Hereditary spastic paraplegia 42

Summary

Hereditary spastic paraplegia 42 (MONDO:0012928) is a disease with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 1
• ClinVar variants: 11
• Phenotypes (HPO): 17

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

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

Signs & symptoms

Clinical features (HPO)

17 HPO clinical features (Orphanet curated; top 17 by frequency):

HPO ID	Term	Frequency
HP:0001347	Hyperreflexia	Very frequent (80-99%)
HP:0002061	Lower limb spasticity	Very frequent (80-99%)
HP:0002064	Spastic gait	Very frequent (80-99%)
HP:0002314	Degeneration of the lateral corticospinal tracts	Very frequent (80-99%)
HP:0003487	Babinski sign	Very frequent (80-99%)
HP:0006895	Lower limb hypertonia	Very frequent (80-99%)
HP:0007020	Progressive spastic paraplegia	Very frequent (80-99%)
HP:0002166	Impaired vibration sensation in the lower limbs	Frequent (30-79%)
HP:0002169	Clonus	Frequent (30-79%)
HP:0007210	Lower limb amyotrophy	Frequent (30-79%)
HP:0007340	Lower limb muscle weakness	Frequent (30-79%)
HP:0100561	Spinal cord lesion	Frequent (30-79%)
HP:0001761	Pes cavus	Occasional (5-29%)
HP:0001250	Seizure	Excluded (0%)
HP:0002921	Abnormality of the cerebrospinal fluid	Excluded (0%)
HP:0003457	EMG abnormality	Excluded (0%)
HP:0012898	Abnormal lower-limb motor evoked potentials	Excluded (0%)

Identifiers

Disease identifiers

Field	Value
Canonical name	hereditary spastic paraplegia 42
Mondo ID	MONDO:0012928
MeSH	C567262
OMIM	612539
Orphanet	171863
DOID	DOID:0110794
SNOMED CT	763070001
UMLS	C2675528
MedGen	393407
GARD	0017073
Is cancer (heuristic)	no

Also known as: autosomal dominant pure spastic paraplegia caused by mutation in SLC33A1 · autosomal dominant spastic paraplegia type 42 · hereditary spastic paraplegia type 42 · SLC33A1 autosomal dominant pure spastic paraplegia · spastic paraplegia 42, autosomal dominant · SPG42

Data availability: 11 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 › pure hereditary spastic paraplegia › hereditary spastic paraplegia 42

Related subtypes (11): hereditary spastic paraplegia 34, hereditary spastic paraplegia 8, hereditary spastic paraplegia 12, hereditary spastic paraplegia 19, hereditary spastic paraplegia 28, hereditary spastic paraplegia 37, hereditary spastic paraplegia 41, hereditary spastic paraplegia 72, hereditary spastic paraplegia 62, hereditary spastic paraplegia 73, autosomal recessive spastic paraplegia type 71

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

11 retrieved; paginated sample, class counts are floors:

7 uncertain significance, 1 benign, 1 conflicting classifications of pathogenicity, 1 benign/likely benign, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
6132	NM_004733.4(SLC33A1):c.339T>G (p.Ser113Arg)	SLC33A1	Pathogenic	no assertion criteria provided
343874	NM_004733.4(SLC33A1):c.1525G>A (p.Gly509Ser)	SLC33A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1029889	NM_004733.4(SLC33A1):c.353C>G (p.Pro118Arg)	SLC33A1	Uncertain significance	criteria provided, single submitter
1043753	NM_004733.4(SLC33A1):c.1559T>C (p.Ile520Thr)	SLC33A1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1509941	NM_004733.4(SLC33A1):c.1505C>T (p.Ser502Leu)	SLC33A1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2584670	NM_004733.4(SLC33A1):c.1363G>A (p.Val455Met)	SLC33A1	Uncertain significance	criteria provided, multiple submitters, no conflicts
3892471	NM_004733.4(SLC33A1):c.914T>C (p.Ile305Thr)	SLC33A1	Uncertain significance	criteria provided, single submitter
3897008	NM_004733.4(SLC33A1):c.322G>T (p.Asp108Tyr)	SLC33A1	Uncertain significance	criteria provided, single submitter
4294001	NM_004733.4(SLC33A1):c.348T>G (p.Phe116Leu)	SLC33A1	Uncertain significance	criteria provided, single submitter
259528	NM_004733.4(SLC33A1):c.512A>G (p.Asp171Gly)	SLC33A1	Benign	criteria provided, multiple submitters, no conflicts
343875	NM_004733.4(SLC33A1):c.1451A>C (p.Asn484Thr)	SLC33A1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 2 · 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
SLC33A1	Supportive	Autosomal dominant	hereditary spastic paraplegia 42	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SLC33A1	Orphanet:171863	Autosomal dominant spastic paraplegia type 42
SLC33A1	Orphanet:300313	Congenital cataract-hearing loss-severe developmental delay syndrome

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
SLC33A1	HGNC:95	ENSG00000169359	O00400	Acetyl-coenzyme A transporter 1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SLC33A1	Acetyl-coenzyme A transporter 1	Acetyl-CoA transporter that mediates active acetyl-CoA import through the endoplasmic reticulum (ER) membrane into the ER lumen where specific ER-based acetyl-CoA:lysine acetyltransferases are responsible for the acetylation of ER-based pr…

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Transporter	1	77.8×	0.013

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SLC33A1	Transporter	yes		AmpG_permease/AT-1, AcetylCoA_trans_1-like, MFS_trans_sf

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
body of pancreas	1
corpus epididymis	1
islet of Langerhans	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SLC33A1	278	ubiquitous	marker	corpus epididymis, body of pancreas, islet of Langerhans

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SLC33A1	2,262

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SLC33A1	O00400	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 7. 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
Defective SLC33A1 causes spastic paraplegia 42 (SPG42)	1	11420.0×	6e-04	SLC33A1
Transport of vitamins, nucleosides, and related molecules	1	271.9×	0.011	SLC33A1
SLC transporter disorders	1	203.9×	0.011	SLC33A1
Disorders of transmembrane transporters	1	139.3×	0.013	SLC33A1
SLC-mediated transmembrane transport	1	59.2×	0.024	SLC33A1
Transport of small molecules	1	25.1×	0.046	SLC33A1
Disease	1	13.1×	0.076	SLC33A1

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
acetyl-CoA transmembrane transport	1	16852.0×	1e-04	SLC33A1
transmembrane transport	1	168.5×	0.006	SLC33A1

Therapeutics

Drug target analysis

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

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
SLC33A1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
SLC33A1	2	Binding:2

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	1	SLC33A1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

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)
SLC33A1	2	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.