ADAM22

Chr 7AR

ADAM metallopeptidase domain 22

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

NCBI Gene: 53616ENSG00000008277UniProt: Q9P0K1

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]

Primary Disease Associations & Inheritance

Developmental and epileptic encephalopathy 61MIM #617933
AR
195
ClinVar variants
21
Pathogenic / LP
0.25
pLI score
0
Active trials
Clinical Summary— ADAM22
⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.23) despite low pLI — interpret in context.
📋
ClinVar Variants
21 Pathogenic / Likely Pathogenic· 122 VUS of 195 total submissions
Some data sources returned errors (1)

clinvar: Error: NCBI fetch failed: 429 https://eutils.ncbi.nlm.nih.gov/entrez/eutils/esearch.fcgi

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
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?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
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?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.23 (0.15–0.36)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.70 (0.64–0.77)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.97
0≤1.21.6
LoF obs/exp: 14 / 60.4Missense obs/exp: 349 / 495.6Syn Z: 0.27

ClinVar Variant Classifications

195 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic16
Likely Pathogenic5
VUS122
Likely Benign36
Benign15
Conflicting1
16
Pathogenic
5
Likely Pathogenic
122
VUS
36
Likely Benign
15
Benign
1
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
2
2
12
0
16
Likely Pathogenic
3
1
1
0
5
VUS
0
111
11
0
122
Likely Benign
0
9
8
19
36
Benign
0
7
5
3
15
Conflicting
—1
Total51303722195

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

View in ClinVar →

Protein Context — Lollipop Plot

ADAM22 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

ADAM22-related developmental and epileptic encephalopathy

strong
ARUndeterminedAbsent Gene Product, Altered Gene Product Structure, Decreased Gene Product Level
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Developmental and epileptic encephalopathy 61

MIM #617933

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Autozygome and high throughput confirmation of disease genes candidacy.
Maddirevula S et al.·Genet Med
2019
The LGI1-ADAM22 protein complex in synaptic transmission and synaptic disorders.
Fukata Y et al.·Neurosci Res
2017Review
Biallelic LGI1 and ADAM23 variants cause hippocampal epileptic encephalopathy via the LGI1-ADAM22/23 pathway.
Hirano Y et al.·Brain
2025
A disintegrin and metalloproteinase 22 activates integrin β1 through its disintegrin domain to promote the progression of pituitary adenoma.
Xing B et al.·Neuro Oncol
2024
Biallelic ADAM22 pathogenic variants cause progressive encephalopathy and infantile-onset refractory epilepsy.
van der Knoop MM et al.·Brain
2022
Insights into the mechanisms of epilepsy from structural biology of LGI1-ADAM22.
Yamagata A et al.·Cell Mol Life Sci
2020Review
Biological characterization of ADAM22 variants reveals the importance of a disintegrin domain sequence in cell surface expression.
Sagane K et al.·J Recept Signal Transduct Res
2010
Structural basis of epilepsy-related ligand-receptor complex LGI1-ADAM22.
Yamagata A et al.·Nat Commun
2018
Human Cerebrospinal Fluid Monoclonal LGI1 Autoantibodies Increase Neuronal Excitability.
Kornau HC et al.·Ann Neurol
2020
ADAM22 acts as a novel predictive biomarker for unfavorable prognosis and facilitates metastasis via PI3K/AKT signaling pathway in nasopharyngeal carcinoma.
Xu K et al.·Pathol Res Pract
2024
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools