Spastic ataxia 2

Summary

Spastic ataxia 2 (MONDO:0012651) is a disease caused by KIF1C (GenCC Strong), with 3 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: KIF1C (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 537
• Phenotypes (HPO): 33

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		19	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

33 HPO clinical features (Orphanet curated; top 33 by frequency):

HPO ID	Term	Frequency
HP:0000668	Hypodontia	Very frequent (80-99%)
HP:0001260	Dysarthria	Very frequent (80-99%)
HP:0002066	Gait ataxia	Very frequent (80-99%)
HP:0002380	Fasciculations	Very frequent (80-99%)
HP:0002395	Lower limb hyperreflexia	Very frequent (80-99%)
HP:0002497	Spastic ataxia	Very frequent (80-99%)
HP:0002500	Abnormal cerebral white matter morphology	Very frequent (80-99%)
HP:0000252	Microcephaly	Frequent (30-79%)
HP:0000666	Horizontal nystagmus	Frequent (30-79%)
HP:0001257	Spasticity	Frequent (30-79%)
HP:0001310	Dysmetria	Frequent (30-79%)
HP:0001337	Tremor	Frequent (30-79%)
HP:0002072	Chorea	Frequent (30-79%)
HP:0002169	Clonus	Frequent (30-79%)
HP:0002359	Frequent falls	Frequent (30-79%)
HP:0003487	Babinski sign	Frequent (30-79%)
HP:0003693	Distal amyotrophy	Frequent (30-79%)
HP:0004322	Short stature	Frequent (30-79%)
HP:0011096	Peripheral demyelination	Frequent (30-79%)
HP:0025357	Erratic myoclonus	Frequent (30-79%)
HP:0030187	Titubation	Frequent (30-79%)
HP:0001347	Hyperreflexia	Occasional (5-29%)
HP:0001256	Intellectual disability, mild	Occasional (5-29%)
HP:0001263	Global developmental delay	Occasional (5-29%)
HP:0002080	Intention tremor	Occasional (5-29%)
HP:0002317	Unsteady gait	Occasional (5-29%)
HP:0007256	Abnormal pyramidal sign	Occasional (5-29%)
HP:0030051	Tip-toe gait	Occasional (5-29%)
HP:0000473	Torticollis	Very rare (<1-4%)
HP:0001272	Cerebellar atrophy	Very rare (<1-4%)
HP:0002059	Cerebral atrophy	Very rare (<1-4%)
HP:0007663	Reduced visual acuity	Very rare (<1-4%)
HP:0009830	Peripheral neuropathy	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	spastic ataxia 2
Mondo ID	MONDO:0012651
MeSH	C566969
OMIM	611302
Orphanet	397946
DOID	DOID:0050941
UMLS	C1969796
MedGen	370750
GARD	0017644
Is cancer (heuristic)	no

Also known as: autosomal recessive spastic ataxia type 2 · KIF1C spastic ataxia · spastic ataxia 2 · spastic ataxia 2, autosomal recessive · spastic ataxia caused by mutation in KIF1C · spastic ataxia type 2 · SPAX2 · SPG58

Data availability: 537 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › complex hereditary spastic paraplegia › spastic ataxia 2

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, 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

537 retrieved; paginated sample, class counts are floors:

241 likely benign, 183 uncertain significance, 37 conflicting classifications of pathogenicity, 28 benign, 21 benign/likely benign, 13 pathogenic, 12 likely pathogenic, 2 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
101066	NM_006612.6(KIF1C):c.2191C>T (p.Arg731Ter)	KIF1C	Pathogenic	criteria provided, multiple submitters, no conflicts
101069	NC_000017.10:g.(4907452_4914761)_(4918508_4926045)del	KIF1C	Pathogenic	no assertion criteria provided
1027417	NM_006612.6(KIF1C):c.765del (p.Asp256fs)	KIF1C	Pathogenic	criteria provided, single submitter
1075456	NM_006612.6(KIF1C):c.726_727insCC (p.Lys243fs)	KIF1C	Pathogenic	criteria provided, single submitter
1406903	NM_006612.6(KIF1C):c.601_604del (p.Lys201fs)	KIF1C	Pathogenic	criteria provided, single submitter
2412751	NM_006612.6(KIF1C):c.2005C>T (p.Arg669Ter)	KIF1C	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2413840	NM_006612.6(KIF1C):c.328C>T (p.Arg110Ter)	KIF1C	Pathogenic	criteria provided, single submitter
265862	NM_006612.6(KIF1C):c.2478del (p.Ala828fs)	KIF1C	Pathogenic	criteria provided, multiple submitters, no conflicts
2851191	NM_006612.6(KIF1C):c.1396_1397del (p.Glu466fs)	KIF1C	Pathogenic	criteria provided, single submitter
3639597	NM_006612.6(KIF1C):c.238del (p.Glu80fs)	KIF1C	Pathogenic	criteria provided, single submitter
3897855	NM_006612.6(KIF1C):c.182C>A (p.Ser61Ter)	KIF1C	Pathogenic	criteria provided, single submitter
4738673	NM_006612.6(KIF1C):c.1039C>T (p.Gln347Ter)	KIF1C	Pathogenic	criteria provided, single submitter
872583	NM_006612.6(KIF1C):c.527C>T (p.Pro176Leu)	KIF1C	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
989135	NM_006612.6(KIF1C):c.445A>T (p.Ile149Phe)	KIF1C	Pathogenic	criteria provided, single submitter
989136	NM_006612.6(KIF1C):c.1019+1dup	KIF1C	Pathogenic	criteria provided, single submitter
101067	NM_006612.6(KIF1C):c.505C>T (p.Arg169Trp)	KIF1C	Likely pathogenic	criteria provided, single submitter
101068	NM_006612.6(KIF1C):c.183G>A (p.Ser61=)	KIF1C	Likely pathogenic	criteria provided, single submitter
2444164	NM_006612.6(KIF1C):c.41C>T (p.Pro14Leu)	KIF1C	Likely pathogenic	criteria provided, single submitter
2583176	NM_006612.6(KIF1C):c.647G>A (p.Arg216His)	KIF1C	Likely pathogenic	criteria provided, single submitter
2847385	NM_006612.6(KIF1C):c.1491+2T>C	KIF1C	Likely pathogenic	criteria provided, single submitter
3252095	NM_006612.6(KIF1C):c.2885_2895del (p.Leu962fs)	KIF1C	Likely pathogenic	criteria provided, single submitter
3256747	NM_006612.6(KIF1C):c.1020-2A>G	KIF1C	Likely pathogenic	no assertion criteria provided
3375268	NM_006612.6(KIF1C):c.1166-2A>T	KIF1C	Likely pathogenic	criteria provided, single submitter
423907	NM_006612.6(KIF1C):c.646C>T (p.Arg216Cys)	KIF1C	Likely pathogenic	criteria provided, multiple submitters, no conflicts
4280619	NM_006612.6(KIF1C):c.64C>T (p.Gln22Ter)	KIF1C	Likely pathogenic	criteria provided, single submitter
4526626	NM_006612.6(KIF1C):c.941-2A>G	KIF1C	Likely pathogenic	criteria provided, single submitter
4728367	NM_006612.6(KIF1C):c.865-1G>A	KIF1C	Likely pathogenic	criteria provided, single submitter
1176653	NM_006612.6(KIF1C):c.1959G>A (p.Gln653=)	KIF1C	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1303279	NM_006612.6(KIF1C):c.1045C>T (p.Arg349Cys)	KIF1C	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1344389	NM_006612.6(KIF1C):c.1023T>C (p.Tyr341=)	KIF1C	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · 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
KIF1C	Strong	Autosomal recessive	spastic ataxia 2	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
KIF1C	Orphanet:397946	Autosomal spastic paraplegia type 58

Cohort genes → proteins

3 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
KIF1C	HGNC:6317	ENSG00000129250	O43896	Kinesin-like protein KIF1C	gencc,clinvar
C17orf107	HGNC:37238	ENSG00000205710	Q6ZR85	Uncharacterized protein C17orf107	clinvar
KIF1C-AS1	HGNC:40324	ENSG00000227495		KIF1C antisense RNA 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
KIF1C	Kinesin-like protein KIF1C	Motor required for the retrograde transport of Golgi vesicles to the endoplasmic reticulum.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 3 · 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	3	1.8×	0.174

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
KIF1C	Other/Unknown	no		FHA_dom, Kinesin_motor_dom, SMAD_FHA_dom_sf
C17orf107	Other/Unknown	no		C17orf107
KIF1C-AS1	Other/Unknown	no

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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
C1 segment of cervical spinal cord	1
gastrocnemius	1
hindlimb stylopod muscle	1
adenohypophysis	1
pituitary gland	1
right atrium auricular region	1
apex of heart	1
male germ line stem cell (sensu Vertebrata) in testis	1
primordial germ cell in gonad	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
KIF1C	292	ubiquitous	marker	C1 segment of cervical spinal cord, gastrocnemius, hindlimb stylopod muscle
C17orf107	131	broad	yes	adenohypophysis, pituitary gland, right atrium auricular region
KIF1C-AS1	157		yes	male germ line stem cell (sensu Vertebrata) in testis, primordial germ cell in gonad, apex of heart

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
KIF1C	1,580
C17orf107	110
KIF1C-AS1	0

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
KIF1C	O43896	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
C17orf107	Q6ZR85	58.75

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 8. Enrichment computed across 3 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
Kinesins	1	178.4×	0.019	KIF1C
Golgi-to-ER retrograde transport	1	132.8×	0.019	KIF1C
COPI-dependent Golgi-to-ER retrograde traffic	1	110.9×	0.019	KIF1C
Intra-Golgi and retrograde Golgi-to-ER traffic	1	104.8×	0.019	KIF1C
Factors involved in megakaryocyte development and platelet production	1	66.4×	0.024	KIF1C
Membrane Trafficking	1	37.1×	0.029	KIF1C
Hemostasis	1	36.0×	0.029	KIF1C
Vesicle-mediated transport	1	34.8×	0.029	KIF1C

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
anterograde neuronal dense core vesicle transport	1	4213.0×	6e-04	KIF1C
retrograde neuronal dense core vesicle transport	1	3370.4×	6e-04	KIF1C
retrograde vesicle-mediated transport, Golgi to endoplasmic reticulum	1	337.0×	0.004	KIF1C
vesicle-mediated transport	1	96.3×	0.010	KIF1C

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 3 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
KIF1C	0	0
C17orf107	0	0
KIF1C-AS1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; 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	3	KIF1C, C17orf107, KIF1C-AS1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
KIF1C	0	—
C17orf107	0	—
KIF1C-AS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.