Neuropathy, congenital hypomyelinating, 2

Summary

Neuropathy, congenital hypomyelinating, 2 (MONDO:0020765) is a disease caused by MPZ (GenCC Definitive), with 3 cohort genes.

At a glance

• Causal gene: MPZ (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 46

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	neuropathy, congenital hypomyelinating, 2
Mondo ID	MONDO:0020765
OMIM	618184
DOID	DOID:0070679
UMLS	C4722277
MedGen	1648446
GARD	0025242
Is cancer (heuristic)	no

Also known as: CHN2 · hypomyelinating neuropathy, congenital, 2 · NEUROPATHY, CONGENITAL HYPOMYELINATING, 2

Data availability: 46 ClinVar variants · 1 GenCC gene-disease record.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › congenital nervous system disorder › neuropathy, congenital hypomelinating › neuropathy, congenital hypomyelinating, 2

Related subtypes (2): Charcot-Marie-Tooth disease type 4E, neuropathy, congenital hypomyelinating, 3

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

46 retrieved; paginated sample, class counts are floors:

21 uncertain significance, 11 conflicting classifications of pathogenicity, 7 pathogenic, 4 benign/likely benign, 2 benign, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
14175	NM_000530.8(MPZ):c.292C>T (p.Arg98Cys)	MPZ	Pathogenic	criteria provided, multiple submitters, no conflicts
14178	NM_000530.8(MPZ):c.643C>T (p.Gln215Ter)	MPZ	Pathogenic	no assertion criteria provided
14191	NM_000530.8(MPZ):c.434A>C (p.Tyr145Ser)	MPZ	Pathogenic	criteria provided, multiple submitters, no conflicts
14196	NM_000530.8(MPZ):c.371C>A (p.Thr124Lys)	MPZ	Pathogenic	no assertion criteria provided
3340162	NM_000530.8(MPZ):c.30del (p.Ser11fs)	MPZ	Pathogenic	criteria provided, single submitter
488548	NM_000530.8(MPZ):c.558del (p.Arg186fs)	MPZ	Pathogenic	criteria provided, multiple submitters, no conflicts
590911	NM_000539.3(RHO):c.549dup (p.Gln184fs)	RHO	Pathogenic	no assertion criteria provided
578468	NM_000530.8(MPZ):c.397C>G (p.Pro133Ala)	MPZ	Likely pathogenic	criteria provided, multiple submitters, no conflicts
237875	NM_000530.8(MPZ):c.200G>A (p.Arg67His)	MPZ	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
246572	NM_000530.8(MPZ):c.637G>C (p.Gly213Arg)	MPZ	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
293299	NM_000530.8(MPZ):c.*1048A>T	MPZ	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
293305	NM_000530.8(MPZ):c.*743C>T	MPZ	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
293310	NM_000530.8(MPZ):c.*195G>T	MPZ	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
293311	NM_000530.8(MPZ):c.*52G>A	MPZ	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
293314	NM_000530.8(MPZ):c.77C>T (p.Pro26Leu)	MPZ	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
293315	NM_000530.8(MPZ):c.-49C>A	MPZ	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
637323	NM_000530.8(MPZ):c.101C>T (p.Thr34Ile)	MPZ	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
637357	NM_000530.8(MPZ):c.550_552delinsG (p.Leu184fs)	MPZ	Conflicting classifications of pathogenicity	no assertion criteria provided
876416	NM_000530.8(MPZ):c.*360C>G	MPZ	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3065517	NM_004067.4(CHN2):c.1381A>G (p.Ile461Val)	CHN2	Uncertain significance	criteria provided, single submitter
2671834	NM_000530.8(MPZ):c.265_270del (p.Ile89_Asp90del)	MPZ	Uncertain significance	criteria provided, single submitter
2683933	NM_000530.8(MPZ):c.215G>A (p.Gly72Glu)	MPZ	Uncertain significance	criteria provided, multiple submitters, no conflicts
2770145	NM_000530.8(MPZ):c.369C>T (p.Gly123=)	MPZ	Uncertain significance	criteria provided, multiple submitters, no conflicts
293298	NM_000530.8(MPZ):c.*1074A>C	MPZ	Uncertain significance	criteria provided, single submitter
293300	NM_000530.8(MPZ):c.*1020G>A	MPZ	Uncertain significance	criteria provided, single submitter
293301	NM_000530.8(MPZ):c.*954C>A	MPZ	Uncertain significance	criteria provided, single submitter
293306	NM_000530.8(MPZ):c.*681A>T	MPZ	Uncertain significance	criteria provided, single submitter
293309	NM_000530.8(MPZ):c.*251C>G	MPZ	Uncertain significance	criteria provided, single submitter
531684	NM_000530.8(MPZ):c.428C>T (p.Thr143Met)	MPZ	Uncertain significance	criteria provided, multiple submitters, no conflicts
638456	NM_000530.8(MPZ):c.637G>A (p.Gly213Arg)	MPZ	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 11 · Orphanet: 11 · 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
MPZ	Definitive	Autosomal dominant	neuropathy, congenital hypomyelinating, 2	11

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MPZ	Orphanet:100046	Autosomal dominant intermediate Charcot-Marie-Tooth disease type D
MPZ	Orphanet:101082	Charcot-Marie-Tooth disease type 1B
MPZ	Orphanet:3115	Roussy-Lévy syndrome
MPZ	Orphanet:324585	Autosomal dominant intermediate Charcot-Marie-Tooth disease with neuropathic pain
MPZ	Orphanet:538574	Palmoplantar keratoderma-hereditary motor and sensory neuropathy syndrome
MPZ	Orphanet:64748	Dejerine-Sottas syndrome
MPZ	Orphanet:99942	Autosomal dominant Charcot-Marie-Tooth disease type 2I
MPZ	Orphanet:99943	Autosomal dominant Charcot-Marie-Tooth disease type 2J
RHO	Orphanet:215	Congenital stationary night blindness
RHO	Orphanet:52427	Retinitis punctata albescens
RHO	Orphanet:791	Retinitis pigmentosa

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
MPZ	HGNC:7225	ENSG00000158887	P25189	Myelin protein P0	gencc,clinvar
RHO	HGNC:10012	ENSG00000163914	P08100	Rhodopsin	clinvar
CHN2	HGNC:1944	ENSG00000106069	P52757	Beta-chimaerin	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MPZ	Myelin protein P0	Is an adhesion molecule necessary for normal myelination in the peripheral nervous system.
RHO	Rhodopsin	Photoreceptor required for image-forming vision at low light intensity.
CHN2	Beta-chimaerin	GTPase-activating protein for p21-rac.

Protein-family classification

Druggable: 2 · Difficult: 1 · Unknown: 0 · Druggable fraction: 0.67

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	9.7×	0.164
GPCR	1	8.0×	0.164
Scaffold/PPI	1	5.8×	0.164

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MPZ	Antibody/Immunoglobulin	yes		Myelin_P0-rel, Ig_sub, Ig-like_dom
RHO	GPCR	yes		GPCR_Rhodpsn, Rhodopsin, Opsin
CHN2	Scaffold/PPI	no		RhoGAP_dom, SH2, PKC_DAG/PE

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
olfactory bulb	1
sural nerve	1
tibial nerve	1
diaphragm	1
neuron projection bundle connecting eye with brain	1
optic choroid	1
cerebellar cortex	1
cerebellar hemisphere	1
cerebellum	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MPZ	178	ubiquitous	marker	tibial nerve, sural nerve, olfactory bulb
RHO	38	tissue_specific	marker	optic choroid, neuron projection bundle connecting eye with brain, diaphragm
CHN2	139	broad	marker	cerebellum, cerebellar cortex, cerebellar hemisphere

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
RHO	3,578
CHN2	1,047
MPZ	25

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
RHO	P08100	4
MPZ	P25189	2
CHN2	P52757	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 10. Enrichment computed across 3 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Opsins	1	423.0×	0.014	RHO
Activation of the phototransduction cascade	1	317.2×	0.014	RHO
The canonical retinoid cycle in rods (twilight vision)	1	173.0×	0.014	RHO
VxPx cargo-targeting to cilium	1	173.0×	0.014	RHO
EGR2 and SOX10-mediated initiation of Schwann cell myelination	1	122.8×	0.016	MPZ
Inactivation, recovery and regulation of the phototransduction cascade	1	105.7×	0.016	RHO
RAC1 GTPase cycle	1	20.4×	0.069	CHN2
Nervous system development	1	14.3×	0.083	MPZ
G alpha (i) signalling events	1	13.0×	0.083	RHO
Developmental Biology	1	4.8×	0.194	MPZ

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
thermotaxis	1	2808.7×	0.003	RHO
cell aggregation	1	2808.7×	0.003	MPZ
rod bipolar cell differentiation	1	2808.7×	0.003	RHO
detection of temperature stimulus involved in thermoception	1	1872.4×	0.003	RHO
G protein-coupled opsin signaling pathway	1	1123.5×	0.004	RHO
absorption of visible light	1	936.2×	0.004	RHO
response to light intensity	1	702.2×	0.004	RHO
podosome assembly	1	702.2×	0.004	RHO
phototransduction, visible light	1	432.1×	0.006	RHO
obsolete cell-cell adhesion via plasma-membrane adhesion molecules	1	374.5×	0.006	MPZ
cellular response to light stimulus	1	351.1×	0.006	RHO
phototransduction	1	165.2×	0.011	RHO
acrosome assembly	1	151.8×	0.011	CHN2
photoreceptor cell maintenance	1	119.5×	0.013	RHO
myelination	1	83.8×	0.017	MPZ
regulation of small GTPase mediated signal transduction	1	48.0×	0.028	CHN2
microtubule cytoskeleton organization	1	40.4×	0.032	RHO
gene expression	1	26.6×	0.042	RHO
visual perception	1	26.5×	0.042	RHO
chemical synaptic transmission	1	25.8×	0.042	MPZ
G protein-coupled receptor signaling pathway	1	12.1×	0.084	RHO
signal transduction	1	5.3×	0.176	CHN2

Therapeutics

Drug target analysis

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

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
MPZ	0	0
RHO	0	0
CHN2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
RHO	1	Binding:1
CHN2	1	Binding:1

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

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	2	MPZ, RHO
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	CHN2

Undrugged target profiles

3 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
MPZ	0	—
RHO	1	—
CHN2	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.