ADAMTS4

Chr 1

ADAM metallopeptidase with thrombospondin type 1 motif 4

Also known as: ADAMTS-2, ADAMTS-4, ADMP-1

NCBI Gene: 9507 ENSG00000158859 UniProt: O75173 OMIM: 603876

This gene encodes a member of the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) protein family. Members of this family share several distinct protein modules, including a propeptide region, a metalloproteinase domain, a disintegrin-like domain, and a thrombospondin type 1 (TS) motif. Individual members of this family differ in the number of C-terminal TS motifs, and some have unique C-terminal domains. The enzyme encoded by this gene lacks a C-terminal TS motif. The encoded preproprotein is proteolytically processed to generate the mature protease. This protease is responsible for the degradation of aggrecan, a major proteoglycan of cartilage, and brevican, a brain-specific extracellular matrix protein. The expression of this gene is upregulated in arthritic disease and this may contribute to disease progression through the degradation of aggrecan. Alternative splicing results in multiple transcript variants, at least one of which encodes an isoform that is proteolytically processed. [provided by RefSeq, Feb 2016]

OMIM Research

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.71

Clinical Summary— ADAMTS4

⚡

Population Constraint (gnomAD)

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

📋

ClinVar Variants

126 VUS of 148 total submissions

💊

Clinical Trials

3 active or recruiting trials — potential therapeutic options may be available

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?

0.71LOEUF

pLI 0.000

Z-score 2.85

OE 0.46 (0.31–0.71)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.15Z-score

OE missense 0.86 (0.79–0.93)

454 obs / 528.7 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.46 (0.31–0.71)

0≤0.351.4

Missense OE?0.86 (0.79–0.93)

0≤0.61.4

Synonymous OE?0.95

0≤1.21.6

LoF obs/exp: 15 / 32.5Missense obs/exp: 454 / 528.7Syn Z: 0.59

This gene — mechanism propensity

0.6936th %ile

GOF

0.6735th %ile

LOF

0.2873th %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

148 submitted variants in ClinVar

ClinVar

Classification Summary

VUS126

Likely Benign7

Benign1

126

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	126	0	126
Likely Benign	6	1	7
Benign	0	1	1
Total	132	2	134

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

View in ClinVar →

12 pathogenic / likely-pathogenic (of 22) ClinVar copy-number / structural variants overlap ADAMTS4 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →