Autosomal recessive spastic paraplegia type 70

Summary

Autosomal recessive spastic paraplegia type 70 (MONDO:0018422) is a disease with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 2
• ClinVar variants: 5
• Phenotypes (HPO): 10

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		4	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

10 HPO clinical features (Orphanet curated; top 10 by frequency):

HPO ID	Term	Frequency
HP:0001256	Intellectual disability, mild	Frequent (30-79%)
HP:0001263	Global developmental delay	Frequent (30-79%)
HP:0002061	Lower limb spasticity	Frequent (30-79%)
HP:0002378	Hand tremor	Frequent (30-79%)
HP:0006530	Abnormal pulmonary interstitial morphology	Frequent (30-79%)
HP:0007020	Progressive spastic paraplegia	Frequent (30-79%)
HP:0009830	Peripheral neuropathy	Frequent (30-79%)
HP:0012447	Abnormal myelination	Frequent (30-79%)
HP:0100022	Abnormality of movement	Frequent (30-79%)
HP:0000100	Nephrotic syndrome	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	autosomal recessive spastic paraplegia type 70
Mondo ID	MONDO:0018422
OMIM	620323
Orphanet	401835
DOID	DOID:0070454
UMLS	C4749431
MedGen	1655287
GARD	0021700
Is cancer (heuristic)	no

Also known as: autosomal recessive spastic paraplegia type 70 · spastic paraplegia 70, autosomal recessive · SPG70

Data availability: 5 ClinVar variants · 1 GenCC gene-disease record.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › complex hereditary spastic paraplegia › autosomal recessive spastic paraplegia type 70

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, spastic ataxia 2, 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, 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

5 retrieved; paginated sample, class counts are floors:

3 uncertain significance, 1 pathogenic, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
2499490	NM_004990.4(MARS1):c.1166G>A (p.Cys389Tyr)	MARS1	Pathogenic	no assertion criteria provided
4845906	NM_004990.4(MARS1):c.1133_1134del (p.Phe378fs)	MARS1	Likely pathogenic	criteria provided, single submitter
120186	NM_004990.4(MARS1):c.13G>A (p.Val5Met)	ARHGAP9	Uncertain significance	criteria provided, multiple submitters, no conflicts
120187	NM_004990.4(MARS1):c.2104C>T (p.Arg702Trp)	MARS1	Uncertain significance	criteria provided, multiple submitters, no conflicts
917127	NM_004990.4(MARS1):c.1873C>T (p.Arg625Trp)	MARS1	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 12 · Orphanet: 3 · 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
MARS1	Supportive	Autosomal recessive	autosomal recessive spastic paraplegia type 70	12

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MARS1	Orphanet:397735	Autosomal dominant Charcot-Marie-Tooth disease type 2U
MARS1	Orphanet:401835	Autosomal recessive spastic paraplegia type 70
MARS1	Orphanet:440427	Severe early-onset pulmonary alveolar proteinosis due to MARS deficiency

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
MARS1	HGNC:6898	ENSG00000166986	P56192	Methionine–tRNA ligase, cytoplasmic	gencc,clinvar
ARHGAP9	HGNC:14130	ENSG00000123329	Q9BRR9	Rho GTPase-activating protein 9	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MARS1	Methionine–tRNA ligase, cytoplasmic	Catalyzes the specific attachment of an amino acid to its cognate tRNA in a 2 step reaction: the amino acid (AA) is first activated by ATP to form AA-AMP and then transferred to the acceptor end of the tRNA.
ARHGAP9	Rho GTPase-activating protein 9	GTPase activator for the Rho-type GTPases by converting them to an inactive GDP-bound state.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 0 · Druggable fraction: 0.5

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
Scaffold/PPI	1	8.6×	0.160
Enzyme (other)	1	6.0×	0.160

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MARS1	Enzyme (other)	yes	6.1.1.10	WHEP-TRS_dom, aa-tRNA-synth_I_CS, GST_C
ARHGAP9	Scaffold/PPI	no		RhoGAP_dom, WW_dom, SH3_domain

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
cerebellar cortex	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1
blood	1
granulocyte	1
spleen	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MARS1	301	ubiquitous	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
ARHGAP9	235	broad	marker	granulocyte, blood, spleen

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MARS1	5,727
ARHGAP9	1,748

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MARS1	P56192	7
ARHGAP9	Q9BRR9	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 14. 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
Cytosolic tRNA aminoacylation	1	219.6×	0.039	MARS1
tRNA Aminoacylation	1	142.8×	0.039	MARS1
Selenoamino acid metabolism	1	98.5×	0.039	MARS1
Transcriptional and post-translational regulation of MITF-M expression and activity	1	89.2×	0.039	MARS1
MITF-M-regulated melanocyte development	1	57.1×	0.045	MARS1
RHOA GTPase cycle	1	37.3×	0.045	ARHGAP9
CDC42 GTPase cycle	1	36.1×	0.045	ARHGAP9
Metabolism of amino acids and derivatives	1	33.8×	0.045	MARS1
Translation	1	31.0×	0.045	MARS1
RAC1 GTPase cycle	1	30.5×	0.045	ARHGAP9
Neutrophil degranulation	1	11.5×	0.108	ARHGAP9
Developmental Biology	1	7.2×	0.156	MARS1
Metabolism of proteins	1	6.2×	0.165	MARS1
Metabolism	1	5.8×	0.165	MARS1

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
methionyl-tRNA aminoacylation	1	4213.0×	0.002	MARS1
positive regulation of transcription of nucleolar large rRNA by RNA polymerase I	1	766.0×	0.005	MARS1
rRNA transcription	1	495.6×	0.005	MARS1
tRNA aminoacylation for protein translation	1	421.3×	0.005	MARS1
cellular response to platelet-derived growth factor stimulus	1	324.1×	0.005	MARS1
cellular response to epidermal growth factor stimulus	1	159.0×	0.008	MARS1
small GTPase-mediated signal transduction	1	91.6×	0.012	ARHGAP9
regulation of small GTPase mediated signal transduction	1	72.0×	0.014	ARHGAP9

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MARS1	0	0
ARHGAP9	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
MARS1	26	Binding:26

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
MARS1	6.1.1.10	methionine-tRNA ligase

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	MARS1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	ARHGAP9

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)
MARS1	26	—
ARHGAP9	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.