MONDO:0014866

Summary

MONDO:0014866 (MONDO:0014866) is a disease caused by variants in DNAJB2 and MME, with 3 cohort genes.

At a glance

• Causal genes: DNAJB2 (GenCC Definitive), MME (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 81

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Mondo ID	MONDO:0014866
UMLS	C4015635
MedGen	864072
GARD	0018653
Is cancer (heuristic)	no

Data availability: 81 ClinVar variants · 7 GenCC gene-disease records.

Disease family

No broader Mondo term or subtypes recorded for this disease.

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

81 retrieved; paginated sample, class counts are floors:

29 uncertain significance, 19 pathogenic, 14 likely pathogenic, 10 pathogenic/likely pathogenic, 5 conflicting classifications of pathogenicity, 2 benign/likely benign, 1 uncertain significance/vus-high, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
209147	NM_006736.6(DNAJB2):c.343G>T (p.Glu115Ter)	DNAJB2	Pathogenic	criteria provided, single submitter
1184498	NM_007289.4(MME):c.2050C>T (p.Gln684Ter)	MME	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1326924	NM_007289.4(MME):c.716_717del (p.Lys239fs)	MME	Pathogenic	criteria provided, single submitter
1335545	NM_007289.4(MME):c.1313_1314del (p.His438fs)	MME	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1709760	NM_007289.4(MME):c.536-1G>A	MME	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1723216	NM_007289.4(MME):c.838G>T (p.Glu280Ter)	MME	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
242837	NM_007289.4(MME):c.654+1G>A	MME	Pathogenic	no assertion criteria provided
242838	NM_007289.4(MME):c.661C>T (p.Gln221Ter)	MME	Pathogenic	no assertion criteria provided
242840	NM_007289.4(MME):c.439+2T>A	MME	Pathogenic	no assertion criteria provided
242841	NM_007289.4(MME):c.655-2A>G	MME	Pathogenic	criteria provided, single submitter
2581575	NM_007289.4(MME):c.1119_1127del (p.Trp373_Ile376delinsTer)	MME	Pathogenic	criteria provided, single submitter
265743	NM_007289.4(MME):c.71G>A (p.Trp24Ter)	MME	Pathogenic	criteria provided, single submitter
2759674	NM_007289.4(MME):c.1066A>T (p.Lys356Ter)	MME	Pathogenic	criteria provided, multiple submitters, no conflicts
3000253	NM_007289.4(MME):c.1645G>T (p.Gly549Ter)	MME	Pathogenic	criteria provided, multiple submitters, no conflicts
3233785	NC_000003.11:g.(?154798107)(154802884_154832782)del	MME	Pathogenic	criteria provided, single submitter
3769636	NM_007289.4(MME):c.1188+428A>G	MME	Pathogenic	criteria provided, single submitter
4073435	NM_007289.4(MME):c.655-1G>C	MME	Pathogenic	criteria provided, single submitter
426945	NM_007289.4(MME):c.467del (p.Pro156fs)	MME	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4277268	NM_007289.4(MME):c.1825dup (p.Gln609fs)	MME	Pathogenic	criteria provided, single submitter
4293211	NM_007289.4(MME):c.400C>T (p.Gln134Ter)	MME	Pathogenic	criteria provided, single submitter
431858	NM_007289.4(MME):c.440-2A>C	MME	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
432777	NM_007289.4(MME):c.1564C>T (p.Gln522Ter)	MME	Pathogenic	criteria provided, multiple submitters, no conflicts
453058	NM_007289.4(MME):c.1781-2A>G	MME	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4689564	NM_007289.4(MME):c.494_495del (p.Tyr165fs)	MME	Pathogenic	criteria provided, single submitter
504903	NM_007289.4(MME):c.1342C>T (p.Arg448Ter)	MME	Pathogenic	criteria provided, multiple submitters, no conflicts
818075	NM_007289.4(MME):c.531del (p.Lys177fs)	MME	Pathogenic	criteria provided, multiple submitters, no conflicts
851617	NM_007289.4(MME):c.202C>T (p.Arg68Ter)	MME	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
930821	NM_007289.4(MME):c.594dup (p.Val199fs)	MME	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
935850	NM_007289.4(MME):c.1400dup (p.Arg468fs)	MME	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
242839	NM_007289.4(MME):c.1861T>C (p.Cys621Arg)	MME	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 17 · Orphanet: 7 · 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
DNAJB2	Definitive	Autosomal recessive	Charcot-Marie-Tooth disease axonal type 2T	5
MME	Definitive	Semidominant	Charcot-Marie-Tooth disease axonal type 2T	12

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
DNAJB2	Orphanet:314485	Young adult-onset distal hereditary motor neuropathy
DNAJB2	Orphanet:443950	DNAJB2-related Charcot-Marie-Tooth disease type 2
MME	Orphanet:495274	Charcot-Marie-Tooth disease type 2T
MME	Orphanet:497757	MME-related autosomal dominant Charcot Marie Tooth disease type 2
MME	Orphanet:497764	Spinocerebellar ataxia type 43
MME	Orphanet:69063	Congenital membranous nephropathy due to fetomaternal anti-neutral endopeptidase alloimmunization
SEC61A1	Orphanet:697417	Common variable immunodeficiency phenotype due to SEC61A1 deficiency

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
DNAJB2	HGNC:5228	ENSG00000135924	P25686	DnaJ homolog subfamily B member 2	gencc,clinvar
MME	HGNC:7154	ENSG00000196549	P08473	Neprilysin	gencc,clinvar
SEC61A1	HGNC:18276	ENSG00000058262	P61619	Protein transport protein Sec61 subunit alpha isoform 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
DNAJB2	DnaJ homolog subfamily B member 2	Functions as a co-chaperone, regulating the substrate binding and activating the ATPase activity of chaperones of the HSP70/heat shock protein 70 family.
MME	Neprilysin	Thermolysin-like specificity, but is almost confined on acting on polypeptides of up to 30 amino acids.
SEC61A1	Protein transport protein Sec61 subunit alpha isoform 1	Component of SEC61 channel-forming translocon complex that mediates transport of signal peptide-containing precursor polypeptides across the endoplasmic reticulum (ER).

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 2 · 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
Protease	1	12.2×	0.159
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
DNAJB2	Other/Unknown	no		DnaJ_domain, UIM_dom, DnaJ_domain_CS
MME	Protease	yes	3.4.24.11	Peptidase_M13, Peptidase_M13_N, Peptidase_M13_C
SEC61A1	Other/Unknown	no		SecY/SEC61-alpha, Translocon_Sec61/SecY_plug_dom, SecY_dom_sf

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
C1 segment of cervical spinal cord	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1
jejunal mucosa	1
metanephric glomerulus	1
renal glomerulus	1
body of pancreas	1
islet of Langerhans	1
stromal cell of endometrium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
DNAJB2	281	ubiquitous	marker	C1 segment of cervical spinal cord, right hemisphere of cerebellum, cerebellar hemisphere
MME	212	ubiquitous	marker	jejunal mucosa, renal glomerulus, metanephric glomerulus
SEC61A1	284	ubiquitous	marker	body of pancreas, stromal cell of endometrium, islet of Langerhans

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DNAJB2	2,884
MME	2,648
SEC61A1	490

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MME	P08473	16
SEC61A1	P61619	15
DNAJB2	P25686	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 16. 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
Physiological factors	1	335.9×	0.017	MME
Metabolism of Angiotensinogen to Angiotensins	1	317.2×	0.017	MME
Developmental Lineage of Mammary Gland Myoepithelial Cells	1	271.9×	0.017	MME
Antigen processing-Cross presentation	1	158.6×	0.017	SEC61A1
Peptide hormone metabolism	1	135.9×	0.017	MME
Immune System	2	13.0×	0.017	MME, SEC61A1
Metabolism of proteins	2	12.4×	0.017	MME, SEC61A1
ER-Phagosome pathway	1	64.9×	0.031	SEC61A1
Cardiac conduction	1	54.4×	0.032	MME
SRP-dependent cotranslational protein targeting to membrane	1	50.1×	0.032	SEC61A1
Muscle contraction	1	38.6×	0.037	MME
Class I MHC mediated antigen processing & presentation	1	35.0×	0.038	SEC61A1
Translation	1	31.0×	0.039	SEC61A1
Adaptive Immune System	1	14.9×	0.075	SEC61A1
Innate Immune System	1	12.8×	0.082	MME
Neutrophil degranulation	1	11.5×	0.085	MME

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
pronephric nephron development	1	5617.3×	0.003	SEC61A1
neuropeptide processing	1	5617.3×	0.003	MME
regulation of protein folding	1	5617.3×	0.003	DNAJB2
creatinine metabolic process	1	2808.7×	0.004	MME
negative regulation of protein deubiquitination	1	2808.7×	0.004	DNAJB2
substance P catabolic process	1	1872.4×	0.005	MME
amygdala development	1	936.2×	0.006	MME
hormone catabolic process	1	936.2×	0.006	MME
bradykinin catabolic process	1	802.5×	0.006	MME
SRP-dependent cotranslational protein targeting to membrane	1	702.2×	0.006	SEC61A1
SRP-dependent cotranslational protein targeting to membrane, translocation	1	702.2×	0.006	SEC61A1
post-translational protein targeting to membrane, translocation	1	702.2×	0.006	SEC61A1
amyloid-beta clearance by cellular catabolic process	1	702.2×	0.006	MME
cotranslational protein targeting to membrane	1	561.7×	0.006	SEC61A1
negative regulation of inclusion body assembly	1	561.7×	0.006	DNAJB2
protein insertion into ER membrane	1	510.7×	0.006	SEC61A1
amyloid-beta metabolic process	1	510.7×	0.006	MME
post-translational protein targeting to endoplasmic reticulum membrane	1	468.1×	0.006	SEC61A1
positive regulation of ATP-dependent activity	1	468.1×	0.006	DNAJB2
cellular response to UV-A	1	468.1×	0.006	MME
cellular response to UV-B	1	468.1×	0.006	MME
angiotensin maturation	1	432.1×	0.006	MME
peptide metabolic process	1	401.2×	0.006	MME
protein targeting to ER	1	374.5×	0.006	SEC61A1
replicative senescence	1	330.4×	0.007	MME
amyloid-beta clearance	1	312.1×	0.007	MME
regulation of protein ubiquitination	1	295.6×	0.007	DNAJB2
positive regulation of long-term synaptic potentiation	1	224.7×	0.009	MME
negative regulation of protein binding	1	208.1×	0.009	DNAJB2
protein refolding	1	208.1×	0.009	DNAJB2

Therapeutics

Drug target analysis

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

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
MME	4	2
DNAJB2	0	0
SEC61A1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CYCLOVALONE	2	MME
OMAPATRILAT	2	MME
SAMPATRILAT	2	MME
CANDOXATRILAT	2	MME

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
MME	125	Binding:110, ADMET:15
SEC61A1	7	Binding:7

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
MME	3.4.24.11	neprilysin

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
MME	125

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

4 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)
CYCLOVALONE	2	MME
OMAPATRILAT	2	MME
SAMPATRILAT	2	MME
CANDOXATRILAT	2	MME

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	MME
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	DNAJB2, SEC61A1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
DNAJB2	0	—
SEC61A1	7	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.