ADAM22
protein-codingADAM metallopeptidase domain 22, the group of ADAM metallopeptidase domain containing
Gene summary
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]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~268.7 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0033370
Submitter: PanelApp Australia
Inheritance Pattern: Unknown
Disease ID:MONDO:0033370
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0033370
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0033370
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0100620
Submitter: ClinGen
*ADAM22* was first reported in relation to autosomal recessive developmental and epileptic encephalopathy (DEE) in 2016 (Muona 2016, PMID: 27066583). Currently, at least 20 individuals have been reported with *ADAM22*-related DEE. All reported individuals have infantile-onset, treatment-resistant epilepsy (PMID: 35373813). Additional clinical features include moderate to profound global development/intellectual disability, hypotonia, delayed motor development, absent speech, spasticity, and brain MRI findings (PMID: 35373813). Six missense, two nonsense, one splicing, one frameshift, and one deletion of exons 3 and 4 that have been reported in thirteen probands in three publications (PMIDs: 27066583, 30237576, and 35373813) are included in this curation. Probands without phasing of the variants were not included in this curation. Functional studies were performed for all variants and supported a loss-of-function disease mechanism (PMIDs: 27066583 and 35373813). This is further supported by a knockout mouse model in which homozygous mice exhibit severe ataxia, convulsions, and die before weaning (PMID: 15876356). Additional evidence is available in the literature beyond what is referenced here; however, the maximum score for genetic and experimental evidence has been reached. In summary, there is definitive evidence to support the relationship between *ADAM22* and autosomal recessive developmental and epileptic encephalopathy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Epilepsy Gene Curation Expert Panel on April 7, 2026 (SOP version 12).
Clinical Genomic Database (CGD)
Manifestation: Craniofacial; Neurologic
Intervention: General
Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to ADAM22 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001324418.2. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 1 | 28 | 2 | 31 | ||
| missense | 1 | 3 | 130 | 10 | 5 | 149 |
| nonsense | 1 | 1 | 2 | |||
| start loss | 0 | |||||
| frameshift | 1 | 2 | 3 | |||
| splice donor/acceptor (+/-2bp) | 1 | 2 | 3 | |||
| Total | 4 | 5 | 134 | 38 | 7 | 188 |
Highest pathogenic variant AF is 0.00003969835
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001311347.1 | 32 | MANE Select | |
| Ensembl | ENSP00000412085.2 | 32 | MANE Select | |
| RefSeq | NP_001311346.1 | 30 | Standard | |
| RefSeq | NP_001311348.1 | 32 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Developmental Biology
- LGI-ADAM interactions
Biological Process
- proteolysis
- cell adhesion
- negative regulation of cell adhesion
- central nervous system development
- adult locomotory behavior
Molecular Function
- metalloendopeptidase activity
- integrin binding
- protein binding
Cellular Component
- plasma membrane
- integral component of membrane
- axon
- glutamatergic synapse
- integral component of postsynaptic density membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000265727
- Coding exons
- 31
- Length
- 268747
- Individuals with no LoFs
- 125141
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 30
- Defined
- 125171
- p
- 0.000120
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 2.34 | 349 | 496 | 0.704 | 0.0000253 | 5934 |
| Missense (PolyPhen) | 86 | 192.12 | 0.44764 | 2292 | ||
| Synonymous | 0.275 | 175 | 180 | 0.974 | 0.00000978 | 1651 |
| Loss of Function | 5.53 | 14 | 60.4 | 0.232 | 0.00000315 | 749 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.000065 | 0.000064 | rare |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00017 | 0.00016 | rare |
| Finnish | 0.00019 | 0.00019 | rare |
| European (Non-Finnish) | 0.00016 | 0.00016 | rare |
| South Asian | 0.000098 | 0.000098 | rare |
| Other | 0.00017 | 0.00016 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Probable ligand for integrin in the brain. This is a non catalytic metalloprotease-like protein (PubMed:19692335). Involved in regulation of cell adhesion and spreading and in inhibition of cell proliferation. Neuronal receptor for LGI1. {ECO:0000269|PubMed:12589811, ECO:0000269|PubMed:15882968, ECO:0000269|PubMed:16385342, ECO:0000269|PubMed:19692335}.;
- Disease
- DISEASE: Epileptic encephalopathy, early infantile, 61 (EIEE61) [MIM:617933]: A form of epileptic encephalopathy, a heterogeneous group of severe childhood onset epilepsies characterized by refractory seizures, neurodevelopmental impairment, and poor prognosis. Development is normal prior to seizure onset, after which cognitive and motor delays become apparent. EIEE61 is an autosomal recessive condition characterized by onset of seizures in infancy. {ECO:0000269|PubMed:27066583}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.103
Intolerance Scores
- LoFtool
- 0.768
- RVIS EVS
- -0.55
- RVIS percentile EVS
- 19.93
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.523
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |