Metaphyseal anadysplasia 2

Summary

Metaphyseal anadysplasia 2 (MONDO:0013113) is a disease caused by MMP9 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: MMP9 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 60

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	metaphyseal anadysplasia 2
Mondo ID	MONDO:0013113
MeSH	C567771
OMIM	613073
UMLS	C2751322
MedGen	414350
GARD	0015610
Is cancer (heuristic)	no

Also known as: MANDP2 · metaphyseal anadysplasia 2 · metaphyseal anadysplasia caused by mutation in MMP9 · metaphyseal anadysplasia type 2 · MMP9 metaphyseal anadysplasia

Data availability: 60 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › skeletal dysplasia › metaphyseal anadysplasia › metaphyseal anadysplasia 2

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

60 retrieved; paginated sample, class counts are floors:

27 uncertain significance, 14 benign, 10 conflicting classifications of pathogenicity, 5 benign/likely benign, 2 likely pathogenic, 1 pathogenic/likely pathogenic, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
1030865	NM_004994.3(MMP9):c.987C>A (p.Cys329Ter)	MMP9	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2498120	NM_004994.3(MMP9):c.929del (p.Gly310fs)	MMP9	Likely pathogenic	criteria provided, single submitter
2498140	NM_004994.3(MMP9):c.151C>T (p.Arg51Cys)	MMP9	Likely pathogenic	criteria provided, single submitter
338558	NM_004994.3(MMP9):c.1891C>A (p.Arg631Ser)	LOC130065978	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
198179	NM_004994.3(MMP9):c.886G>A (p.Gly296Ser)	MMP9	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
284343	NM_004994.3(MMP9):c.773C>T (p.Thr258Ile)	MMP9	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3018466	NM_004994.3(MMP9):c.630G>A (p.Trp210Ter)	MMP9	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
338552	NM_004994.3(MMP9):c.906C>A (p.Cys302Ter)	MMP9	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
719765	NM_004994.3(MMP9):c.81C>T (p.Thr27=)	MMP9	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
895813	NM_004994.3(MMP9):c.521-15G>C	MMP9	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
896095	NM_004994.3(MMP9):c.782A>G (p.Asn261Ser)	MMP9	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
897685	NM_004994.3(MMP9):c.1404C>T (p.Cys468=)	MMP9	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
898779	NM_004994.3(MMP9):c.139-5C>T	MMP9	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
338564	NM_004994.3(MMP9):c.*189C>T	LOC100128028	Uncertain significance	criteria provided, single submitter
898845	NM_004994.3(MMP9):c.1906G>C (p.Asp636His)	LOC130065978	Uncertain significance	criteria provided, single submitter
898846	NM_004994.3(MMP9):c.1925T>C (p.Val642Ala)	LOC130065978	Uncertain significance	criteria provided, multiple submitters, no conflicts
1035934	NM_004994.3(MMP9):c.2089G>A (p.Val697Met)	MMP9	Uncertain significance	criteria provided, multiple submitters, no conflicts
1301672	NM_004994.3(MMP9):c.80C>T (p.Thr27Ile)	MMP9	Uncertain significance	criteria provided, multiple submitters, no conflicts
1342615	NM_004994.3(MMP9):c.1222G>A (p.Gly408Ser)	MMP9	Uncertain significance	criteria provided, single submitter
1525460	NM_004994.3(MMP9):c.458C>A (p.Pro153Gln)	MMP9	Uncertain significance	criteria provided, multiple submitters, no conflicts
17107	NM_004994.3(MMP9):c.2T>A (p.Met1Lys)	MMP9	Uncertain significance	criteria provided, multiple submitters, no conflicts
2689435	NM_004994.3(MMP9):c.831C>A (p.Tyr277Ter)	MMP9	Uncertain significance	criteria provided, single submitter
283364	NM_004994.3(MMP9):c.1414C>T (p.Pro472Ser)	MMP9	Uncertain significance	criteria provided, multiple submitters, no conflicts
338545	NM_004994.3(MMP9):c.58G>A (p.Ala20Thr)	MMP9	Uncertain significance	criteria provided, single submitter
338547	NM_004994.3(MMP9):c.464C>T (p.Thr155Ile)	MMP9	Uncertain significance	criteria provided, multiple submitters, no conflicts
338551	NM_004994.3(MMP9):c.878T>A (p.Ile293Asn)	MMP9	Uncertain significance	criteria provided, multiple submitters, no conflicts
338555	NM_004994.3(MMP9):c.1174+14C>T	MMP9	Uncertain significance	criteria provided, single submitter
338557	NM_004994.3(MMP9):c.1671C>A (p.Ala557=)	MMP9	Uncertain significance	criteria provided, single submitter
338560	NM_004994.3(MMP9):c.2042G>A (p.Arg681His)	MMP9	Uncertain significance	criteria provided, multiple submitters, no conflicts
631876	NM_004994.3(MMP9):c.1764G>A (p.Trp588Ter)	MMP9	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · Orphanet: 1 · 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
MMP9	Strong	Autosomal recessive	metaphyseal anadysplasia 2	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MMP9	Orphanet:1040	Metaphyseal anadysplasia

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
MMP9	HGNC:7176	ENSG00000100985	P14780	Matrix metalloproteinase-9	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MMP9	Matrix metalloproteinase-9	Matrix metalloproteinase that plays an essential role in local proteolysis of the extracellular matrix and in leukocyte migration.

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
Protease	1	36.6×	0.027

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MMP9	Protease	yes	3.4.24.35	FN_type2_dom, Hemopexin-like_dom, Pept_M10_metallopeptidase

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
periodontal ligament	1
tibia	1
trabecular bone tissue	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MMP9	204	broad	marker	periodontal ligament, trabecular bone tissue, tibia

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MMP9	6,708

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MMP9	P14780	29

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 24. Enrichment computed across 1 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Collagen formation	1	456.8×	0.018	MMP9
Activation of Matrix Metalloproteinases	1	308.6×	0.018	MMP9
Signaling by SCF-KIT	1	248.3×	0.018	MMP9
EPH-ephrin mediated repulsion of cells	1	219.6×	0.018	MMP9
Assembly of collagen fibrils and other multimeric structures	1	200.3×	0.018	MMP9
Collagen degradation	1	175.7×	0.018	MMP9
Extra-nuclear estrogen signaling	1	170.4×	0.018	MMP9
EPH-Ephrin signaling	1	165.5×	0.018	MMP9
ESR-mediated signaling	1	128.3×	0.020	MMP9
Degradation of the extracellular matrix	1	117.7×	0.020	MMP9
Interleukin-4 and Interleukin-13 signaling	1	102.9×	0.020	MMP9
Signaling by Nuclear Receptors	1	102.0×	0.020	MMP9
Signaling by Interleukins	1	64.2×	0.027	MMP9
Extracellular matrix organization	1	63.1×	0.027	MMP9
Signaling by Receptor Tyrosine Kinases	1	51.7×	0.031	MMP9
Dengue Virus-Host Interactions	1	45.7×	0.031	MMP9
Axon guidance	1	45.1×	0.031	MMP9
Nervous system development	1	42.9×	0.031	MMP9
Cytokine Signaling in Immune system	1	40.8×	0.031	MMP9
Innate Immune System	1	25.5×	0.047	MMP9
Neutrophil degranulation	1	23.1×	0.050	MMP9
Developmental Biology	1	14.5×	0.075	MMP9
Immune System	1	13.0×	0.080	MMP9
Signal Transduction	1	10.2×	0.098	MMP9

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
negative regulation of cation transmembrane transport	1	16852.0×	8e-04	MMP9
negative regulation of epithelial cell differentiation involved in kidney development	1	16852.0×	8e-04	MMP9
cellular response to UV-A	1	1404.3×	0.004	MMP9
regulation of neuroinflammatory response	1	1404.3×	0.004	MMP9
positive regulation of keratinocyte migration	1	1296.3×	0.004	MMP9
positive regulation of DNA binding	1	1203.7×	0.004	MMP9
response to amyloid-beta	1	991.3×	0.004	MMP9
positive regulation of release of cytochrome c from mitochondria	1	766.0×	0.004	MMP9
negative regulation of intrinsic apoptotic signaling pathway	1	766.0×	0.004	MMP9
endodermal cell differentiation	1	495.6×	0.004	MMP9
positive regulation of epidermal growth factor receptor signaling pathway	1	495.6×	0.004	MMP9
macrophage differentiation	1	468.1×	0.004	MMP9
positive regulation of vascular associated smooth muscle cell proliferation	1	432.1×	0.004	MMP9
collagen catabolic process	1	391.9×	0.004	MMP9
extracellular matrix disassembly	1	366.4×	0.004	MMP9
embryo implantation	1	351.1×	0.004	MMP9
ephrin receptor signaling pathway	1	343.9×	0.004	MMP9
positive regulation of protein phosphorylation	1	276.3×	0.005	MMP9
skeletal system development	1	125.8×	0.011	MMP9
extracellular matrix organization	1	122.1×	0.011	MMP9
cellular response to lipopolysaccharide	1	98.0×	0.013	MMP9
cell migration	1	61.5×	0.019	MMP9
positive regulation of apoptotic process	1	56.7×	0.020	MMP9
negative regulation of apoptotic process	1	34.8×	0.030	MMP9
proteolysis	1	34.2×	0.030	MMP9
apoptotic process	1	28.7×	0.035	MMP9

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
MMP9	CHLOROXINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MMP9	26	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CHLOROXINE	4	MMP9
BUDESONIDE	4	MMP9
PRAZOSIN	4	MMP9
ZOLEDRONIC ACID	4	MMP9
SECOBARBITAL	4	MMP9
DACARBAZINE	4	MMP9
CHLORHEXIDINE	4	MMP9
ECONAZOLE	4	MMP9
BUSULFAN	4	MMP9
CURCUMIN	3	MMP9
CAFFEIC ACID	3	MMP9
MARIMASTAT	3	MMP9
QUERCETIN	3	MMP9
PRINOMASTAT	3	MMP9
CIPEMASTAT	2	MMP9
LUTEOLIN	2	MMP9
ILOMASTAT	2	MMP9
APRATASTAT	2	MMP9
TOSEDOSTAT	2	MMP9
SOLIMASTAT	2	MMP9
TANOMASTAT	2	MMP9
BATIMASTAT	2	MMP9
CTS-1027	2	MMP9
REBIMASTAT	2	MMP9
AMINOQUINURIDE	2	MMP9
S-3304	1	MMP9

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
MMP9	713	Binding:685, ADMET:20, Functional:8

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
MMP9	3.4.24.35	gelatinase B

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
MMP9	713

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

26 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)
CHLOROXINE	4	MMP9
BUDESONIDE	4	MMP9
PRAZOSIN	4	MMP9
ZOLEDRONIC ACID	4	MMP9
SECOBARBITAL	4	MMP9
DACARBAZINE	4	MMP9
CHLORHEXIDINE	4	MMP9
ECONAZOLE	4	MMP9
BUSULFAN	4	MMP9
CURCUMIN	3	MMP9
CAFFEIC ACID	3	MMP9
MARIMASTAT	3	MMP9
QUERCETIN	3	MMP9
PRINOMASTAT	3	MMP9
CIPEMASTAT	2	MMP9
LUTEOLIN	2	MMP9
ILOMASTAT	2	MMP9
APRATASTAT	2	MMP9
TOSEDOSTAT	2	MMP9
SOLIMASTAT	2	MMP9
TANOMASTAT	2	MMP9
BATIMASTAT	2	MMP9
CTS-1027	2	MMP9
REBIMASTAT	2	MMP9
AMINOQUINURIDE	2	MMP9
S-3304	1	MMP9

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	MMP9
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.