ADAM22

Chr 7

ADAM metallopeptidase domain 22

Also known as: ADAM 22, DEE61, EIEE61, MDC2

NCBI Gene: 53616 ENSG00000008277 UniProt: Q9P0K1

ADAM22 encodes a non-catalytic metalloprotease-like protein that functions as a neuronal receptor for LGI1 and serves as a probable integrin ligand in the brain, regulating cell adhesion and proliferation. Biallelic mutations cause developmental and epileptic encephalopathy 61 through autosomal recessive inheritance. The gene shows significant constraint against loss-of-function variation (LOEUF 0.363), reflecting its critical role in neuronal function.

ResearchSummary from RefSeq, OMIM, 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. Unlike other members of the ADAM protein family, the protein encoded by this gene lacks metalloprotease activity since it has no zinc-binding motif. This gene is highly expressed in the brain and may function as an integrin ligand in the brain. In mice, it has been shown to be essential for correct myelination in the peripheral nervous system. Alternative splicing results in several transcript variants.[provided by RefSeq, Dec 2010]

ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.36

Clinical Summary— ADAM22

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Gene-Disease Validity (ClinGen)

developmental and epileptic encephalopathy · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.23) despite low pLI — interpret in context.

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ClinVar Variants

9 unique Pathogenic / Likely Pathogenic· 114 VUS of 193 total submissions

Explore recent and relevant literature in Research Assistant →

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.36LOEUF

pLI 0.251

Z-score 5.53

OE 0.23 (0.15–0.36)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

2.34Z-score

OE missense 0.70 (0.64–0.77)

349 obs / 495.6 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.23 (0.15–0.36)

0≤0.351.4

Missense OE?0.70 (0.64–0.77)

0≤0.61.4

Synonymous OE?0.97

0≤1.21.6

LoF obs/exp: 14 / 60.4Missense obs/exp: 349 / 495.6Syn Z: 0.27

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongADAM22-related developmental and epileptic encephalopathyOTHERAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.6161th %ile

GOF

0.6150th %ile

LOF

0.4136th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

193 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic5

Likely Pathogenic4

VUS114

Likely Benign37

Benign15

Conflicting1

Pathogenic

Likely Pathogenic

114

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	3	2	0	0	5
Likely Pathogenic	3	1	0	0	4
VUS	0	111	3	0	114
Likely Benign	0	9	8	20	37
Benign	0	7	5	3	15
Conflicting	—				1
Total	6	130	16	23	176

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

View in ClinVar →

12 pathogenic / likely-pathogenic (of 21) ClinVar copy-number / structural variants overlap ADAM22 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →