MMP25

Chr 16

matrix metallopeptidase 25

Also known as: MMP-25, MMP20, MMP20A, MMPL1, MT-MMP 6, MT-MMP6, MT6-MMP, MT6MMP

NCBI Gene: 64386 ENSG00000008516 UniProt: Q9H239 OMIM: 608482

MMP25 encodes a membrane-type matrix metalloproteinase that degrades extracellular matrix components and inactivates alpha-1 proteinase inhibitor during inflammatory responses, facilitating neutrophil migration to inflammatory sites. The gene shows very low constraint against loss-of-function variants (pLI near zero), and no established Mendelian disease associations have been reported to date. Current evidence suggests this gene may not be critical for normal human development or associated with pediatric neurological disorders.

OMIM ResearchSummary from RefSeq, UniProt

Proteins of the matrix metalloproteinase (MMP) family are involved in the breakdown of extracellular matrix in normal physiological processes, such as embryonic development, reproduction, and tissue remodeling, as well as in disease processes, such as arthritis and metastasis. Most MMPs are secreted as inactive proproteins which are activated when cleaved by extracellular proteinases. However, the protein encoded by this gene is a member of the membrane-type MMP (MT-MMP) subfamily, attached to the plasma membrane via a glycosylphosphatidyl inositol anchor. In response to bacterial infection or inflammation, the encoded protein is thought to inactivate alpha-1 proteinase inhibitor, a major tissue protectant against proteolytic enzymes released by activated neutrophils, facilitating the transendothelial migration of neutrophils to inflammatory sites. The encoded protein may also play a role in tumor invasion and metastasis through activation of MMP2. The gene has previously been referred to as MMP20 but has been renamed MMP25. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 1.25

Clinical Summary— MMP25

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

134 VUS of 145 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.25LOEUF

pLI 0.000

Z-score 0.60

OE 0.87 (0.62–1.25)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.88Z-score

OE missense 1.13 (1.04–1.23)

387 obs / 341.3 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.87 (0.62–1.25)

0≤0.351.4

Missense OE?1.13 (1.04–1.23)

0≤0.61.4

Synonymous OE?1.20

0≤1.21.6

LoF obs/exp: 22 / 25.2Missense obs/exp: 387 / 341.3Syn Z: -1.97

This gene — mechanism propensity

0.6743th %ile

GOF

0.6735th %ile

LOF

0.3552th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median

GOFprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

145 submitted variants in ClinVar

ClinVar

Classification Summary

VUS134

Likely Benign2

134

VUS

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Total
Pathogenic	0	0	0
Likely Pathogenic	0	0	0
VUS	1	133	134
Likely Benign	0	2	2
Benign	0	0	0
Total	1	135	136

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

35 pathogenic / likely-pathogenic (of 46) ClinVar copy-number / structural variants overlap MMP25 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →