MMP2

Chr 16AR

matrix metallopeptidase 2

Also known as: CLG4, CLG4A, MMP-2, MMP-II, MONA, TBE-1

NCBI Gene: 4313 ENSG00000087245 UniProt: P08253 OMIM: 120360

This gene encodes gelatinase A (matrix metalloproteinase-2), a zinc-dependent enzyme that degrades extracellular matrix proteins including type IV and V collagen and elastin, and also cleaves nonmatrix proteins involved in vascular regulation and tissue remodeling. Biallelic mutations cause multicentric osteolysis, nodulosis, and arthropathy (also known as Winchester syndrome or NAO syndrome), an autosomal recessive disorder affecting bone, joints, and connective tissues. The gene is highly constrained against loss-of-function variants (pLI 0.84, LOEUF 0.37), indicating that heterozygous loss-of-function is likely not tolerated.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene is a member of the matrix metalloproteinase (MMP) gene family, that are zinc-dependent enzymes capable of cleaving components of the extracellular matrix and molecules involved in signal transduction. The protein encoded by this gene is a gelatinase A, type IV collagenase, that contains three fibronectin type II repeats in its catalytic site that allow binding of denatured type IV and V collagen and elastin. Unlike most MMP family members, activation of this protein can occur on the cell membrane. This enzyme can be activated extracellularly by proteases, or, intracellulary by its S-glutathiolation with no requirement for proteolytical removal of the pro-domain. This protein is thought to be involved in multiple pathways including roles in the nervous system, endometrial menstrual breakdown, regulation of vascularization, and metastasis. Mutations in this gene have been associated with Winchester syndrome and Nodulosis-Arthropathy-Osteolysis (NAO) syndrome. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Oct 2014]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Multicentric osteolysis, nodulosis, and arthropathyMIM #259600

Clinical highlights

Gene–disease validity

Not independently assessedOMIM lists Multicentric osteolysis, nodulosis, and arthropathy; no ClinGen or GenCC tier

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype) and the gene is intolerant of it in the population — truncating, frameshift and canonical splice variants carry more prior weight here than missense.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

1078

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.36

LOEUF

LOF

Mechanism· G2P

📖

GeneReview available — MMP2

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.36LOEUF

pLI 0.839

Z-score 4.30

OE 0.19 (0.10–0.36)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

0.71Z-score

OE missense 0.90 (0.82–0.98)

351 obs / 390.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.19 (0.10–0.36)

0≤0.351.4

Missense OE?0.90 (0.82–0.98)

0≤0.61.4

Synonymous OE?1.13

0≤1.21.6

LoF obs/exp: 6 / 32.4Missense obs/exp: 351 / 390.5Syn Z: -1.27

Background carrier burden — how many people carry a rare variant somewhere in MMP2?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 66

849 rare PASS variants

Rare truncating (LoF)

1 in 2,700

91 rare PASS variants

Rare synonymous (reference)

1 in 110

390 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for MMP2. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 79	1 in 3,100
South Asian	~43k	1 in 75	1 in 2,500
Remaining (unassigned)	~30k	1 in 60	1 in 2,300
European (Finnish)	~27k	1 in 440	≈ 1 in 6,700
Admixed American	~22k	1 in 69	1 in 3,200
African / African American	~21k	1 in 77	1 in 1,900
East Asian	~20k	1 in 130	1 in 1,100
Ashkenazi Jewish	~13k	1 in 180	1 in 1,400
Middle Eastern	~2,884	1 in 61	≈ 1 in 1,400

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 13 coding exons well covered in gnomAD exomes and genomes.? see exons ↓