autosomal recessive Parkinson disease 14

Summary

autosomal recessive Parkinson disease 14 (MONDO:0013060) is a disease caused by PLA2G6 (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: PLA2G6 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 94
• Phenotypes (HPO): 32

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		14	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

32 HPO clinical features (Orphanet curated; top 32 by frequency):

HPO ID	Term	Frequency
HP:0000338	Hypomimic face	Frequent (30-79%)
HP:0000571	Hypometric saccades	Frequent (30-79%)
HP:0000658	Eyelid apraxia	Frequent (30-79%)
HP:0001257	Spasticity	Frequent (30-79%)
HP:0001260	Dysarthria	Frequent (30-79%)
HP:0001337	Tremor	Frequent (30-79%)
HP:0001347	Hyperreflexia	Frequent (30-79%)
HP:0002015	Dysphagia	Frequent (30-79%)
HP:0002063	Rigidity	Frequent (30-79%)
HP:0002067	Bradykinesia	Frequent (30-79%)
HP:0002145	Frontotemporal dementia	Frequent (30-79%)
HP:0002172	Postural instability	Frequent (30-79%)
HP:0002185	Neurofibrillary tangles	Frequent (30-79%)
HP:0002312	Clumsiness	Frequent (30-79%)
HP:0002548	Parkinsonism with favorable response to dopaminergic medication	Frequent (30-79%)
HP:0004373	Focal dystonia	Frequent (30-79%)
HP:0006892	Frontotemporal cerebral atrophy	Frequent (30-79%)
HP:0007058	Generalized cerebral atrophy/hypoplasia	Frequent (30-79%)
HP:0007153	Progressive extrapyramidal movement disorder	Frequent (30-79%)
HP:0010522	Dyslexia	Frequent (30-79%)
HP:0025262	Stiff hip	Frequent (30-79%)
HP:0040081	Abnormal circulating creatine kinase concentration	Frequent (30-79%)
HP:0000605	Supranuclear gaze palsy	Occasional (5-29%)
HP:0000716	Depression	Occasional (5-29%)
HP:0000746	Delusion	Occasional (5-29%)
HP:0000751	Personality changes	Occasional (5-29%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0001263	Global developmental delay	Occasional (5-29%)
HP:0001332	Dystonia	Occasional (5-29%)
HP:0001336	Myoclonus	Occasional (5-29%)
HP:0011999	Paranoia	Occasional (5-29%)
HP:0012675	Iron accumulation in brain	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	autosomal recessive Parkinson disease 14
Mondo ID	MONDO:0013060
MeSH	C567844
OMIM	612953
Orphanet	199351
DOID	DOID:0060900
SNOMED CT	720466001
UMLS	C2751842
MedGen	414488
GARD	0012568
Is cancer (heuristic)	no

Also known as: autosomal recessive Parkinson disease type 14 · dystonia-parkinsonism, Paisan-Ruiz type · hereditary late onset Parkinson disease caused by mutation in PLA2G6 · PARK14 · Parkinson disease 14, autosomal recessive · PLA2G6 hereditary late onset Parkinson disease · PLA2G6-related dystonia-parkinsonism

Data availability: 94 ClinVar variants · 4 GenCC gene-disease records · 7 cell lines.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › brain disorder › basal ganglia disorder › parkinsonian disorder › Parkinson disease › late-onset Parkinson disease › autosomal recessive Parkinson disease 14

Related subtypes (6): autosomal dominant Parkinson disease 1, autosomal dominant Parkinson disease 4, autosomal dominant Parkinson disease 8, Parkinson disease 17, Parkinson disease 21, Parkinson disease 22, autosomal dominant

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

94 retrieved; paginated sample, class counts are floors:

31 conflicting classifications of pathogenicity, 26 pathogenic/likely pathogenic, 18 uncertain significance, 10 pathogenic, 8 likely pathogenic, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1028628	NM_003560.4(PLA2G6):c.1933C>T (p.Arg645Ter)	PLA2G6	Pathogenic	criteria provided, multiple submitters, no conflicts
1180814	NM_003560.4(PLA2G6):c.1893G>A (p.Trp631Ter)	PLA2G6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1197568	NM_003560.4(PLA2G6):c.1798C>T (p.Arg600Trp)	PLA2G6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
159728	NM_003560.4(PLA2G6):c.1117G>A (p.Gly373Arg)	PLA2G6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
159742	NM_003560.4(PLA2G6):c.1674del (p.Leu560fs)	PLA2G6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
159748	NM_003560.4(PLA2G6):c.1799G>A (p.Arg600Gln)	PLA2G6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
159749	NM_003560.4(PLA2G6):c.1903C>T (p.Arg635Ter)	PLA2G6	Pathogenic	criteria provided, multiple submitters, no conflicts
159762	NM_003560.4(PLA2G6):c.2233C>T (p.Arg745Trp)	PLA2G6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
159778	NM_003560.4(PLA2G6):c.755del (p.Asn252fs)	PLA2G6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1722386	NM_003560.4(PLA2G6):c.1511C>T (p.Ser504Leu)	PLA2G6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
208712	NM_003560.4(PLA2G6):c.1019_1025del (p.Gly340fs)	PLA2G6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2501145	NM_003560.4(PLA2G6):c.1743-2A>G	PLA2G6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2581775	NM_003560.4(PLA2G6):c.1186+1G>T	PLA2G6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
265448	NM_003560.4(PLA2G6):c.2221C>T (p.Arg741Trp)	PLA2G6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2724426	NM_003560.4(PLA2G6):c.1982C>T (p.Thr661Met)	PLA2G6	Pathogenic	criteria provided, multiple submitters, no conflicts
279875	NM_003560.4(PLA2G6):c.1077G>A (p.Ser359=)	PLA2G6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
30366	NM_003560.4(PLA2G6):c.1904G>A (p.Arg635Gln)	PLA2G6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
30367	NM_003560.4(PLA2G6):c.1354C>T (p.Gln452Ter)	PLA2G6	Pathogenic	no assertion criteria provided
30368	NM_003560.4(PLA2G6):c.216C>A (p.Phe72Leu)	PLA2G6	Pathogenic	no assertion criteria provided
30370	NM_003560.4(PLA2G6):c.109C>T (p.Arg37Ter)	PLA2G6	Pathogenic	criteria provided, multiple submitters, no conflicts
30371	NM_003560.4(PLA2G6):c.991G>T (p.Asp331Tyr)	PLA2G6	Pathogenic	criteria provided, multiple submitters, no conflicts
3382608	NM_003560.4(PLA2G6):c.1536dup (p.Asp513Ter)	PLA2G6	Pathogenic	criteria provided, single submitter
3588039	NM_003560.4(PLA2G6):c.857del (p.Tyr286fs)	PLA2G6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3764717	NM_003560.4(PLA2G6):c.111_112dup (p.Val38fs)	PLA2G6	Pathogenic	criteria provided, single submitter
437465	NM_003560.4(PLA2G6):c.1427+1G>A	PLA2G6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
561085	NM_003560.4(PLA2G6):c.1592-2A>C	PLA2G6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
6196	NM_003560.4(PLA2G6):c.1634A>C (p.Lys545Thr)	PLA2G6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
6199	NM_003560.4(PLA2G6):c.1894C>T (p.Arg632Trp)	PLA2G6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
6201	NM_003560.4(PLA2G6):c.2370_2371del (p.Tyr790_Glu791delinsTer)	PLA2G6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
6202	NM_003560.4(PLA2G6):c.238G>A (p.Ala80Thr)	PLA2G6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 12 · 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
PLA2G6	Strong	Autosomal recessive	autosomal recessive Parkinson disease 14	12

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PLA2G6	Orphanet:199351	Adult-onset dystonia-parkinsonism
PLA2G6	Orphanet:35069	Infantile neuroaxonal dystrophy

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
PLA2G6	HGNC:9039	ENSG00000184381	O60733	85/88 kDa calcium-independent phospholipase A2	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PLA2G6	85/88 kDa calcium-independent phospholipase A2	Calcium-independent phospholipase involved in phospholipid remodeling with implications in cellular membrane homeostasis, mitochondrial integrity and signal transduction.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 0 · 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
Scaffold/PPI	1	17.3×	0.058

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PLA2G6	Scaffold/PPI	no	3.1.1.4	Ankyrin_rpt, PNPLA_dom, Acyl_Trfase/lysoPLipase

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
left lobe of thyroid gland	1
right lobe of thyroid gland	1
right uterine tube	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PLA2G6	232	ubiquitous	marker	right uterine tube, right lobe of thyroid gland, left lobe of thyroid gland

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PLA2G6	1,769

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PLA2G6	O60733	86.16

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 5. 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
Acyl chain remodeling of CL	1	1903.3×	0.003	PLA2G6
Role of phospholipids in phagocytosis	1	456.8×	0.003	PLA2G6
Acyl chain remodelling of PC	1	423.0×	0.003	PLA2G6
Acyl chain remodelling of PE	1	393.8×	0.003	PLA2G6
COPI-independent Golgi-to-ER retrograde traffic	1	207.6×	0.005	PLA2G6

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
platelet activating factor metabolic process	1	5617.3×	8e-04	PLA2G6
cardiolipin acyl-chain remodeling	1	4213.0×	8e-04	PLA2G6
phosphatidylethanolamine catabolic process	1	4213.0×	8e-04	PLA2G6
phosphatidic acid metabolic process	1	2808.7×	8e-04	PLA2G6
positive regulation of ceramide biosynthetic process	1	2407.4×	8e-04	PLA2G6
phosphatidylcholine catabolic process	1	1296.3×	0.001	PLA2G6
Fc-gamma receptor signaling pathway involved in phagocytosis	1	702.2×	0.002	PLA2G6
positive regulation of insulin secretion involved in cellular response to glucose stimulus	1	374.5×	0.003	PLA2G6
antibacterial humoral response	1	330.4×	0.003	PLA2G6
chemotaxis	1	135.9×	0.007	PLA2G6

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
PLA2G6	1	2

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
VARESPLADIB	2	PLA2G6

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
PLA2G6	47	Binding:47

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PLA2G6	3.1.1.4	phospholipase A2

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)
VARESPLADIB	2	PLA2G6

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	PLA2G6
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.