ADAM8

Chr 10

ADAM metallopeptidase domain 8

Also known as: CD156, CD156a, MS2

NCBI Gene: 101 ENSG00000151651 UniProt: P78325 OMIM: 602267

The protein is a membrane-anchored metalloprotease and disintegrin involved in cell-cell and cell-matrix interactions during neurogenesis and neurodegeneration, and may facilitate leukocyte extravasation. No definitive disease associations have been established for ADAM8 mutations based on the available information.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a member of the ADAM (a disintegrin and metalloprotease domain) family. Members of this family are membrane-anchored proteins 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. The protein encoded by this gene may be involved in cell adhesion during neurodegeneration, and it is thought to be a target for allergic respiratory diseases, including asthma. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2009]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.93

Clinical Summary— ADAM8

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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

146 VUS of 209 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?

0.93LOEUF

pLI 0.000

Z-score 1.94

OE 0.68 (0.50–0.93)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.38Z-score

OE missense 0.95 (0.88–1.03)

467 obs / 490.7 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.68 (0.50–0.93)

0≤0.351.4

Missense OE?0.95 (0.88–1.03)

0≤0.61.4

Synonymous OE?1.11

0≤1.21.6

LoF obs/exp: 28 / 41.5Missense obs/exp: 467 / 490.7Syn Z: -1.26

This gene — mechanism propensity

0.73top 25%

GOF

0.6931th %ile

LOF

0.2679th %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

209 submitted variants in ClinVar

ClinVar

Classification Summary

VUS146

Likely Benign46

Benign4

Conflicting2

146

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0	0
Likely Pathogenic	0	0	0	0	0
VUS	1	145	0	0	146
Likely Benign	1	41	0	4	46
Benign	0	4	0	0	4
Conflicting	—				2
Total	2	190	0	4	198

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

View in ClinVar →

98 pathogenic / likely-pathogenic (of 118) ClinVar copy-number / structural variants overlap ADAM8 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →