Hereditary spastic paraplegia 43

Summary

Hereditary spastic paraplegia 43 (MONDO:0014024) is a disease with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 1
• ClinVar variants: 147
• Phenotypes (HPO): 17

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)

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

HPO ID	Term	Frequency
HP:0001288	Gait disturbance	Very frequent (80-99%)
HP:0002064	Spastic gait	Very frequent (80-99%)
HP:0002313	Spastic paraparesis	Very frequent (80-99%)
HP:0002460	Distal muscle weakness	Very frequent (80-99%)
HP:0003487	Babinski sign	Very frequent (80-99%)
HP:0003693	Distal amyotrophy	Very frequent (80-99%)
HP:0007010	Poor fine motor coordination	Very frequent (80-99%)
HP:0001257	Spasticity	Frequent (30-79%)
HP:0001290	Generalized hypotonia	Frequent (30-79%)
HP:0001348	Brisk reflexes	Frequent (30-79%)
HP:0001761	Pes cavus	Frequent (30-79%)
HP:0002495	Impaired vibratory sensation	Frequent (30-79%)
HP:0003438	Absent Achilles reflex	Frequent (30-79%)
HP:0006380	Knee flexion contracture	Frequent (30-79%)
HP:0006466	Ankle flexion contracture	Frequent (30-79%)
HP:0007083	Hyperactive patellar reflex	Frequent (30-79%)
HP:0012785	Flexion contracture of finger	Frequent (30-79%)

Identifiers

Disease identifiers

Field	Value
Canonical name	hereditary spastic paraplegia 43
Mondo ID	MONDO:0014024
OMIM	615043
Orphanet	320370
DOID	DOID:0110795
SNOMED CT	764736001
UMLS	C2680446
MedGen	760531
GARD	0017473
Is cancer (heuristic)	no

Also known as: autosomal recessive complex spastic paraplegia caused by mutation in C19orf12 · autosomal recessive spastic paraplegia type 43 · C19orf12 autosomal recessive complex spastic paraplegia · hereditary spastic paraplegia type 43 · spastic paraplegia 43, autosomal recessive · SPG43

Data availability: 147 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 43

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 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 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

147 retrieved; paginated sample, class counts are floors:

73 uncertain significance, 46 likely benign, 11 conflicting classifications of pathogenicity, 8 pathogenic/likely pathogenic, 4 benign/likely benign, 3 likely pathogenic, 2 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1344261	NM_031448.6(C19orf12):c.166del	C19orf12	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
225875	NM_031448.6(C19orf12):c.215C>T (p.Pro72Leu)	C19orf12	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
31155	NM_031448.6(C19orf12):c.171_181del (p.Gly58fs)	C19orf12	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
31156	NM_031448.6(C19orf12):c.-2C>T	C19orf12	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
31157	NM_031448.6(C19orf12):c.172G>A (p.Gly58Arg)	C19orf12	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
617481	NM_031448.6(C19orf12):c.161G>A (p.Gly54Glu)	C19orf12	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
634443	NM_031448.6(C19orf12):c.371dup (p.Met124fs)	C19orf12	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
88866	NM_001031726.4(C19orf12):c.164_166delGGG	C19orf12	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1332802	NM_031448.6(C19orf12):c.152T>C (p.Leu51Pro)	C19orf12	Likely pathogenic	criteria provided, single submitter
2584972	NM_031448.6(C19orf12):c.36_40del (p.Cys13fs)	C19orf12	Likely pathogenic	criteria provided, single submitter
3703741	NM_031448.6(C19orf12):c.161-2A>T	C19orf12	Likely pathogenic	criteria provided, single submitter
1344262	NM_031448.6(C19orf12):c.180G>C (p.Leu60=)	C19orf12	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1682831	NM_001031726.4(C19orf12):c.166dup	C19orf12	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
183298	NM_031448.6(C19orf12):c.124G>A (p.Gly42Arg)	C19orf12	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2584363	NM_031448.6(C19orf12):c.105_106del (p.Ala37fs)	C19orf12	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2585400	NM_031448.6(C19orf12):c.118T>G (p.Phe40Val)	C19orf12	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
286392	NM_031448.6(C19orf12):c.313G>A (p.Val105Met)	C19orf12	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
31158	NM_031448.6(C19orf12):c.391A>G (p.Lys131Glu)	C19orf12	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
328731	NM_031448.6(C19orf12):c.68C>T (p.Ala23Val)	C19orf12	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
434550	NM_031448.6(C19orf12):c.161-2del	C19orf12	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
506451	NM_031448.6(C19orf12):c.177G>A (p.Gly59=)	C19orf12	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
88865	NM_031448.6(C19orf12):c.154G>C (p.Ala52Pro)	C19orf12	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1008373	NM_031448.6(C19orf12):c.326C>T (p.Ala109Val)	C19orf12	Uncertain significance	criteria provided, single submitter
1014734	NC_000019.9:g.(?30193609)(30205846_?)dup	C19orf12	Uncertain significance	criteria provided, single submitter
1188837	NM_031448.6(C19orf12):c.85G>C (p.Gly29Arg)	C19orf12	Uncertain significance	criteria provided, single submitter
1195848	NM_031448.6(C19orf12):c.161G>C (p.Gly54Ala)	C19orf12	Uncertain significance	criteria provided, multiple submitters, no conflicts
1299224	NM_031448.6(C19orf12):c.268A>G (p.Asn90Asp)	C19orf12	Uncertain significance	criteria provided, multiple submitters, no conflicts
1335335	NM_031448.6(C19orf12):c.214C>T (p.Pro72Ser)	C19orf12	Uncertain significance	criteria provided, multiple submitters, no conflicts
1678772	NM_031448.6(C19orf12):c.343G>A (p.Glu115Lys)	C19orf12	Uncertain significance	criteria provided, multiple submitters, no conflicts
1682751	NC_000019.9:g.(?30205794)(30205836_?)del	C19orf12	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 10 · 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
C19orf12	Limited	Autosomal recessive	hereditary spastic paraplegia 43	10

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
C19orf12	Orphanet:289560	Mitochondrial membrane protein-associated neurodegeneration
C19orf12	Orphanet:320370	Autosomal recessive spastic paraplegia type 43

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
C19orf12	HGNC:25443	ENSG00000131943	Q9NSK7	Protein C19orf12	gencc,clinvar

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)
C19orf12	Other/Unknown	no		C19orf12

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
endothelial cell	1
epithelial cell of pancreas	1
kidney epithelium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
C19orf12	253	ubiquitous	marker	endothelial cell, kidney epithelium, epithelial cell of pancreas

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
C19orf12	584

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
C19orf12	Q9NSK7	59.50

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
mitochondrial calcium ion homeostasis	1	991.3×	0.004	C19orf12
response to oxidative stress	1	130.6×	0.012	C19orf12
autophagy	1	110.1×	0.012	C19orf12
apoptotic process	1	28.7×	0.035	C19orf12

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
C19orf12	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	C19orf12

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)
C19orf12	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.