Hereditary spastic paraplegia 6

Summary

Hereditary spastic paraplegia 6 (MONDO:0010878) is a disease caused by NIPA1 (GenCC Strong), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: NIPA1 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 299
• Phenotypes (HPO): 13

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		10	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:0001258	Spastic paraplegia	Very frequent (80-99%)
HP:0001288	Gait disturbance	Very frequent (80-99%)
HP:0002061	Lower limb spasticity	Very frequent (80-99%)
HP:0002395	Lower limb hyperreflexia	Very frequent (80-99%)
HP:0002495	Impaired vibratory sensation	Very frequent (80-99%)
HP:0003487	Babinski sign	Very frequent (80-99%)
HP:0001761	Pes cavus	Frequent (30-79%)
HP:0002069	Bilateral tonic-clonic seizure	Frequent (30-79%)
HP:0003202	Skeletal muscle atrophy	Frequent (30-79%)
HP:0008800	Limited hip movement	Frequent (30-79%)
HP:0010505	Limitation of movement at ankles	Frequent (30-79%)
HP:0000020	Urinary incontinence	Occasional (5-29%)
HP:0002174	Postural tremor	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	hereditary spastic paraplegia 6
Mondo ID	MONDO:0010878
MeSH	C536866
OMIM	600363
Orphanet	100988
DOID	DOID:0110811
SNOMED CT	732949006
UMLS	C1838192
MedGen	324965
GARD	0004928
Is cancer (heuristic)	no

Also known as: autosomal dominant spastic paraplegia type 6 · familial spastic paraplegia autosomal dominant 3 · FSP3 · hereditary spastic paraplegia caused by mutation in NIPA1 · hereditary spastic paraplegia type 6 · NIPA1 hereditary spastic paraplegia · spastic paraplegia 6 · spastic paraplegia 6, autosomal dominant · SPG6

Data availability: 299 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › palsy › paraplegia › hereditary spastic paraplegia › hereditary spastic paraplegia 6

Related subtypes (44): hereditary spastic paraplegia 3A, hereditary spastic paraplegia 4, mast syndrome, hereditary spastic paraplegia 5A, hereditary spastic paraplegia 16, hereditary spastic paraplegia 2, macrocephaly-spastic paraplegia-dysmorphism syndrome, Charcot-Marie-Tooth disease type 5, hereditary spastic paraplegia 10, hereditary spastic paraplegia 14, hereditary spastic paraplegia 13, hereditary spastic paraplegia 7, hereditary spastic paraplegia 33, hereditary spastic paraplegia 31, hereditary spastic paraplegia 30, hereditary spastic paraplegia 35, hereditary spastic paraplegia 50, hereditary spastic paraplegia 48, hereditary spastic paraplegia 51, hereditary spastic paraplegia 47, hereditary spastic paraplegia 52, hereditary spastic paraplegia 56, early-onset progressive neurodegeneration-blindness-ataxia-spasticity syndrome, hereditary spastic paraplegia 77, pure hereditary spastic paraplegia, complex hereditary spastic paraplegia, pure or complex hereditary spastic paraplegia, spastic paraplegia 87, autosomal recessive, spastic paraplegia 80, autosomal dominant, spastic paraplegia 81, autosomal recessive, spastic paraplegia 82, autosomal recessive, spastic paraplegia 83, autosomal recessive, spastic paraplegia 88, autosomal dominant, spastic paraplegia 79A, autosomal dominant, with ataxia, spastic paraplegia 89, autosomal recessive, spastic paraplegia 90A, autosomal dominant, spastic paraplegia 90B, autosomal recessive, spastic paraplegia 91, autosomal dominant, with or without cerebellar ataxia, spastic paraplegia 72b, autosomal recessive, spastic paraplegia 92, autosomal recessive, spastic paraplegia 93, autosomal recessive, IFIH1-related hereditary spastic paraplegia, RNASEH2B-related hereditary spastic paraplegia, ADAR-related hereditary spastic paraplegia

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

299 retrieved; paginated sample, class counts are floors:

153 uncertain significance, 68 likely benign, 48 benign, 19 conflicting classifications of pathogenicity, 7 benign/likely benign, 4 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
2520	NM_144599.5(NIPA1):c.134C>G (p.Thr45Arg)	LOC130056709	Pathogenic	criteria provided, multiple submitters, no conflicts
2521	NM_144599.5(NIPA1):c.316G>C (p.Gly106Arg)	NIPA1	Pathogenic	criteria provided, multiple submitters, no conflicts
2523	NM_144599.5(NIPA1):c.316G>A (p.Gly106Arg)	NIPA1	Pathogenic	criteria provided, multiple submitters, no conflicts
948417	NM_144599.5(NIPA1):c.731A>G (p.Gln244Arg)	NIPA1	Pathogenic	criteria provided, single submitter
380931	NM_144599.5(NIPA1):c.21A>G (p.Ala7=)	LOC130056709	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
447766	NM_144599.5(NIPA1):c.17C>G (p.Ala6Gly)	LOC130056709	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
533362	NM_144599.5(NIPA1):c.24GGC[11] (p.Ala14_Ala16dup)	LOC130056709	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
872110	NM_144599.5(NIPA1):c.24GGC[4] (p.Ala13_Ala16del)	LOC130056709	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
887004	NM_144599.5(NIPA1):c.8C>T (p.Thr3Ile)	LOC130056709	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1344438	NM_144599.5(NIPA1):c.222C>T (p.Ile74=)	NIPA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1344439	NM_144599.5(NIPA1):c.479-7G>T	NIPA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
193496	NM_144599.5(NIPA1):c.24GGC[10] (p.Ala15_Ala16dup)	NIPA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2434357	NM_144599.5(NIPA1):c.21_38del (p.Ala11_Ala16del)	NIPA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
289458	NM_144599.5(NIPA1):c.312G>A (p.Pro104=)	NIPA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
315338	NM_144599.5(NIPA1):c.*5185C>T	NIPA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
315386	NM_144599.5(NIPA1):c.*2070A>C	NIPA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
315423	NM_144599.5(NIPA1):c.753G>C (p.Ala251=)	NIPA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
425060	NM_144599.5(NIPA1):c.266C>T (p.Ala89Val)	NIPA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
447767	NM_144599.5(NIPA1):c.315C>T (p.Phe105=)	NIPA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
515029	NM_144599.5(NIPA1):c.798C>T (p.Val266=)	NIPA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
533363	NM_144599.5(NIPA1):c.403G>A (p.Val135Met)	NIPA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
699096	NM_144599.5(NIPA1):c.681C>T (p.Leu227=)	NIPA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
885998	NM_144599.5(NIPA1):c.267G>A (p.Ala89=)	NIPA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1502711	NM_144599.5(NIPA1):c.121G>A (p.Val41Met)	LOC130056709	Uncertain significance	criteria provided, single submitter
1995648	NM_144599.5(NIPA1):c.28G>A (p.Ala10Thr)	LOC130056709	Uncertain significance	criteria provided, single submitter
2160285	NM_144599.5(NIPA1):c.67C>T (p.Pro23Ser)	LOC130056709	Uncertain significance	criteria provided, multiple submitters, no conflicts
2693831	NM_144599.5(NIPA1):c.139G>A (p.Val47Met)	LOC130056709	Uncertain significance	criteria provided, multiple submitters, no conflicts
2744438	NM_144599.5(NIPA1):c.166G>A (p.Ala56Thr)	LOC130056709	Uncertain significance	criteria provided, single submitter
2760707	NM_144599.5(NIPA1):c.32C>T (p.Ala11Val)	LOC130056709	Uncertain significance	criteria provided, single submitter
2963692	NM_144599.5(NIPA1):c.17C>T (p.Ala6Val)	LOC130056709	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · 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
NIPA1	Strong	Autosomal dominant	hereditary spastic paraplegia 6	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NIPA1	Orphanet:100988	Autosomal dominant spastic paraplegia type 6
NIPA1	Orphanet:261183	15q11.2 microdeletion syndrome
NIPA2	Orphanet:261183	15q11.2 microdeletion 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
NIPA1	HGNC:17043	ENSG00000170113	Q7RTP0	Magnesium transporter NIPA1	gencc,clinvar
NIPA2	HGNC:17044	ENSG00000140157	Q8N8Q9	Magnesium transporter NIPA2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NIPA1	Magnesium transporter NIPA1	Acts as a Mg(2+) transporter.
NIPA2	Magnesium transporter NIPA2	Acts as a selective Mg(2+) transporter.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · 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	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
NIPA1	Other/Unknown	no		Mg_trans_NIPA, EmrE-like
NIPA2	Other/Unknown	no		Mg_trans_NIPA, EmrE-like

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
C1 segment of cervical spinal cord	1
globus pallidus	1
medial globus pallidus	1
colonic mucosa	1
mucosa of sigmoid colon	1
pancreatic ductal cell	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NIPA1	240	ubiquitous	marker	medial globus pallidus, globus pallidus, C1 segment of cervical spinal cord
NIPA2	288	ubiquitous	marker	pancreatic ductal cell, colonic mucosa, mucosa of sigmoid colon

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NIPA1	870
NIPA2	639

Intra-cohort edges

A	B	Sources
NIPA1	NIPA2	biogrid_interaction, intact

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
NIPA1	Q7RTP0	86.00
NIPA2	Q8N8Q9	82.52

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. 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
Miscellaneous transport and binding events	2	439.2×	5e-06	NIPA1, NIPA2

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
magnesium ion transport	2	1203.7×	1e-06	NIPA1, NIPA2
transmembrane transport	1	84.3×	0.012	NIPA1

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 2 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
NIPA1	0	0
NIPA2	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	2	NIPA1, NIPA2

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)
NIPA1	0	—
NIPA2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.