neurodegeneration with brain iron accumulation 2B

Summary

neurodegeneration with brain iron accumulation 2B (MONDO:0012444) is a disease caused by PLA2G6 (GenCC Definitive), with 3 cohort genes and 1 clinical trial.

At a glance

• Causal gene: PLA2G6 (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 116
• Clinical trials: 1

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	neurodegeneration with brain iron accumulation 2B
Mondo ID	MONDO:0012444
OMIM	610217
DOID	DOID:0110736
UMLS	C1857747
MedGen	346658
GARD	0010688
Is cancer (heuristic)	no

Also known as: atypical neuroaxonal dystrophy · early-onset progressive cerebellar ataxia dystonia spasticity and intellectual decline · NBIA2B · NBIA2b · neuroaxonal dystrophy, atypical · neurodegeneration with brain iron accumulation 2B · neurodegeneration with brain iron accumulation type 2B · neurodegeneration with brain iron accumulation type 2b · neurodegeneration with brain iron accumulation, Pla2g6-related

Data availability: 116 ClinVar variants · 3 GenCC gene-disease records.

Disease family

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 › neurodegeneration with brain iron accumulation 2B

Related subtypes (2): 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

116 retrieved; paginated sample, class counts are floors:

36 conflicting classifications of pathogenicity, 31 pathogenic/likely pathogenic, 22 uncertain significance, 14 pathogenic, 12 likely pathogenic, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
599341	NM_025233.7(COASY):c.1486-3C>G	COASY	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1012263	NM_003560.4(PLA2G6):c.668C>A (p.Pro223Gln)	PLA2G6	Pathogenic	no assertion criteria provided
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
1252075	NM_003560.4(PLA2G6):c.1125del (p.Val376fs)	PLA2G6	Pathogenic	no assertion criteria provided
1343814	NM_003560.4(PLA2G6):c.1690del (p.Phe563_Leu564insTer)	PLA2G6	Pathogenic	criteria provided, single submitter
159728	NM_003560.4(PLA2G6):c.1117G>A (p.Gly373Arg)	PLA2G6	Pathogenic/Likely 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
159739	NM_003560.4(PLA2G6):c.1613G>A (p.Arg538His)	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
1686078	NM_003560.4(PLA2G6):c.1069G>A (p.Ala357Thr)	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
211909	NM_003560.4(PLA2G6):c.1349-2A>G	PLA2G6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2412655	NM_003560.4(PLA2G6):c.1A>G (p.Met1Val)	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
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

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 12 · Orphanet: 5 · 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	Definitive	Autosomal recessive	neurodegeneration with brain iron accumulation 2A	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
C19orf12	Orphanet:289560	Mitochondrial membrane protein-associated neurodegeneration
C19orf12	Orphanet:320370	Autosomal recessive spastic paraplegia type 43
COASY	Orphanet:397725	COASY protein-associated neurodegeneration

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PLA2G6	HGNC:9039	ENSG00000184381	O60733	85/88 kDa calcium-independent phospholipase A2	gencc,clinvar
C19orf12	HGNC:25443	ENSG00000131943	Q9NSK7	Protein C19orf12	clinvar
COASY	HGNC:29932	ENSG00000068120	Q13057	Bifunctional coenzyme A synthase	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.
COASY	Bifunctional coenzyme A synthase	Bifunctional enzyme that catalyzes the fourth step of the coenzyme A biosynthetic pathway, the adenylation of 4’-phosphopantetheine, and the fifth step, the phosphorylation of dephospho-CoA to CoA.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 1 · Druggable fraction: 0.33

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	9.2×	0.246
Scaffold/PPI	1	5.8×	0.246
Other/Unknown	1	0.6×	0.914

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
C19orf12	Other/Unknown	no		C19orf12
COASY	Kinase	yes	2.7.1.24	Depp_CoAkinase, Cyt_trans-like, Rossmann-like_a/b/a_fold

Expression context

Cohort genes with no expression data: 0.

3 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)	3
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
endothelial cell	1
epithelial cell of pancreas	1
kidney epithelium	1
lower esophagus mucosa	1
mucosa of transverse colon	1
parotid gland	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
C19orf12	253	ubiquitous	marker	endothelial cell, kidney epithelium, epithelial cell of pancreas
COASY	280	ubiquitous	marker	parotid gland, mucosa of transverse colon, lower esophagus mucosa

Protein interactions among cohort

Intra-cohort edges: 2.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
COASY	3,273
PLA2G6	1,769
C19orf12	584

Intra-cohort edges

A	B	Sources
C19orf12	COASY	string_interaction
C19orf12	PLA2G6	string_interaction

Structural data

PDB: 0 · AlphaFold-only: 3 · No structure: 0

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
COASY	Q13057	89.51
PLA2G6	O60733	86.16
C19orf12	Q9NSK7	59.50

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 6. Enrichment computed across 3 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×	0.004	PLA2G6
Coenzyme A biosynthesis	1	713.8×	0.004	COASY
Role of phospholipids in phagocytosis	1	228.4×	0.006	PLA2G6
Acyl chain remodelling of PC	1	211.5×	0.006	PLA2G6
Acyl chain remodelling of PE	1	196.9×	0.006	PLA2G6
COPI-independent Golgi-to-ER retrograde traffic	1	103.8×	0.010	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 3 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	1872.4×	0.004	PLA2G6
cardiolipin acyl-chain remodeling	1	1404.3×	0.004	PLA2G6
phosphatidylethanolamine catabolic process	1	1404.3×	0.004	PLA2G6
phosphatidic acid metabolic process	1	936.2×	0.004	PLA2G6
positive regulation of ceramide biosynthetic process	1	802.5×	0.004	PLA2G6
coenzyme A biosynthetic process	1	510.7×	0.005	COASY
phosphatidylcholine catabolic process	1	432.1×	0.005	PLA2G6
mitochondrial calcium ion homeostasis	1	330.4×	0.006	C19orf12
Fc-gamma receptor signaling pathway involved in phagocytosis	1	234.1×	0.007	PLA2G6
positive regulation of insulin secretion involved in cellular response to glucose stimulus	1	124.8×	0.012	PLA2G6
antibacterial humoral response	1	110.1×	0.012	PLA2G6
chemotaxis	1	45.3×	0.026	PLA2G6
response to oxidative stress	1	43.5×	0.026	C19orf12
autophagy	1	36.7×	0.029	C19orf12
apoptotic process	1	9.6×	0.101	C19orf12

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 2 · Undrugged: 1

Druggability breadth: 2 of 3 evidence-associated genes (67%) 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
COASY	1	2
C19orf12	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
VARESPLADIB	2	PLA2G6
MOLIBRESIB	2	COASY

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
PLA2G6	47	Binding:47
COASY	10	Binding:10

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PLA2G6	3.1.1.4	phospholipase A2
COASY	2.7.1.24, 2.7.7.3	dephospho-CoA kinase, pantetheine-phosphate adenylyltransferase

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

2 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
MOLIBRESIB	2	COASY

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	2	PLA2G6, COASY
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	PLA2G6

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
NCT05440994	Not specified	UNKNOWN	Phenotypic Description of Patients With Atypical Clinical Forms of PLA2G6 Mutations