ADAM12

Chr 10

ADAM metallopeptidase domain 12

Also known as: ADAM12-OT1, CAR10, MCMP, MCMPMltna, MLTN, MLTNA

NCBI Gene: 8038 ENSG00000148848 UniProt: O43184 OMIM: 602714

The protein functions in skeletal muscle regeneration at the onset of cell fusion and is involved in macrophage-derived giant cell and osteoclast formation. This gene is highly tolerant to loss-of-function variants based on constraint metrics, and no established Mendelian disease associations have been reported in the provided data.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a member of a family of proteins that are structurally related to snake venom disintegrins and have been implicated in a variety of biological processes involving cell-cell and cell-matrix interactions, including fertilization, muscle development, and neurogenesis. Expression of this gene has been used as a maternal serum marker for pre-natal development. Alternative splicing results in multiple transcript variants encoding different isoforms. Shorter isoforms are secreted, while longer isoforms are membrane-bound form. [provided by RefSeq, Jan 2014]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.59

Clinical Summary— ADAM12

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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

111 VUS of 143 total submissions

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Clinical Trials

1 active or recruiting trial — 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

Moderate LoF intolerance

LoF Constraint?

0.59LOEUF

pLI 0.000

Z-score 3.78

OE 0.41 (0.28–0.59)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.27Z-score

OE missense 0.84 (0.78–0.91)

438 obs / 519.3 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.41 (0.28–0.59)

0≤0.351.4

Missense OE?0.84 (0.78–0.91)

0≤0.61.4

Synonymous OE?0.99

0≤1.21.6

LoF obs/exp: 19 / 46.9Missense obs/exp: 438 / 519.3Syn Z: 0.10

This gene — mechanism propensity

0.75top 25%

GOF

0.6541th %ile

LOF

0.3067th %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

143 submitted variants in ClinVar

ClinVar

Classification Summary

VUS111

Likely Benign10

Benign6

111

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0
Likely Pathogenic	0	0	0	0
VUS	111	0	0	111
Likely Benign	8	0	2	10
Benign	2	1	3	6
Total	121	1	5	127

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

View in ClinVar →

70 pathogenic / likely-pathogenic (of 78) ClinVar copy-number / structural variants overlap ADAM12 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →