Gene	Classification	Review
162100	NM_004984.4(KIF5A):c.694G>A (p.Asp232Asn)	KIF5A	Pathogenic	no assertion criteria provided
2500188	NM_004984.4(KIF5A):c.737G>T (p.Gly246Val)	KIF5A	Pathogenic	criteria provided, single submitter
3338325	NM_004984.4(KIF5A):c.1233dup (p.Glu412fs)	KIF5A	Pathogenic	no assertion criteria provided
37127	NM_004984.4(KIF5A):c.751G>A (p.Glu251Lys)	KIF5A	Pathogenic	criteria provided, multiple submitters, no conflicts
37129	NM_004984.4(KIF5A):c.611G>A (p.Arg204Gln)	KIF5A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
37130	NM_004984.4(KIF5A):c.839G>A (p.Arg280His)	KIF5A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
409666	NM_004984.4(KIF5A):c.967C>T (p.Arg323Trp)	KIF5A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
424651	NM_004984.4(KIF5A):c.610C>T (p.Arg204Trp)	KIF5A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
424658	NM_004984.4(KIF5A):c.833C>T (p.Pro278Leu)	KIF5A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
504478	NM_004984.4(KIF5A):c.3020+1G>A	KIF5A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
6806	NM_004984.4(KIF5A):c.767A>G (p.Asn256Ser)	KIF5A	Pathogenic	criteria provided, single submitter
6807	NM_004984.4(KIF5A):c.838C>T (p.Arg280Cys)	KIF5A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
6808	NM_004984.4(KIF5A):c.827A>G (p.Tyr276Cys)	KIF5A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
944917	NM_004984.4(KIF5A):c.484C>T (p.Arg162Trp)	KIF5A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
989064	NM_004984.4(KIF5A):c.395A>G (p.Lys132Arg)	KIF5A	Pathogenic	criteria provided, single submitter
989067	NM_004984.4(KIF5A):c.604A>G (p.Ser202Gly)	KIF5A	Pathogenic	criteria provided, single submitter
989068	NM_004984.4(KIF5A):c.605G>A (p.Ser202Asn)	KIF5A	Pathogenic	criteria provided, single submitter
989069	NM_004984.4(KIF5A):c.728G>A (p.Gly243Glu)	KIF5A	Pathogenic	criteria provided, single submitter
989071	NM_004984.4(KIF5A):c.765C>G (p.Ile255Met)	KIF5A	Pathogenic	criteria provided, single submitter
989072	NM_004984.4(KIF5A):c.854C>T (p.Thr285Ile)	KIF5A	Pathogenic	criteria provided, single submitter
1184563	NM_004984.4(KIF5A):c.687T>A (p.Tyr229Ter)	KIF5A	Likely pathogenic	no assertion criteria provided
1709386	NM_004984.4(KIF5A):c.217G>A (p.Asp73Asn)	KIF5A	Likely pathogenic	criteria provided, single submitter
1709701	NM_004984.4(KIF5A):c.501+2T>C	KIF5A	Likely pathogenic	criteria provided, single submitter
1711150	NM_004984.4(KIF5A):c.129+1G>A	KIF5A	Likely pathogenic	no assertion criteria provided
2505561	NM_004984.4(KIF5A):c.566C>G (p.Ser189Ter)	KIF5A	Likely pathogenic	criteria provided, single submitter
3235264	NM_004984.4(KIF5A):c.806T>C (p.Leu269Pro)	KIF5A	Likely pathogenic	criteria provided, single submitter
37131	NM_004984.4(KIF5A):c.704G>A (p.Gly235Glu)	KIF5A	Likely pathogenic	criteria provided, single submitter
430828	NM_004984.4(KIF5A):c.799T>C (p.Ser267Pro)	KIF5A	Likely pathogenic	no assertion criteria provided
973760	NM_004984.4(KIF5A):c.698T>A (p.Leu233Gln)	KIF5A	Likely pathogenic	criteria provided, single submitter
1029912	NM_004984.4(KIF5A):c.2590C>T (p.Arg864Ter)	KIF5A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 15 · Orphanet: 2 · 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
KIF5A	Strong	Autosomal dominant	hereditary spastic paraplegia 10	15

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
KIF5A	Orphanet:100991	Autosomal dominant spastic paraplegia type 10
KIF5A	Orphanet:324611	Autosomal dominant Charcot-Marie-Tooth disease type 2 due to KIF5A mutation

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
KIF5A	HGNC:6323	ENSG00000155980	Q12840	Kinesin heavy chain isoform 5A	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
KIF5A	Kinesin heavy chain isoform 5A	Microtubule-dependent motor required for slow axonal transport of neurofilament proteins (NFH, NFM and NFL).

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · 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	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
KIF5A	Other/Unknown	no		Kinesin_motor_dom, Kinesin_motor_CS, P-loop_NTPase

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
cerebellar hemisphere	1
right frontal lobe	1
right hemisphere of cerebellum	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
KIF5A	198	broad	marker	right frontal lobe, right hemisphere of cerebellum, cerebellar hemisphere

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
KIF5A	3,241

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
KIF5A	Q12840	4

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 19. 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
RHO GTPases activate KTN1	1	1038.2×	0.018	KIF5A
Insulin processing	1	456.8×	0.021	KIF5A
Peptide hormone metabolism	1	271.9×	0.023	KIF5A
Kinesins	1	178.4×	0.026	KIF5A
Golgi-to-ER retrograde transport	1	132.8×	0.026	KIF5A
COPI-dependent Golgi-to-ER retrograde traffic	1	110.9×	0.026	KIF5A
Intra-Golgi and retrograde Golgi-to-ER traffic	1	104.8×	0.026	KIF5A
MHC class II antigen presentation	1	89.2×	0.027	KIF5A
RHO GTPase Effectors	1	68.0×	0.029	KIF5A
Factors involved in megakaryocyte development and platelet production	1	66.4×	0.029	KIF5A
Membrane Trafficking	1	37.1×	0.038	KIF5A
Hemostasis	1	36.0×	0.038	KIF5A
Vesicle-mediated transport	1	34.8×	0.038	KIF5A
Signaling by Rho GTPases	1	34.2×	0.038	KIF5A
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1	33.5×	0.038	KIF5A
Adaptive Immune System	1	29.8×	0.040	KIF5A
Immune System	1	13.0×	0.085	KIF5A
Metabolism of proteins	1	12.4×	0.085	KIF5A
Signal Transduction	1	10.2×	0.098	KIF5A

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
retrograde neuronal dense core vesicle transport	1	3370.4×	0.001	KIF5A
anterograde dendritic transport of neurotransmitter receptor complex	1	2407.4×	0.001	KIF5A
anterograde axonal protein transport	1	2106.5×	0.001	KIF5A
synaptic vesicle transport	1	842.6×	0.002	KIF5A
microtubule-based movement	1	295.6×	0.005	KIF5A
vesicle-mediated transport	1	96.3×	0.013	KIF5A
axon guidance	1	90.6×	0.013	KIF5A
chemical synaptic transmission	1	77.3×	0.013	KIF5A

Therapeutics

Drug target analysis

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

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
KIF5A	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
KIF5A	8	Binding:8

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	1	KIF5A

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
KIF5A	8	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.