PLA2G6-associated neurodegeneration

Summary

PLA2G6-associated neurodegeneration (MONDO:0017998) is a disease with 2 cohort genes and 1 clinical trial.

At a glance

• Cohort genes: 2
• ClinVar variants: 165
• Clinical trials: 1

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	PLA2G6-associated neurodegeneration
Mondo ID	MONDO:0017998
Orphanet	329303
GARD	0012567
NORD	1302
Is cancer (heuristic)	no

Also known as: neurodegeneration with brain iron accumulation caused by mutation in PLA2G6 · PLA2G6 neurodegeneration with brain iron accumulation · PLAN

Data availability: 165 ClinVar variants.

Disease family

An umbrella term covering 3 Mondo subtypes.

Classification path: disease › human disease › disease by developmental or physiological process › metabolic disease › mineral metabolism disease › iron metabolism disease › neurodegeneration with brain iron accumulation › PLA2G6-associated neurodegeneration

Related subtypes (13): pantothenate kinase-associated neurodegeneration, Woodhouse-Sakati syndrome, neurodegeneration with brain iron accumulation 5, aceruloplasminemia, neuroferritinopathy, Kufor-Rakeb syndrome, neurodegeneration with brain iron accumulation 4, neurodegeneration with brain iron accumulation 6, fatty acid hydroxylase-associated neurodegeneration, early-onset progressive encephalopathy-spastic ataxia-distal spinal muscular atrophy syndrome, neurodegeneration with brain iron accumulation 7, neurodegeneration with brain iron accumulation 8, neurodegeneration with brain iron accumulation 9

Subtypes (3): neurodegeneration with brain iron accumulation 2B, autosomal recessive Parkinson disease 14, neurodegeneration with brain iron accumulation 2A

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

165 retrieved; paginated sample, class counts are floors:

60 conflicting classifications of pathogenicity, 50 uncertain significance, 27 pathogenic/likely pathogenic, 10 pathogenic, 6 likely pathogenic, 6 benign, 5 benign/likely benign, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
4056471	Single allele	BAIAP2L2	Pathogenic	criteria provided, single submitter
1012697	NM_003560.4(PLA2G6):c.2349G>A (p.Trp783Ter)	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
1298894	NM_003560.4(PLA2G6):c.1771C>T (p.Arg591Trp)	PLA2G6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
159730	NC_000022.10:g.38522454delG	PLA2G6	Pathogenic	criteria provided, multiple submitters, no conflicts
159731	NM_003560.4(PLA2G6):c.1442T>A (p.Leu481Gln)	PLA2G6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
159738	NM_003560.4(PLA2G6):c.1612C>T (p.Arg538Cys)	PLA2G6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
159739	NM_003560.4(PLA2G6):c.1613G>A (p.Arg538His)	PLA2G6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
159741	NM_003560.4(PLA2G6):c.1634A>G (p.Lys545Arg)	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
159778	NM_003560.4(PLA2G6):c.755del (p.Asn252fs)	PLA2G6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2138448	NM_003560.4(PLA2G6):c.1765_1768del (p.Ser589fs)	PLA2G6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2196766	NM_003560.4(PLA2G6):c.1670C>T (p.Ser557Leu)	PLA2G6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2412648	NM_003560.4(PLA2G6):c.1427+2T>C	PLA2G6	Pathogenic	criteria provided, single submitter
2412654	NM_003560.4(PLA2G6):c.127C>T (p.Gln43Ter)	PLA2G6	Pathogenic	criteria provided, single submitter
2412655	NM_003560.4(PLA2G6):c.1A>G (p.Met1Val)	PLA2G6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2501533	NM_003560.4(PLA2G6):c.1915del (p.Ala639fs)	PLA2G6	Pathogenic	criteria provided, single submitter
265448	NM_003560.4(PLA2G6):c.2221C>T (p.Arg741Trp)	PLA2G6	Pathogenic/Likely 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
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
3383959	NM_003560.4(PLA2G6):c.1631T>C (p.Met544Thr)	PLA2G6	Pathogenic	no assertion criteria provided
4056470	Single allele	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
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

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 2 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

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

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
BAIAP2L2	HGNC:26203	ENSG00000128298	Q6UXY1	BAR/IMD domain-containing adapter protein 2-like 2	clinvar
PLA2G6	HGNC:9039	ENSG00000184381	O60733	85/88 kDa calcium-independent phospholipase A2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
BAIAP2L2	BAR/IMD domain-containing adapter protein 2-like 2	Phosphoinositides-binding protein that induces the formation of planar or gently curved membrane structures.
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: 2 · 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	8.6×	0.225
Transcription factor	1	4.1×	0.228

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
BAIAP2L2	Transcription factor	no		SH3_domain, I-BAR_dom, AH/BAR_dom_sf
PLA2G6	Scaffold/PPI	no	3.1.1.4	Ankyrin_rpt, PNPLA_dom, Acyl_Trfase/lysoPLipase

Expression context

Cohort genes with no expression data: 0.

2 cohort genes 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
lower esophagus mucosa	1
mucosa of transverse colon	1
small intestine Peyer’s patch	1
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
BAIAP2L2	178	broad	marker	mucosa of transverse colon, small intestine Peyer’s patch, lower esophagus mucosa
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
BAIAP2L2	825

Structural data

PDB: 0 · AlphaFold-only: 2 · No structure: 0

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PLA2G6	O60733	86.16
BAIAP2L2	Q6UXY1	71.34

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 10. Enrichment computed across 2 evidence-associated genes (2 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 2 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	951.7×	0.011	PLA2G6
Role of phospholipids in phagocytosis	1	228.4×	0.013	PLA2G6
Acyl chain remodelling of PC	1	211.5×	0.013	PLA2G6
Acyl chain remodelling of PE	1	196.9×	0.013	PLA2G6
RHOF GTPase cycle	1	129.8×	0.015	BAIAP2L2
COPI-independent Golgi-to-ER retrograde traffic	1	103.8×	0.016	PLA2G6
RHO GTPase cycle	1	30.1×	0.047	BAIAP2L2
Signaling by Rho GTPases	1	17.1×	0.065	BAIAP2L2
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1	16.7×	0.065	BAIAP2L2
Signal Transduction	1	5.1×	0.187	BAIAP2L2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 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	2808.7×	0.002	PLA2G6
cardiolipin acyl-chain remodeling	1	2106.5×	0.002	PLA2G6
phosphatidylethanolamine catabolic process	1	2106.5×	0.002	PLA2G6
phosphatidic acid metabolic process	1	1404.3×	0.002	PLA2G6
positive regulation of ceramide biosynthetic process	1	1203.7×	0.002	PLA2G6
phosphatidylcholine catabolic process	1	648.1×	0.004	PLA2G6
actin crosslink formation	1	601.9×	0.004	BAIAP2L2
plasma membrane organization	1	443.5×	0.004	BAIAP2L2
Fc-gamma receptor signaling pathway involved in phagocytosis	1	351.1×	0.005	PLA2G6
membrane organization	1	255.3×	0.006	BAIAP2L2
actin filament bundle assembly	1	227.7×	0.006	BAIAP2L2
positive regulation of insulin secretion involved in cellular response to glucose stimulus	1	187.2×	0.006	PLA2G6
antibacterial humoral response	1	165.2×	0.006	PLA2G6
positive regulation of actin filament polymerization	1	165.2×	0.006	BAIAP2L2
chemotaxis	1	68.0×	0.015	PLA2G6

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 evidence-associated genes (50%) 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
BAIAP2L2	0	0

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: 2; 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	1	BAIAP2L2

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)
BAIAP2L2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05522374	Not specified	RECRUITING	TIRCON International NBIA Registry