Spastic paraplegia 88, autosomal dominant

Summary

Spastic paraplegia 88, autosomal dominant (MONDO:0859309) is a disease caused by KPNA3 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: KPNA3 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 9

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	spastic paraplegia 88, autosomal dominant
Mondo ID	MONDO:0859309
OMIM	620106
DOID	DOID:0070457
UMLS	C5774247
MedGen	1824020
GARD	0026689
Is cancer (heuristic)	no

Data availability: 9 ClinVar variants · 3 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 › spastic paraplegia 88, autosomal dominant

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 6, 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 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

9 retrieved; paginated sample, class counts are floors:

4 pathogenic, 4 uncertain significance, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1713272	NM_002267.4(KPNA3):c.1001T>G (p.Leu334Arg)	KPNA3	Pathogenic	no assertion criteria provided
1713274	NM_002267.4(KPNA3):c.1049T>C (p.Leu350Pro)	KPNA3	Pathogenic	no assertion criteria provided
1713275	NM_002267.4(KPNA3):c.983T>C (p.Leu328Pro)	KPNA3	Pathogenic	no assertion criteria provided
1713276	NM_002267.4(KPNA3):c.1220T>G (p.Leu407Arg)	KPNA3	Pathogenic	no assertion criteria provided
1713273	NM_002267.4(KPNA3):c.944C>T (p.Thr315Ile)	KPNA3	Likely pathogenic	criteria provided, single submitter
2920672	NM_002267.4(KPNA3):c.1116G>A (p.Met372Ile)	KPNA3	Uncertain significance	criteria provided, single submitter
3067964	NM_002267.4(KPNA3):c.465G>T (p.Gln155His)	KPNA3	Uncertain significance	criteria provided, single submitter
3362765	NM_002267.4(KPNA3):c.1418T>C (p.Ile473Thr)	KPNA3	Uncertain significance	criteria provided, single submitter
3382490	NM_002267.4(KPNA3):c.368T>G (p.Leu123Arg)	KPNA3	Uncertain significance	criteria provided, single submitter

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
KPNA3	Strong	Autosomal dominant	spastic paraplegia 88, autosomal dominant	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
KPNA3	Orphanet:171612	Autosomal dominant spastic paraplegia type 37

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
KPNA3	HGNC:6396	ENSG00000102753	O00505	Importin subunit alpha-4	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
KPNA3	Importin subunit alpha-4	Functions in nuclear protein import as an adapter protein for nuclear receptor KPNB1.

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)
KPNA3	Other/Unknown	no		Armadillo, Importin-a_IBB, ARM-like

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
biceps brachii	1
skeletal muscle tissue of biceps brachii	1
skeletal muscle tissue of rectus abdominis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
KPNA3	299	ubiquitous	marker	biceps brachii, skeletal muscle tissue of rectus abdominis, skeletal muscle tissue of biceps brachii

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
KPNA3	3,652

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
KPNA3	O00505	86.15

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 11. 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
NS1 Mediated Effects on Host Pathways	1	285.5×	0.015	KPNA3
Maturation of DENV proteins	1	211.5×	0.015	KPNA3
Antimicrobial mechanism of IFN-stimulated genes	1	196.9×	0.015	KPNA3
Influenza Infection	1	175.7×	0.015	KPNA3
ISG15 antiviral mechanism	1	150.3×	0.015	KPNA3
Interferon Signaling	1	120.2×	0.015	KPNA3
Cytokine Signaling in Immune system	1	40.8×	0.039	KPNA3
Viral Infection Pathways	1	30.8×	0.045	KPNA3
Infectious disease	1	24.8×	0.049	KPNA3
Disease	1	13.1×	0.077	KPNA3
Immune System	1	13.0×	0.077	KPNA3

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
viral penetration into host nucleus	1	8426.0×	6e-04	KPNA3
NLS-bearing protein import into nucleus	1	802.5×	0.003	KPNA3
symbiont entry into host cell	1	401.2×	0.004	KPNA3
protein import into nucleus	1	144.0×	0.009	KPNA3
protein-containing complex assembly	1	113.9×	0.009	KPNA3

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 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
KPNA3	1	2

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOLIBRESIB	2	KPNA3

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
KPNA3	8	Binding:8

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

1 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.

Compound	Max phase	Cohort target (bioactivity)
MOLIBRESIB	2	KPNA3

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	1	KPNA3
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

0 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Clinical trials & evidence

Clinical trials

Clinical trials: 0.