Spastic paraplegia 84, autosomal recessive

Summary

Spastic paraplegia 84, autosomal recessive (MONDO:0030482) is a disease with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 1
• ClinVar variants: 14

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

Identifiers

Disease identifiers

Field	Value
Canonical name	spastic paraplegia 84, autosomal recessive
Mondo ID	MONDO:0030482
OMIM	619621
Orphanet	631079
DOID	DOID:0112347
UMLS	C5562025
MedGen	1794235
GARD	0025577
Is cancer (heuristic)	no

Also known as: autosomal recessive spastic paraplegia type 84 · SPG84

Data availability: 14 ClinVar variants.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › complex hereditary spastic paraplegia › spastic paraplegia 84, autosomal recessive

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 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 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

14 retrieved; paginated sample, class counts are floors:

5 likely pathogenic, 5 uncertain significance, 3 pathogenic, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
1325874	NM_058004.4(PI4KA):c.6156_6159del (p.Thr2053fs)	PI4KA	Pathogenic	criteria provided, multiple submitters, no conflicts
1325875	NM_058004.4(PI4KA):c.5456AAG[1] (p.Glu1820del)	PI4KA	Pathogenic	criteria provided, single submitter
1325877	NM_058004.4(PI4KA):c.5159C>T (p.Thr1720Ile)	PI4KA	Pathogenic	criteria provided, single submitter
1676320	NM_058004.4(PI4KA):c.1852C>T (p.Arg618Ter)	PI4KA	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3384182	NM_058004.4(PI4KA):c.574C>T (p.Arg192Ter)	PI4KA	Likely pathogenic	criteria provided, single submitter
3384183	NM_058004.4(PI4KA):c.4156T>G (p.Phe1386Val)	PI4KA	Likely pathogenic	criteria provided, single submitter
3587850	NM_058004.4(PI4KA):c.2988-2A>G	PI4KA	Likely pathogenic	criteria provided, single submitter
4845912	NM_058004.4(PI4KA):c.4160+1G>A	PI4KA	Likely pathogenic	criteria provided, single submitter
1325876	NM_058004.4(PI4KA):c.4666G>A (p.Val1556Met)	PI4KA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1705451	NM_058004.4(PI4KA):c.5653C>T (p.Arg1885Cys)	PI4KA	Uncertain significance	criteria provided, single submitter
3896941	NM_058004.4(PI4KA):c.3G>A (p.Met1Ile)	PI4KA	Uncertain significance	criteria provided, multiple submitters, no conflicts
3898022	NM_058004.4(PI4KA):c.4682+4G>A	PI4KA	Uncertain significance	criteria provided, single submitter
4537460	NM_058004.4(PI4KA):c.4747G>A (p.Val1583Ile)	PI4KA	Uncertain significance	criteria provided, single submitter
623974	NM_058004.4(PI4KA):c.5596G>A (p.Asp1866Asn)	PI4KA	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 3 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PI4KA	Orphanet:436252	Combined immunodeficiency-multiple intestinal atresia
PI4KA	Orphanet:631079	Autosomal recessive spastic paraplegia type 84
PI4KA	Orphanet:98889	Bilateral perisylvian polymicrogyria

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
PI4KA	HGNC:8983	ENSG00000241973	P42356	Phosphatidylinositol 4-kinase alpha	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PI4KA	Phosphatidylinositol 4-kinase alpha	Acts on phosphatidylinositol (PtdIns) in the first committed step in the production of the second messenger inositol-1,4,5,-trisphosphate.

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
Kinase	1	27.7×	0.036

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PI4KA	Kinase	yes		PI3/4_kinase_cat_dom, PI3K_accessory_dom, Kinase-like_dom_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
Brodmann (1909) area 9	1
right frontal lobe	1
superior frontal gyrus	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PI4KA	143	ubiquitous	marker	superior frontal gyrus, right frontal lobe, Brodmann (1909) area 9

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PI4KA	1,755

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PI4KA	P42356	4

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. 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
Synthesis of PIPs at the ER membrane	1	2284.0×	9e-04	PI4KA
Synthesis of PIPs at the Golgi membrane	1	634.4×	0.002	PI4KA

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
reorganization of cellular membranes to establish viral sites of replication	1	16852.0×	4e-04	PI4KA
host-mediated perturbation of viral process	1	1872.4×	0.002	PI4KA
phosphatidylinositol-mediated signaling	1	702.2×	0.003	PI4KA
phosphatidylinositol phosphate biosynthetic process	1	481.5×	0.003	PI4KA
phosphatidylinositol biosynthetic process	1	366.4×	0.003	PI4KA
signal transduction	1	16.1×	0.062	PI4KA

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · 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).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
PI4KA	ADENOSINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PI4KA	1	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
ADENOSINE	4	PI4KA

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
PI4KA	86	Binding:83, Functional:2, ADMET:1

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)
ADENOSINE	4	PI4KA

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	PI4KA
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	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.