Hereditary spastic paraplegia 61

Summary

Hereditary spastic paraplegia 61 (MONDO:0014304) is a disease caused by ARL6IP1 (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: ARL6IP1 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 63
• Phenotypes (HPO): 8

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)

8 HPO clinical features (Orphanet curated; top 8 by frequency):

HPO ID	Term	Frequency
HP:0001257	Spasticity	Frequent (30-79%)
HP:0001271	Polyneuropathy	Frequent (30-79%)
HP:0001288	Gait disturbance	Frequent (30-79%)
HP:0002815	Abnormality of the knee	Frequent (30-79%)
HP:0005109	Abnormality of the Achilles tendon	Frequent (30-79%)
HP:0007083	Hyperactive patellar reflex	Frequent (30-79%)
HP:0007178	Motor polyneuropathy	Frequent (30-79%)
HP:0012407	Scissor gait	Frequent (30-79%)

Identifiers

Disease identifiers

Field	Value
Canonical name	hereditary spastic paraplegia 61
Mondo ID	MONDO:0014304
OMIM	615685
Orphanet	401780
DOID	DOID:0110812
SNOMED CT	726611001
UMLS	C3810294
MedGen	816624
GARD	0017656
Is cancer (heuristic)	no

Also known as: ARL6IP1 autosomal recessive complex spastic paraplegia · autosomal recessive complex spastic paraplegia caused by mutation in ARL6IP1 · autosomal recessive spastic paraplegia type 61 · hereditary spastic paraplegia 61 · hereditary spastic paraplegia type 61 · spastic paraplegia 61, autosomal recessive · SPG61

Data availability: 63 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › complex hereditary spastic paraplegia › hereditary spastic paraplegia 61

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 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

63 retrieved; paginated sample, class counts are floors:

29 likely benign, 19 uncertain significance, 7 benign, 4 pathogenic, 3 likely pathogenic, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
3024197	NM_015161.3(ARL6IP1):c.112C>T (p.Arg38Ter)	ARL6IP1	Pathogenic	criteria provided, multiple submitters, no conflicts
3024198	NM_015161.3(ARL6IP1):c.92T>C (p.Leu31Pro)	ARL6IP1	Pathogenic	no assertion criteria provided
4809175	NM_015161.3(ARL6IP1):c.198_202del (p.Leu67fs)	ARL6IP1	Pathogenic	criteria provided, single submitter
620202	NM_015161.3(ARL6IP1):c.346C>T (p.Arg116Ter)	ARL6IP1	Pathogenic	criteria provided, multiple submitters, no conflicts
101079	NM_015161.3(ARL6IP1):c.577_580del (p.Lys193fs)	ARL6IP1	Likely pathogenic	criteria provided, single submitter
474862	NM_015161.3(ARL6IP1):c.409-2A>G	ARL6IP1	Likely pathogenic	criteria provided, single submitter
4813361	NM_015161.3(ARL6IP1):c.407_409-197del	ARL6IP1	Likely pathogenic	criteria provided, single submitter
2978983	NM_015161.3(ARL6IP1):c.430T>C (p.Ser144Pro)	ARL6IP1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1403306	NM_015161.3(ARL6IP1):c.566G>A (p.Arg189Lys)	ARL6IP1	Uncertain significance	criteria provided, single submitter
1918023	NM_015161.3(ARL6IP1):c.17A>G (p.Asn6Ser)	ARL6IP1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1962152	NM_015161.3(ARL6IP1):c.324T>G (p.Ile108Met)	ARL6IP1	Uncertain significance	criteria provided, single submitter
1980701	NM_015161.3(ARL6IP1):c.347G>A (p.Arg116Gln)	ARL6IP1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2048441	NM_015161.3(ARL6IP1):c.113G>A (p.Arg38Gln)	ARL6IP1	Uncertain significance	criteria provided, single submitter
2057371	NM_015161.3(ARL6IP1):c.440C>T (p.Ala147Val)	ARL6IP1	Uncertain significance	criteria provided, single submitter
2089281	NM_015161.3(ARL6IP1):c.493+5G>A	ARL6IP1	Uncertain significance	criteria provided, single submitter
2135617	NM_015161.3(ARL6IP1):c.391G>A (p.Glu131Lys)	ARL6IP1	Uncertain significance	criteria provided, single submitter
2159213	NM_015161.3(ARL6IP1):c.260T>C (p.Leu87Pro)	ARL6IP1	Uncertain significance	criteria provided, single submitter
2193556	NM_015161.3(ARL6IP1):c.263C>T (p.Ala88Val)	ARL6IP1	Uncertain significance	criteria provided, single submitter
2196302	NM_015161.3(ARL6IP1):c.433C>G (p.Leu145Val)	ARL6IP1	Uncertain significance	criteria provided, single submitter
3065376	NM_015161.3(ARL6IP1):c.190C>G (p.Pro64Ala)	ARL6IP1	Uncertain significance	criteria provided, single submitter
3900990	NM_015161.3(ARL6IP1):c.25A>G (p.Thr9Ala)	ARL6IP1	Uncertain significance	criteria provided, single submitter
474863	NM_015161.3(ARL6IP1):c.490A>C (p.Ile164Leu)	ARL6IP1	Uncertain significance	criteria provided, multiple submitters, no conflicts
583366	NM_015161.3(ARL6IP1):c.26C>G (p.Thr9Ser)	ARL6IP1	Uncertain significance	criteria provided, multiple submitters, no conflicts
584319	NC_000016.9:g.(?18804554)(18812808_?)dup	ARL6IP1	Uncertain significance	criteria provided, single submitter
657883	NM_015161.3(ARL6IP1):c.408+4C>G	ARL6IP1	Uncertain significance	criteria provided, single submitter
941897	NM_015161.3(ARL6IP1):c.205G>A (p.Gly69Ser)	ARL6IP1	Uncertain significance	criteria provided, single submitter
945031	NM_015161.3(ARL6IP1):c.171G>A (p.Leu57=)	ARL6IP1	Uncertain significance	criteria provided, single submitter
1081749	NM_015161.3(ARL6IP1):c.345T>C (p.Thr115=)	ARL6IP1	Likely benign	criteria provided, single submitter
1169207	NM_015161.3(ARL6IP1):c.199C>T (p.Leu67=)	ARL6IP1	Benign	criteria provided, single submitter
1240660	NM_015161.3(ARL6IP1):c.409-18T>C	ARL6IP1	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · 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
ARL6IP1	Strong	Autosomal recessive	hereditary spastic paraplegia 61	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ARL6IP1	Orphanet:401780	Autosomal recessive spastic paraplegia type 61

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
ARL6IP1	HGNC:697	ENSG00000170540	Q15041	ADP-ribosylation factor-like protein 6-interacting protein 1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ARL6IP1	ADP-ribosylation factor-like protein 6-interacting protein 1	Positively regulates SLC1A1/EAAC1-mediated glutamate transport by increasing its affinity for glutamate in a PKC activity-dependent manner.

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)
ARL6IP1	Other/Unknown	no		ER_autophagy_membrane_reg, RETREG1-3-like_RHD

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
pigmented layer of retina	1
retina	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ARL6IP1	303	ubiquitous	marker	pigmented layer of retina, ventricular zone, retina

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ARL6IP1	3,865

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ARL6IP1	Q15041	84.78

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 1 evidence-associated genes (0 with Reactome annotation).

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
positive regulation of L-glutamate import across plasma membrane	1	8426.0×	4e-04	ARL6IP1
regulation of endoplasmic reticulum tubular network organization	1	8426.0×	4e-04	ARL6IP1
endoplasmic reticulum tubular network formation	1	2808.7×	8e-04	ARL6IP1
endoplasmic reticulum tubular network membrane organization	1	2106.5×	8e-04	ARL6IP1
cotranslational protein targeting to membrane	1	1685.2×	8e-04	ARL6IP1
negative regulation of apoptotic process	1	34.8×	0.034	ARL6IP1
apoptotic process	1	28.7×	0.035	ARL6IP1

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
ARL6IP1	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	ARL6IP1

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)
ARL6IP1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.