megalencephalic leukoencephalopathy with subcortical cysts 2B, remitting, with or without intellectual disability

Summary

megalencephalic leukoencephalopathy with subcortical cysts 2B, remitting, with or without intellectual disability (MONDO:0013491) is a disease caused by HEPACAM (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: HEPACAM (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 21

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	megalencephalic leukoencephalopathy with subcortical cysts 2B, remitting, with or without intellectual disability
Mondo ID	MONDO:0013491
OMIM	613926
DOID	DOID:0080317
UMLS	C3151356
MedGen	462706
GARD	0015729
Is cancer (heuristic)	no

Also known as: megalencephalic leukoencephalopathy with subcortical cysts 2B, remitting, with or without intellectual disability · megalencephalic leukoencephalopathy with subcortical cysts 2B, remitting, with or without mental retardation · MLC2B

Data availability: 21 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › brain disorder › leukoencephalopathy, megalencephalic › megalencephalic leukoencephalopathy with subcortical cysts › megalencephalic leukoencephalopathy with subcortical cysts 2B, remitting, with or without intellectual disability

Related subtypes (2): megalencephalic leukoencephalopathy with subcortical cysts 2A, megalencephalic leukoencephalopathy with subcortical cysts 1

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

21 retrieved; paginated sample, class counts are floors:

8 uncertain significance, 4 conflicting classifications of pathogenicity, 3 pathogenic, 2 benign, 1 likely benign, 1 benign/likely benign, 1 pathogenic/likely pathogenic, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1068633	NM_152722.5(HEPACAM):c.523A>T (p.Lys175Ter)	HEPACAM	Pathogenic	criteria provided, multiple submitters, no conflicts
30919	NM_152722.5(HEPACAM):c.265G>A (p.Gly89Ser)	HEPACAM	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
30921	NM_152722.5(HEPACAM):c.274C>T (p.Arg92Trp)	HEPACAM	Pathogenic	criteria provided, multiple submitters, no conflicts
4531823	NM_152722.5(HEPACAM):c.265G>C (p.Gly89Arg)	HEPACAM	Pathogenic	criteria provided, single submitter
433199	NM_152722.5(HEPACAM):c.442C>T (p.Pro148Ser)	HEPACAM	Likely pathogenic	no assertion criteria provided
1218905	NM_152722.5(HEPACAM):c.382G>A (p.Asp128Asn)	HEPACAM	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1367723	NM_152722.5(HEPACAM):c.96G>C (p.Glu32Asp)	HEPACAM	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
393149	NM_152722.5(HEPACAM):c.1198G>A (p.Val400Met)	HEPACAM	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
562146	NM_152722.5(HEPACAM):c.803+1G>A	HEPACAM	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1187211	NM_152722.5(HEPACAM):c.217C>T (p.Arg73Trp)	HEPACAM	Uncertain significance	criteria provided, multiple submitters, no conflicts
1339869	NM_152722.5(HEPACAM):c.616C>T (p.Arg206Cys)	HEPACAM	Uncertain significance	criteria provided, multiple submitters, no conflicts
1341787	NM_152722.5(HEPACAM):c.952T>A (p.Ser318Thr)	HEPACAM	Uncertain significance	criteria provided, multiple submitters, no conflicts
1510664	NM_152722.5(HEPACAM):c.484G>A (p.Glu162Lys)	HEPACAM	Uncertain significance	criteria provided, multiple submitters, no conflicts
2572972	NM_152722.5(HEPACAM):c.769G>C (p.Val257Leu)	HEPACAM	Uncertain significance	criteria provided, single submitter
435410	NM_152722.5(HEPACAM):c.614C>T (p.Thr205Ile)	HEPACAM	Uncertain significance	criteria provided, multiple submitters, no conflicts
522820	NM_152722.5(HEPACAM):c.592G>A (p.Asp198Asn)	HEPACAM	Uncertain significance	criteria provided, multiple submitters, no conflicts
638399	NM_152722.5(HEPACAM):c.128T>A (p.Ile43Asn)	HEPACAM	Uncertain significance	criteria provided, multiple submitters, no conflicts
1582595	NM_152722.5(HEPACAM):c.1062C>T (p.Pro354=)	HEPACAM	Likely benign	criteria provided, multiple submitters, no conflicts
262680	NM_152722.5(HEPACAM):c.618C>T (p.Arg206=)	HEPACAM	Benign	criteria provided, multiple submitters, no conflicts
262681	NM_152722.5(HEPACAM):c.652A>G (p.Met218Val)	HEPACAM	Benign	criteria provided, multiple submitters, no conflicts
303335	NM_152722.5(HEPACAM):c.258G>A (p.Glu86=)	HEPACAM	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · 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
HEPACAM	Strong	Autosomal recessive	megalencephalic leukoencephalopathy with subcortical cysts 2A	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
HEPACAM	Orphanet:210548	Macrocephaly-intellectual disability-autism syndrome
HEPACAM	Orphanet:2478	Megalencephalic leukoencephalopathy with subcortical cysts

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
HEPACAM	HGNC:26361	ENSG00000165478	Q14CZ8	Hepatic and glial cell adhesion molecule	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
HEPACAM	Hepatic and glial cell adhesion molecule	Involved in regulating cell motility and cell-matrix interactions.

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
Antibody/Immunoglobulin	1	29.2×	0.034

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
HEPACAM	Antibody/Immunoglobulin	yes		Ig_sub2, Ig_sub, Ig-like_dom

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
lateral globus pallidus	1
medial globus pallidus	1
substantia nigra pars reticulata	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
HEPACAM	167	broad	marker	lateral globus pallidus, substantia nigra pars reticulata, medial globus pallidus

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
HEPACAM	661

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
HEPACAM	Q14CZ8	1

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
protein localization to cell-cell junction	1	1872.4×	0.002	HEPACAM
regulation of cell cycle	1	74.6×	0.027	HEPACAM
immune response	1	47.1×	0.027	HEPACAM
cell adhesion	1	37.5×	0.027	HEPACAM

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
HEPACAM	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	1	HEPACAM
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

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)
HEPACAM	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.