hereditary spastic paraplegia 9A

Summary

hereditary spastic paraplegia 9A (MONDO:0011006) is a disease with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 2
• ClinVar variants: 42
• Phenotypes (HPO): 34

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		2	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

34 HPO clinical features (Orphanet curated; top 34 by frequency):

HPO ID	Term	Frequency
HP:0002064	Spastic gait	Very frequent (80-99%)
HP:0002395	Lower limb hyperreflexia	Very frequent (80-99%)
HP:0007350	Hyperreflexia in upper limbs	Very frequent (80-99%)
HP:0001761	Pes cavus	Frequent (30-79%)
HP:0003487	Babinski sign	Frequent (30-79%)
HP:0006895	Lower limb hypertonia	Frequent (30-79%)
HP:0007256	Abnormal pyramidal sign	Frequent (30-79%)
HP:0010832	Abnormality of pain sensation	Frequent (30-79%)
HP:0100515	Pollakisuria	Occasional (5-29%)
HP:0000012	Urinary urgency	Occasional (5-29%)
HP:0000020	Urinary incontinence	Occasional (5-29%)
HP:0000407	Sensorineural hearing impairment	Occasional (5-29%)
HP:0000519	Developmental cataract	Occasional (5-29%)
HP:0000666	Horizontal nystagmus	Occasional (5-29%)
HP:0000709	Psychosis	Occasional (5-29%)
HP:0000726	Dementia	Occasional (5-29%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0001317	Abnormal cerebellum morphology	Occasional (5-29%)
HP:0001324	Muscle weakness	Occasional (5-29%)
HP:0001337	Tremor	Occasional (5-29%)
HP:0001653	Mitral regurgitation	Occasional (5-29%)
HP:0002166	Impaired vibration sensation in the lower limbs	Occasional (5-29%)
HP:0002172	Postural instability	Occasional (5-29%)
HP:0002280	Enlarged cisterna magna	Occasional (5-29%)
HP:0002354	Memory impairment	Occasional (5-29%)
HP:0002425	Anarthria	Occasional (5-29%)
HP:0002464	Spastic dysarthria	Occasional (5-29%)
HP:0002500	Abnormal cerebral white matter morphology	Occasional (5-29%)
HP:0002527	Falls	Occasional (5-29%)
HP:0003394	Muscle spasm	Occasional (5-29%)
HP:0003419	Low back pain	Occasional (5-29%)
HP:0007371	Corpus callosum atrophy	Occasional (5-29%)
HP:0011397	Abnormality of the dorsal column of the spinal cord	Occasional (5-29%)
HP:0012514	Lower limb pain	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	hereditary spastic paraplegia 9A
Mondo ID	MONDO:0011006
MeSH	C536868
OMIM	601162
Orphanet	447753
DOID	DOID:0110824
UMLS	C5568978
MedGen	1800401
GARD	0009583
Is cancer (heuristic)	no

Also known as: AD-SPG9A · hereditary spastic paraplegia type 9A · spastic paraplegia 9A, autosomal dominant · SPG9A

Data availability: 42 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal dominant disease › autosomal dominant complex spastic paraplegia › autosomal dominant spastic paraplegia type 9 › hereditary spastic paraplegia 9A

Related subtypes (1): autosomal dominant complex spastic paraplegia type 9B

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

42 retrieved; paginated sample, class counts are floors:

18 uncertain significance, 8 benign, 7 pathogenic, 3 likely benign, 3 conflicting classifications of pathogenicity, 2 likely pathogenic, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
217117	NM_002860.4(ALDH18A1):c.755G>A (p.Arg252Gln)	ALDH18A1	Pathogenic	criteria provided, multiple submitters, no conflicts
217118	NM_002860.4(ALDH18A1):c.359T>C (p.Val120Ala)	ALDH18A1	Pathogenic	criteria provided, single submitter
217119	NM_002860.4(ALDH18A1):c.1994G>T (p.Arg665Leu)	ALDH18A1	Pathogenic	no assertion criteria provided
217259	NM_002860.4(ALDH18A1):c.412C>T (p.Arg138Trp)	ALDH18A1	Pathogenic	criteria provided, multiple submitters, no conflicts
217260	NM_002860.4(ALDH18A1):c.413G>A (p.Arg138Gln)	ALDH18A1	Pathogenic	criteria provided, multiple submitters, no conflicts
3767627	NM_002860.4(ALDH18A1):c.475C>T (p.Arg159Ter)	ALDH18A1	Pathogenic	criteria provided, multiple submitters, no conflicts
989201	NM_002860.4(ALDH18A1):c.478G>T (p.Ala160Ser)	ALDH18A1	Pathogenic	criteria provided, single submitter
217116	NM_002860.4(ALDH18A1):c.727G>C (p.Val243Leu)	ALDH18A1	Likely pathogenic	criteria provided, single submitter
2431929	NM_002860.4(ALDH18A1):c.377G>A (p.Arg126His)	ALDH18A1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1285129	NM_002860.4(ALDH18A1):c.809-1G>C	ALDH18A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1679568	NM_002860.4(ALDH18A1):c.89-1G>C	ALDH18A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
424961	NM_002860.4(ALDH18A1):c.1867G>A (p.Asp623Asn)	ALDH18A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1301642	NM_002860.4(ALDH18A1):c.1237G>C (p.Glu413Gln)	ALDH18A1	Uncertain significance	criteria provided, single submitter
1333857	NM_002860.4(ALDH18A1):c.1493G>T (p.Gly498Val)	ALDH18A1	Uncertain significance	criteria provided, single submitter
2505531	NM_002860.4(ALDH18A1):c.41A>G (p.Asn14Ser)	ALDH18A1	Uncertain significance	criteria provided, single submitter
2928043	NM_002860.4(ALDH18A1):c.1780G>A (p.Val594Ile)	ALDH18A1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2932585	NM_002860.4(ALDH18A1):c.34C>G (p.Pro12Ala)	ALDH18A1	Uncertain significance	criteria provided, multiple submitters, no conflicts
3068566	NM_002860.4(ALDH18A1):c.721A>G (p.Ile241Val)	ALDH18A1	Uncertain significance	criteria provided, multiple submitters, no conflicts
3108824	NM_002860.4(ALDH18A1):c.86C>T (p.Ser29Phe)	ALDH18A1	Uncertain significance	criteria provided, multiple submitters, no conflicts
3598737	NM_002860.4(ALDH18A1):c.1784A>G (p.Asp595Gly)	ALDH18A1	Uncertain significance	criteria provided, single submitter
3775237	NM_002860.4(ALDH18A1):c.1502T>C (p.Leu501Ser)	ALDH18A1	Uncertain significance	criteria provided, single submitter
441102	NM_002860.4(ALDH18A1):c.1942C>T (p.Pro648Ser)	ALDH18A1	Uncertain significance	criteria provided, multiple submitters, no conflicts
517143	NM_002860.4(ALDH18A1):c.1201G>A (p.Asp401Asn)	ALDH18A1	Uncertain significance	criteria provided, multiple submitters, no conflicts
575749	NM_002860.4(ALDH18A1):c.1370G>A (p.Arg457His)	ALDH18A1	Uncertain significance	criteria provided, multiple submitters, no conflicts
660899	NM_002860.4(ALDH18A1):c.169C>A (p.His57Asn)	ALDH18A1	Uncertain significance	criteria provided, multiple submitters, no conflicts
872769	NM_002860.4(ALDH18A1):c.1393G>A (p.Glu465Lys)	ALDH18A1	Uncertain significance	criteria provided, multiple submitters, no conflicts
879506	NM_002860.4(ALDH18A1):c.1740C>G (p.Ser580Arg)	ALDH18A1	Uncertain significance	criteria provided, multiple submitters, no conflicts
956990	NM_002860.4(ALDH18A1):c.973G>T (p.Val325Phe)	ALDH18A1	Uncertain significance	criteria provided, single submitter
970639	NM_002860.4(ALDH18A1):c.1551C>A (p.His517Gln)	ALDH18A1	Uncertain significance	criteria provided, multiple submitters, no conflicts
985227	NM_002860.4(ALDH18A1):c.1112G>A (p.Arg371Gln)	ALDH18A1	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 33 · Orphanet: 7 · 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
ALDH18A1	Definitive	Autosomal dominant	autosomal recessive complex spastic paraplegia type 9B	25
FAR1	Strong	Autosomal dominant	spastic paraparesis-cataracts-speech delay syndrome	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ALDH18A1	Orphanet:35664	ALDH18A1-related De Barsy syndrome
ALDH18A1	Orphanet:447753	Autosomal dominant spastic paraplegia type 9A
ALDH18A1	Orphanet:447757	Autosomal dominant spastic paraplegia type 9B
ALDH18A1	Orphanet:447760	Autosomal recessive spastic paraplegia type 9B
ALDH18A1	Orphanet:90348	Autosomal dominant cutis laxa
FAR1	Orphanet:438178	Fatty acyl-CoA reductase 1 deficiency
FAR1	Orphanet:615938	Spastic paraparesis-cataracts-speech delay syndrome

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ALDH18A1	HGNC:9722	ENSG00000059573	P54886	Delta-1-pyrroline-5-carboxylate synthase	gencc,clinvar
FAR1	HGNC:26222	ENSG00000197601	Q8WVX9	Fatty acyl-CoA reductase 1	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ALDH18A1	Delta-1-pyrroline-5-carboxylate synthase	Bifunctional enzyme that converts glutamate to glutamate 5-semialdehyde, an intermediate in the biosynthesis of proline, ornithine and arginine.
FAR1	Fatty acyl-CoA reductase 1	Catalyzes the reduction of saturated and unsaturated C16 or C18 fatty acyl-CoA to fatty alcohols.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Kinase	1	13.9×	0.142
Enzyme (other)	1	6.0×	0.160

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ALDH18A1	Kinase	yes		GPR_dom, Asp/Glu/Uridylate_kinase, Glu/AcGlu_kinase
FAR1	Enzyme (other)	yes	1.2.1.84	FAR_NAD-bd, FAR, FAR_C

Expression context

Cohort genes with no expression data: 0.

2 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
jejunal mucosa	2
ileal mucosa	1
parotid gland	1
corpus callosum	1
esophagus squamous epithelium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ALDH18A1	263	ubiquitous	marker	parotid gland, jejunal mucosa, ileal mucosa
FAR1	252	ubiquitous	marker	corpus callosum, esophagus squamous epithelium, jejunal mucosa

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ALDH18A1	7,351
FAR1	1,666

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ALDH18A1	P54886	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
FAR1	Q8WVX9	94.13

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. Enrichment computed across 2 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Wax biosynthesis	1	1427.5×	0.002	FAR1
Glutamate and glutamine metabolism	1	407.9×	0.004	ALDH18A1
Mitochondrial protein degradation	1	57.1×	0.017	ALDH18A1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
L-ornithine biosynthetic process	1	8426.0×	0.001	ALDH18A1
wax biosynthetic process	1	2106.5×	0.001	FAR1
L-citrulline biosynthetic process	1	2106.5×	0.001	ALDH18A1
L-proline biosynthetic process	1	1404.3×	0.001	ALDH18A1
long-chain fatty-acyl-CoA metabolic process	1	1203.7×	0.001	FAR1
ether lipid biosynthetic process	1	936.2×	0.001	FAR1
glycerophospholipid biosynthetic process	1	936.2×	0.001	FAR1
response to temperature stimulus	1	766.0×	0.001	ALDH18A1
glutamate metabolic process	1	561.7×	0.002	ALDH18A1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 2 of 2 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
ALDH18A1	0	0
FAR1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
ALDH18A1	3	Binding:3
FAR1	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
FAR1	1.2.1.84	alcohol-forming fatty acyl-CoA reductase (NADPH)

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	1	ALDH18A1
D	Druggable family + AlphaFold only, no drug	1	FAR1
E	Difficult family or no structure, no drug	0

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)
ALDH18A1	3	—
FAR1	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.