MATN2

Chr 8

matrilin 2

NCBI Gene: 4147 ENSG00000132561 UniProt: O00339 OMIM: 602108

This protein is involved in extracellular matrix assembly and contains five von Willebrand factor A domains that contribute to filamentous network formation in various tissues. Mutations cause autosomal dominant bicuspid aortic valve with calcific aortic stenosis, primarily affecting the cardiovascular system. The gene shows extremely low constraint against loss-of-function variants, suggesting tolerance to such mutations.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a member of the von Willebrand factor A domain containing protein family. This family of proteins is thought to be involved in the formation of filamentous networks in the extracellular matrices of various tissues. This protein contains five von Willebrand factor A domains. The specific function of this gene has not yet been determined. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.88

Clinical Summary— MATN2

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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

128 VUS of 156 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.88LOEUF

pLI 0.000

Z-score 2.22

OE 0.64 (0.47–0.88)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.67Z-score

OE missense 0.80 (0.74–0.86)

437 obs / 546.8 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.64 (0.47–0.88)

0≤0.351.4

Missense OE?0.80 (0.74–0.86)

0≤0.61.4

Synonymous OE?0.88

0≤1.21.6

LoF obs/exp: 28 / 43.9Missense obs/exp: 437 / 546.8Syn Z: 1.34

This gene — mechanism propensity

0.77top 25%

GOF

0.7127th %ile

LOF

0.2484th %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

156 submitted variants in ClinVar

ClinVar

Classification Summary

VUS128

Likely Benign4

Benign2

128

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Synonymous	Total
Pathogenic	0	0	0
Likely Pathogenic	0	0	0
VUS	128	0	128
Likely Benign	3	1	4
Benign	1	1	2
Total	132	2	134

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

View in ClinVar →

34 pathogenic / likely-pathogenic (of 36) ClinVar copy-number / structural variants overlap MATN2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →