Autosomal recessive spastic paraplegia type 69

Summary

Autosomal recessive spastic paraplegia type 69 (MONDO:0018421) is a disease with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 1
• Phenotypes (HPO): 13

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)

13 HPO clinical features (Orphanet curated; top 13 by frequency):

HPO ID	Term	Frequency
HP:0000365	Hearing impairment	Frequent (30-79%)
HP:0000518	Cataract	Frequent (30-79%)
HP:0001256	Intellectual disability, mild	Frequent (30-79%)
HP:0001263	Global developmental delay	Frequent (30-79%)
HP:0001274	Agenesis of corpus callosum	Frequent (30-79%)
HP:0002061	Lower limb spasticity	Frequent (30-79%)
HP:0002120	Cerebral cortical atrophy	Frequent (30-79%)
HP:0002378	Hand tremor	Frequent (30-79%)
HP:0002464	Spastic dysarthria	Frequent (30-79%)
HP:0006817	Aplasia/Hypoplasia of the cerebellar vermis	Frequent (30-79%)
HP:0007020	Progressive spastic paraplegia	Frequent (30-79%)
HP:0012447	Abnormal myelination	Frequent (30-79%)
HP:0100022	Abnormality of movement	Frequent (30-79%)

Identifiers

Disease identifiers

Field	Value
Canonical name	autosomal recessive spastic paraplegia type 69
Mondo ID	MONDO:0018421
Orphanet	401830
UMLS	C5190577
MedGen	1679277
GARD	0021699
Is cancer (heuristic)	no

Also known as: SPG69

Data availability: 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 69

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 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

No tiered GWAS variants or ClinVar records for this disease.

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · 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
RAB3GAP2	Supportive	Autosomal recessive	autosomal recessive spastic paraplegia type 69	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
RAB3GAP2	Orphanet:1387	Cataract-intellectual disability-hypogonadism syndrome
RAB3GAP2	Orphanet:2510	Micro syndrome
RAB3GAP2	Orphanet:401830	Autosomal recessive spastic paraplegia type 69

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
RAB3GAP2	HGNC:17168	ENSG00000118873	Q9H2M9	Rab3 GTPase-activating protein non-catalytic subunit	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
RAB3GAP2	Rab3 GTPase-activating protein non-catalytic subunit	Regulatory subunit of the Rab3 GTPase-activating (Rab3GAP) complex composed of RAB3GAP1 and RAB3GAP2, which accelerates the otherwise slow GTP hydrolysis catalyzed by Rab proteins.

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)
RAB3GAP2	Other/Unknown	no		Rab3GAP2, RAB3GAP2_C, RAB3GAP_N

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
choroid plexus epithelium	1
dorsal root ganglion	1
lateral nuclear group of thalamus	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RAB3GAP2	295	ubiquitous	marker	choroid plexus epithelium, lateral nuclear group of thalamus, dorsal root ganglion

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
RAB3GAP2	1,794

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
RAB3GAP2	Q9H2M9	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. 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
COPI-independent Golgi-to-ER retrograde traffic	1	207.6×	0.008	RAB3GAP2
RAB GEFs exchange GTP for GDP on RABs	1	124.1×	0.008	RAB3GAP2

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
establishment of protein localization to endoplasmic reticulum membrane	1	5617.3×	6e-04	RAB3GAP2
positive regulation of protein lipidation	1	4213.0×	6e-04	RAB3GAP2
positive regulation of endoplasmic reticulum tubular network organization	1	4213.0×	6e-04	RAB3GAP2
synaptic signaling	1	1532.0×	0.001	RAB3GAP2
positive regulation of autophagosome assembly	1	802.5×	0.002	RAB3GAP2
regulation of GTPase activity	1	510.7×	0.003	RAB3GAP2
macroautophagy	1	240.7×	0.005	RAB3GAP2
intracellular protein transport	1	64.8×	0.015	RAB3GAP2

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 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
RAB3GAP2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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	RAB3GAP2

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)
RAB3GAP2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.