# ADAM21

> Gene · canonical: https://sugi.bio/atlas/gene/ADAM21/
> Atlas v1.12.2 · generated 2026-10-13T13:32:47+00:00

## Summary

**ADAM21** (ADAM metallopeptidase domain 21, HGNC:200) is a protein-coding gene on chromosome 14q24.2, encoding **Disintegrin and metalloproteinase domain-containing protein 21** (Q9UKJ8). May be involved in sperm maturation and/or fertilization.

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 expression of this gene expression is testis-specific.

*Source: [NCBI Gene 8747](https://www.ncbi.nlm.nih.gov/gene/8747) — RefSeq curated summary.*

**At a glance**

- **GWAS associations:** 2
- **Clinical variants (ClinVar):** 114 total
- **Regional missense constraint (gnomAD):** 1 of 4 regions constrained (≈5% of expected missense variation)
- **GTEx eGene:** eQTL in 22 tissues, sQTL in 0 (q < 0.05)
- **Constraint (gnomAD):** pLI 0.14 (intermediate), LOEUF 1.91 (unconstrained)
- **MANE Select transcript:** `NM_003813`
- **Notable:** 114 clinical variants but no curated precision-oncology (CIViC) evidence yet




## Identifiers

### Gene identifiers

| Field | Value |
| --- | --- |
| HGNC ID | HGNC:200 |
| Approved symbol | ADAM21 |
| Name | ADAM metallopeptidase domain 21 |
| Location | 14q24.2 |
| Locus type | gene with protein product |
| Status | Approved |
| Aliases | ADAM31 |
| Ensembl gene | ENSG00000139985 |
| Ensembl biotype | protein_coding |
| OMIM | 603713 |
| Entrez | 8747 |

## Gene structure

### Transcript identifiers

**Ensembl transcripts: 5** — 5 protein_coding

**MANE Select:** `ENST00000603540`

**Transcript support level (Ensembl TSL; 1 = fully mRNA-supported):** TSL 3: 1

`ENST00000603540`, `ENST00000679631`, `ENST00000942462`, `ENST00000942463`, `ENST00001139660`

**RefSeq mRNA: 1** — MANE Select: `NM_003813`
`NM_003813`

**CCDS:** `CCDS9804`

#### Canonical transcript exons

`ENST00000603540` — 2 exons

| Exon | Start | End |
| --- | --- | --- |
| ENSE00002452332 | 70452174 | 70452263 |
| ENSE00003575393 | 70457349 | 70459905 |

### Expression profiles

**Bgee:** expression breadth **ubiquitous**, 121 present calls, max score 94.51.

**FANTOM5 (CAGE):** breadth **tissue_specific**, TPM avg 0.0146 / max 13.9836, expressed in 3 samples.

**Highest expression (Bgee):** sperm, male germ cell, male germ line stem cell (sensu Vertebrata) in testis, secondary oocyte, testis.

#### Genetic regulation across tissues (GTEx eQTL / sQTL)

ADAM21 is an **eGene** in GTEx v10 — its expression is genetically regulated (eQTL) in **22** tissues and its splicing (sQTL) in **0** (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant's alternative allele.

showing 20 of 22 significant tissue × QTL associations:

| Tissue | QTL | q-value | Slope | Lead variant |
| --- | --- | --- | --- | --- |
| Cells Cultured fibroblasts | eqtl | 3.2e-22 | +0.39 | 14:70455425:C:A |
| Thyroid | eqtl | 3.9e-10 | -0.57 | 14:70514449:A:C |
| Artery Tibial | eqtl | 3.5e-09 | -0.47 | 14:70580348:AT:A |
| Skin Sun Exposed Lower leg | eqtl | 1.1e-05 | -0.32 | 14:70587667:T:C |
| Esophagus Muscularis | eqtl | 7.0e-05 | -0.36 | 14:70581841:C:T |
| Esophagus Gastroesophageal Junction | eqtl | 8.2e-05 | -0.47 | 14:70579708:A:G |
| Nerve Tibial | eqtl | 3.5e-04 | -0.27 | 14:70568360:G:GA |
| Pancreas | eqtl | 7.5e-04 | -0.52 | 14:70595715:T:C |
| Pituitary | eqtl | 9.5e-04 | -0.49 | 14:70595715:T:C |
| Artery Aorta | eqtl | 9.9e-04 | -0.27 | 14:70457532:A:G |
| Testis | eqtl | 1.3e-03 | -0.12 | 14:70457532:A:G |
| Breast Mammary Tissue | eqtl | 1.6e-03 | -0.43 | 14:70574785:T:C |
| Skin Not Sun Exposed Suprapubic | eqtl | 1.7e-03 | -0.37 | 14:70576840:C:T |
| Brain Frontal Cortex BA9 | eqtl | 1.7e-03 | +0.25 | 14:70425508:C:T |
| Adipose Visceral Omentum | eqtl | 2.6e-03 | -0.24 | 14:70202285:A:G |
| Small Intestine Terminal Ileum | eqtl | 1.4e-02 | -0.43 | 14:70291860:T:C |
| Brain Cortex | eqtl | 2.1e-02 | -0.25 | 14:70457532:A:G |
| Muscle Skeletal | eqtl | 3.6e-02 | +0.32 | 14:70439006:G:A |
| Brain Caudate basal ganglia | eqtl | 4.0e-02 | -0.24 | 14:70457532:A:G |
| Brain Cerebellar Hemisphere | eqtl | 4.4e-02 | -0.31 | 14:70305157:A:G |

#### FANTOM5 promoters

1 alternative TSS:

| Promoter ID | TPM avg | Samples expressed |
| --- | --- | --- |
| 140401 | 0.0146 | 3 |

#### Top tissues by expression

showing 100 of 259 tissues by Bgee expression score (0-100, higher = more expressed):

| Tissue | Anatomy ID | Expression score | Quality |
| --- | --- | --- | --- |
| sperm | CL:0000019 | 94.51 | gold quality |
| male germ cell | CL:0000015 | 90.66 | gold quality |
| male germ line stem cell (sensu Vertebrata) in testis | CL:0000089 ∩ UBERON:0000473 | 77.61 | gold quality |
| secondary oocyte | CL:0000655 | 76.53 | gold quality |
| right testis | UBERON:0004534 | 71.38 | gold quality |
| left testis | UBERON:0004533 | 71.10 | gold quality |
| testis | UBERON:0000473 | 70.10 | gold quality |
| ileal mucosa | UBERON:0000331 | 68.09 | gold quality |
| tibialis anterior | UBERON:0001385 | 67.96 | silver quality |
| buccal mucosa cell | CL:0002336 | 63.72 | gold quality |
| oocyte | CL:0000023 | 61.10 | silver quality |
| stromal cell of endometrium | CL:0002255 | 60.48 | gold quality |
| pancreatic ductal cell | CL:0002079 | 59.03 | silver quality |
| tendon of biceps brachii | UBERON:0008188 | 58.08 | gold quality |
| decidua | UBERON:0002450 | 56.55 | gold quality |
| endothelial cell | CL:0000115 | 56.53 | gold quality |
| hair follicle | UBERON:0002073 | 56.04 | gold quality |
| prefrontal cortex | UBERON:0000451 | 55.86 | gold quality |
| right adrenal gland cortex | UBERON:0035827 | 54.73 | gold quality |
| deltoid | UBERON:0001476 | 54.35 | silver quality |
| tendon | UBERON:0000043 | 54.06 | silver quality |
| right adrenal gland | UBERON:0001233 | 53.81 | gold quality |
| left adrenal gland | UBERON:0001234 | 53.32 | gold quality |
| lower lobe of lung | UBERON:0008949 | 53.12 | gold quality |
| islet of Langerhans | UBERON:0000006 | 52.73 | gold quality |
| calcaneal tendon | UBERON:0003701 | 52.39 | silver quality |
| left adrenal gland cortex | UBERON:0035825 | 52.11 | gold quality |
| quadriceps femoris | UBERON:0001377 | 52.07 | gold quality |
| adrenal cortex | UBERON:0001235 | 51.78 | gold quality |
| bone marrow cell | CL:0002092 | 51.66 | gold quality |
| muscle tissue | UBERON:0002385 | 51.47 | silver quality |
| primordial germ cell in gonad | CL:0000670 ∩ UBERON:0000991 | 51.09 | gold quality |
| epithelial cell of pancreas | CL:0000083 | 51.03 | silver quality |
| adrenal gland | UBERON:0002369 | 50.80 | gold quality |
| metanephric glomerulus | UBERON:0004736 | 50.80 | gold quality |
| vastus lateralis | UBERON:0001379 | 50.73 | gold quality |
| frontal pole | UBERON:0002795 | 50.41 | gold quality |
| frontal cortex | UBERON:0001870 | 50.38 | gold quality |
| middle frontal gyrus | UBERON:0002702 | 50.30 | gold quality |
| adult organism | UBERON:0007023 | 50.25 | silver quality |
| paraflocculus | UBERON:0005351 | 50.18 | gold quality |
| Brodmann (1909) area 10 | UBERON:0013541 | 50.18 | gold quality |
| oviduct epithelium | UBERON:0004804 | 50.03 | gold quality |
| Brodmann (1909) area 9 | UBERON:0013540 | 49.62 | gold quality |
| Brodmann (1909) area 46 | UBERON:0006483 | 49.30 | gold quality |
| muscle organ | UBERON:0001630 | 49.29 | gold quality |
| cerebellar vermis | UBERON:0004720 | 49.25 | gold quality |
| cervix squamous epithelium | UBERON:0006922 | 49.20 | gold quality |
| olfactory bulb | UBERON:0002264 | 48.92 | gold quality |
| gastrocnemius | UBERON:0001388 | 48.89 | gold quality |
| neocortex | UBERON:0001950 | 48.87 | gold quality |
| myocardium | UBERON:0002349 | 48.87 | gold quality |
| type B pancreatic cell | CL:0000169 | 48.83 | gold quality |
| cardiac atrium | UBERON:0002081 | 48.82 | gold quality |
| right atrium auricular region | UBERON:0006631 | 48.70 | gold quality |
| muscle of leg | UBERON:0001383 | 48.67 | gold quality |
| thymus | UBERON:0002370 | 48.63 | gold quality |
| descending thoracic aorta | UBERON:0002345 | 48.59 | gold quality |
| corpus callosum | UBERON:0002336 | 48.55 | silver quality |
| cardiac muscle of right atrium | UBERON:0003379 | 48.55 | gold quality |
| kidney epithelium | UBERON:0004819 | 48.51 | gold quality |
| CA1 field of hippocampus | UBERON:0003881 | 48.50 | gold quality |
| left ventricle myocardium | UBERON:0006566 | 48.24 | gold quality |
| orbitofrontal cortex | UBERON:0004167 | 48.20 | gold quality |
| upper arm skin | UBERON:0004263 | 48.06 | gold quality |
| cervix epithelium | UBERON:0004801 | 48.04 | gold quality |
| dorsolateral prefrontal cortex | UBERON:0009834 | 47.98 | gold quality |
| right hemisphere of cerebellum | UBERON:0014890 | 47.97 | silver quality |
| tongue squamous epithelium | UBERON:0006919 | 47.92 | gold quality |
| mucosa of urinary bladder | UBERON:0001259 | 47.80 | gold quality |
| heart | UBERON:0000948 | 47.78 | gold quality |
| heart left ventricle | UBERON:0002084 | 47.73 | gold quality |
| cerebellar cortex | UBERON:0002129 | 47.70 | silver quality |
| uterine cervix | UBERON:0000002 | 47.61 | silver quality |
| cerebellar hemisphere | UBERON:0002245 | 47.59 | silver quality |
| cerebellum | UBERON:0002037 | 47.56 | silver quality |
| cardiac ventricle | UBERON:0002082 | 47.47 | gold quality |
| nephron tubule | UBERON:0001231 | 47.30 | gold quality |
| smooth muscle tissue | UBERON:0001135 | 47.25 | gold quality |
| diaphragm | UBERON:0001103 | 47.05 | gold quality |
| gluteal muscle | UBERON:0002000 | 47.03 | gold quality |
| triceps brachii | UBERON:0001509 | 47.01 | gold quality |
| hypothalamus | UBERON:0001898 | 46.95 | gold quality |
| thoracic aorta | UBERON:0001515 | 46.89 | gold quality |
| endometrium epithelium | UBERON:0004811 | 46.85 | gold quality |
| middle temporal gyrus | UBERON:0002771 | 46.83 | gold quality |
| cerebral cortex | UBERON:0000956 | 46.66 | gold quality |
| ascending aorta | UBERON:0001496 | 46.64 | gold quality |
| colonic epithelium | UBERON:0000397 | 46.60 | gold quality |
| aorta | UBERON:0000947 | 45.87 | gold quality |
| layer of synovial tissue | UBERON:0007616 | 45.76 | gold quality |
| right coronary artery | UBERON:0001625 | 45.75 | gold quality |
| nasal cavity epithelium | UBERON:0005384 | 45.61 | gold quality |
| left coronary artery | UBERON:0001626 | 45.58 | gold quality |
| sural nerve | UBERON:0015488 | 45.50 | gold quality |
| vermiform appendix | UBERON:0001154 | 45.49 | silver quality |
| cingulate cortex | UBERON:0003027 | 45.49 | gold quality |
| dorsal root ganglion | UBERON:0000044 | 45.34 | gold quality |
| right frontal lobe | UBERON:0002810 | 45.33 | gold quality |
| coronary artery | UBERON:0001621 | 45.28 | gold quality |

#### Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

| Experiment | Marker? | Max mean expression |
| --- | --- | --- |
| [E-ANND-3](https://www.ebi.ac.uk/gxa/sc/experiments/E-ANND-3) | no | 2.45 |

#### HPA expression

RNA tissue specificity: **Tissue enriched**

44 HPA tissues / cells by nTPM:

| Tissue / cell | Axis | nTPM | Protein (IHC) |
| --- | --- | --- | --- |
| Testis | tissue | 8.1 | medium |
| Postcentral gyrus | tissue | 5.8 |  |
| Choroid plexus | tissue | 4.1 |  |
| Nucleus accumbens | tissue | 3.9 |  |
| Hippocampus | tissue | 3.7 | not detected |
| Locus coeruleus | tissue | 3.5 |  |
| Retina | tissue | 1.2 |  |
| Cerebral cortex | tissue | 0.3 | not detected |
| Basal ganglia | tissue | 0.3 | not detected |
| Putamen | tissue | 0.3 |  |
| Amygdala | tissue | 0.3 |  |
| Ventral forebrain | tissue | 0.3 |  |
| Retrosplenial and cingulate cortex | tissue | 0.3 |  |
| Insular cortex | tissue | 0.3 |  |
| Pituitary gland | tissue | 0.2 |  |
| Prefrontal cortex | tissue | 0.2 |  |
| Heart muscle | tissue | 0.2 | not detected |
| Hypothalamus | tissue | 0.2 |  |
| Spinal cord | tissue | 0.2 |  |
| Hippocampal formation | tissue | 0.2 |  |
| Entorhinal cortex | tissue | 0.2 |  |
| Septum | tissue | 0.2 |  |
| Retrosplenial cortex | tissue | 0.2 |  |
| Temporal cortex | tissue | 0.2 |  |
| Lymph node | tissue | 0.1 | not detected |
| Pons | tissue | 0.1 |  |
| Ovary | tissue | 0.1 | not detected |
| Vagina | tissue | 0.1 | not detected |
| Skeletal muscle | tissue | 0.1 | not detected |
| Motor cortex | tissue | 0.1 |  |
| Tongue | tissue | 0.1 |  |
| Frontal cortex | tissue | 0.1 |  |
| Midbrain | tissue | 0.1 |  |
| Medulla oblongata | tissue | 0.1 |  |
| Thalamus | tissue | 0.1 |  |
| Superior colliculi | tissue | 0.1 |  |
| Substantia nigra | tissue | 0.1 |  |
| Corpus callosum | tissue | 0.1 |  |
| Adrenal gland | tissue | 0.1 | not detected |
| Periaqueductal gray | tissue | 0.1 |  |
| Olfactory bulb | tissue | 0.1 |  |
| Somatosensory cortex | tissue | 0.1 |  |
| Appendix | tissue | 0.1 | not detected |
| Occipital cortex | tissue | 0.1 |  |

**Brain sub-regions (HPA Brain Atlas):** detected in 189; highest nTPM — Parietal operculum (5.2), Postcentral gyrus, middle (5.1), Precentral gyrus (5.1), Frontal eye field (4.9), Posterior cingulate cortex (4.8).

### Regulation

**Is transcription factor: no**

#### miRNA regulators (miRDB)

Targeting ADAM21 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

22 miRNAs:

| miRNA | Max score | Avg score | miRNA target_count |
| --- | --- | --- | --- |
| HSA-MIR-4747-5P | 100.00 | 67.90 | 2681 |
| HSA-MIR-5196-5P | 100.00 | 67.98 | 2761 |
| HSA-MIR-4728-5P | 99.85 | 69.39 | 4718 |
| HSA-MIR-1321 | 99.84 | 65.30 | 1811 |
| HSA-MIR-4739 | 99.84 | 65.25 | 1832 |
| HSA-MIR-4756-5P | 99.84 | 64.98 | 1809 |
| HSA-MIR-6785-5P | 99.82 | 68.68 | 4428 |
| HSA-MIR-1299 | 99.77 | 71.24 | 2389 |
| HSA-MIR-6505-5P | 99.73 | 69.25 | 1595 |
| HSA-MIR-149-3P | 99.72 | 68.22 | 3963 |
| HSA-MIR-10393-3P | 99.72 | 66.56 | 961 |
| HSA-MIR-6801-5P | 99.72 | 66.50 | 981 |
| HSA-MIR-33A-3P | 99.70 | 70.27 | 3362 |
| HSA-MIR-6883-5P | 99.69 | 68.05 | 3785 |
| HSA-MIR-5700 | 99.64 | 69.88 | 2280 |
| HSA-MIR-6507-5P | 99.36 | 70.46 | 2524 |
| HSA-MIR-1301-3P | 98.64 | 68.27 | 1071 |
| HSA-MIR-5047 | 98.64 | 68.62 | 1035 |
| HSA-MIR-5011-3P | 98.63 | 64.81 | 638 |
| HSA-MIR-9500 | 98.62 | 66.54 | 1845 |
| HSA-MIR-4536-5P | 98.47 | 64.39 | 657 |
| HSA-MIR-12128 | 96.67 | 66.98 | 1471 |

### Functional genomics

**gnomAD constraint:** pLI 0.141, LOEUF 1.91, missense Z 2.33 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). [gnomAD](https://gnomad.broadinstitute.org/)

#### Regional missense constraint (gnomAD)

`ENST00000603540` splits into 4 regions with different missense tolerance; **1 is missense-constrained** (≈5% of the expected missense variation). Missense variants in a constrained region (low observed/expected) are more likely to be pathogenic. [gnomAD](https://gnomad.broadinstitute.org/)

| Region (GRCh38) | Missense obs / exp | o/e | Constrained |
| --- | --- | --- | --- |
| 14:70,457,500–70,457,651 | 51 / 59.5 | 0.86 | no |
| 14:70,457,652–70,457,764 | 15 / 47.3 | 0.32 | yes (p 2.6e-06) |
| 14:70,457,765–70,459,276 | 448 / 611.2 | 0.73 | no |
| 14:70,459,277–70,459,665 | 164 / 156.4 | 1.05 | no |

### Literature-anchored findings (GeneRIF, showing 1)

- ADAM21 was overexpressed in KYN-2 hepatocellular carcinoma (HCC) cell line, and its knockdown reduced invasion, migration, proliferation, and metastasis relative to controls. In HCC clinical specimens, ADAM21 positivity was associated with vascular invasion, large tumor size, high histological grade, and lower overall and recurrence-free survival as compared to cases that were negative for ADAM21 expression. (PMID:29138461)

### Cross-species orthologs

**10 orthologs**

| Organism | Symbol | Gene ID |
| --- | --- | --- |
| danio_rerio | adam10b | ENSDARG00000015502 |
| danio_rerio | adam10a | ENSDARG00000053468 |
| danio_rerio | adam9b | ENSDARG00000057138 |
| danio_rerio | si:ch1073-396h14.1 | ENSDARG00000057590 |
| mus_musculus | Adam21 | ENSMUSG00000008438 |
| rattus_norvegicus | LOC103690152 | ENSRNOG00000047682 |
| drosophila_melanogaster | mmd | FBGN0259110 |
| drosophila_melanogaster | kuz | FBGN0259984 |
| caenorhabditis_elegans | sup-17 | WBGENE00006324 |
| caenorhabditis_elegans |  | WBGENE00006804 |

**Paralogs (20):** ADAM22 (ENSG00000008277), ADAM28 (ENSG00000042980), ADAM7 (ENSG00000069206), ADAM11 (ENSG00000073670), ADAM2 (ENSG00000104755), ADAM23 (ENSG00000114948), ADAM20 (ENSG00000134007), ADAMDEC1 (ENSG00000134028), ADAM30 (ENSG00000134249), ADAM19 (ENSG00000135074), ADAM10 (ENSG00000137845), ADAM15 (ENSG00000143537), ADAM12 (ENSG00000148848), ADAM33 (ENSG00000149451), ADAM8 (ENSG00000151651), ADAM17 (ENSG00000151694), ADAM29 (ENSG00000168594), ADAM9 (ENSG00000168615), ADAM18 (ENSG00000168619), ADAM32 (ENSG00000197140)

#### Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara's model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions' gene symbols aren't in biobtree yet, so each row shows the UniProt accession.

| Organism | UniProt | Identity | Method |
| --- | --- | --- | --- |
| Trichophyton verrucosum HKI 0517 | [D4DCV9](https://www.uniprot.org/uniprotkb/D4DCV9/entry) | 97.9% | Diamond |
| Macaca fascicularis | [Q28478](https://www.uniprot.org/uniprotkb/Q28478/entry) | 91.4% | Diamond |
| Xenopus laevis | [Q9PSZ3](https://www.uniprot.org/uniprotkb/Q9PSZ3/entry) | 77.8% | Diamond |
| Bos taurus | [O77780](https://www.uniprot.org/uniprotkb/O77780/entry) | 65.0% | Diamond |
| Oryctolagus cuniculus | [Q28660](https://www.uniprot.org/uniprotkb/Q28660/entry) | 64.6% | Diamond |
| Cavia porcellus | [Q60411](https://www.uniprot.org/uniprotkb/Q60411/entry) | 56.5% | Diamond |

### Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

| Symbol | Type | Entrez |
| --- | --- | --- |
| [COX16](/atlas/gene/COX16/) | protein-coding | 51241 |
| [SYNJ2BP](/atlas/gene/SYNJ2BP/) | protein-coding | 55333 |
| SYNJ2BP-COX16 | protein-coding | 100529257 |
| [ADAM20](/atlas/gene/ADAM20/) | protein-coding | 8748 |

<a id="protein-Q9UKJ8"></a>

## Protein

### Protein identifiers

**Disintegrin and metalloproteinase domain-containing protein 21** — `Q9UKJ8` (reviewed: Q9UKJ8)

**All UniProt accessions (1):** `Q9UKJ8`

#### UniProt curated annotations — [full annotation on UniProt →](https://www.uniprot.org/uniprotkb/Q9UKJ8/entry)

**Function.** May be involved in sperm maturation and/or fertilization. May also be involved in epithelia functions associated with establishing and maintaining gradients of ions or nutrients.

**Subcellular location.** Membrane.

**Post-translational modifications.** Has no obvious cleavage site for furin endopeptidase, suggesting that the proteolytic processing is regulated.

**Cofactor.** Binds 1 zinc ion per subunit.

**Domain organisation.** A tripeptide motif (VGE) within disintegrin-like domain could be involved in the binding to egg integrin receptor and thus could mediate sperm/egg binding. The cysteine-rich domain encodes putative cell-fusion peptides, which could be involved in sperm-egg fusion. The conserved cysteine present in the cysteine-switch motif binds the catalytic zinc ion, thus inhibiting the enzyme. The dissociation of the cysteine from the zinc ion upon the activation-peptide release activates the enzyme.

**Miscellaneous.** May be the functional equivalent of ADAM 1/fertilin alpha which is a pseudogene in human.

**RefSeq proteins (1):** `NP_003804`*  (*=MANE)

#### Domains & families (InterPro)

| ID | Name | Type |
| --- | --- | --- |
| IPR000742 | EGF | Domain |
| IPR001590 | Peptidase_M12B | Domain |
| IPR001762 | Disintegrin_dom | Domain |
| IPR002870 | Peptidase_M12B_N | Domain |
| IPR006586 | ADAM_Cys-rich | Domain |
| IPR018358 | Disintegrin_CS | Conserved_site |
| IPR024079 | MetalloPept_cat_dom_sf | Homologous_superfamily |
| IPR034027 | Reprolysin_adamalysin | Domain |
| IPR036436 | Disintegrin_dom_sf | Homologous_superfamily |

**Pfam:** `PF00200`, `PF01421`, `PF01562`, `PF08516`

**UniProt features (35 total):** glycosylation site 7, disulfide bond 7, sequence conflict 6, binding site 4, domain 3, topological domain 2, signal peptide 1, propeptide 1, active site 1, chain 1, transmembrane region 1, short sequence motif 1

### Structure

#### Predicted structure (AlphaFold)

| Model | pLDDT | Fraction very-high |
| --- | --- | --- |
| AF-Q9UKJ8-F1 | 83.17 | 0.48 |

### Human Protein Atlas

**Protein class:** Predicted membrane proteins

**Protein evidence:** Evidence at protein level

**Antibody reliability (HPA):** IH uncertain

### Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. *Source: UniProtKB sequence features.*

#### Catalytic / active sites (1)

| Position | Role |
| --- | --- |
| 342 |  |

#### Ligand- & substrate-binding residues (4)

| Position | Role |
| --- | --- |
| 173 | Zn(2+) |
| 341 | Zn(2+) |
| 345 | Zn(2+) |
| 351 | Zn(2+) |

#### Disulfide bonds (7)

| Type | Positions |
| --- | --- |
| Disulfide bond | 316–393, 356–378, 358–363, 464–484, 634–645, 639–651, 653–662 |

#### Glycosylation sites (7)

| Type | Positions |
| --- | --- |
| N-linked (glcnac...) asparagine | 164, 227, 377, 437, 478, 546, 600 |

## Function

### Pathways and Gene Ontology

#### Reactome pathways

**1 curated (TAS)** of 3; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

3 pathways:

| ID | Pathway | Evidence |
| --- | --- | --- |
| R-HSA-2534343 | Interaction With Cumulus Cells And The Zona Pellucida | curated |
| R-HSA-1187000 | Fertilization | — |
| R-HSA-1474165 | Reproduction | — |

**MSigDB gene sets: 60** (showing top):
`GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_MCMV_INFECTION_DN`, `GOBP_SINGLE_FERTILIZATION`, `GOMF_METALLOPEPTIDASE_ACTIVITY`, `XU_HGF_TARGETS_REPRESSED_BY_AKT1_DN`, `GOCC_CELL_SURFACE`, `chr14q24`, `GOBP_REPRODUCTIVE_SYSTEM_DEVELOPMENT`, `BLALOCK_ALZHEIMERS_DISEASE_UP`, `GOBP_SEX_DIFFERENTIATION`, `GOBP_DEVELOPMENTAL_PROCESS_INVOLVED_IN_REPRODUCTION`, `GOCC_NEURON_PROJECTION`, `GOBP_FERTILIZATION`, `GOBP_MALE_SEX_DIFFERENTIATION`, `GOBP_DEVELOPMENT_OF_PRIMARY_SEXUAL_CHARACTERISTICS`, `GOCC_SIDE_OF_MEMBRANE`

**GO Biological Process (3):**
proteolysis (GO:0006508), single fertilization (GO:0007338), male gonad development (GO:0008584)

**GO Molecular Function (6):**
metalloendopeptidase activity (GO:0004222), metallopeptidase activity (GO:0008237), metal ion binding (GO:0046872), protein binding (GO:0005515), peptidase activity (GO:0008233), hydrolase activity (GO:0016787)

**GO Cellular Component (7):**
plasma membrane (GO:0005886), external side of plasma membrane (GO:0009897), axon (GO:0030424), neuronal cell body (GO:0043025), sperm head plasma membrane (GO:1990913), membrane (GO:0016020), neuron projection (GO:0043005)

#### Reactome top-level categories

2 top-level categories:

| Category | Pathways |
| --- | --- |
| Fertilization | 1 |
| Reproduction | 1 |

#### GO top-level categories

25 GO namespaces:

| Category | Terms |
| --- | --- |
| protein metabolic process | 1 |
| fertilization | 1 |
| gonad development | 1 |
| development of primary male sexual characteristics | 1 |
| endopeptidase activity | 1 |
| metallopeptidase activity | 1 |
| peptidase activity | 1 |
| cation binding | 1 |
| binding | 1 |
| hydrolase activity | 1 |
| catalytic activity, acting on a protein | 1 |
| catalytic activity | 1 |
| membrane | 1 |
| cell periphery | 1 |
| plasma membrane | 1 |
| cell surface | 1 |
| side of membrane | 1 |
| neuron projection | 1 |
| somatodendritic compartment | 1 |
| cell body | 1 |
| sperm head | 1 |
| sperm plasma membrane | 1 |
| plasma membrane region | 1 |
| cellular anatomical structure | 1 |
| plasma membrane bounded cell projection | 1 |

### Protein interactions and networks

#### STRING

showing 15 of 542 interactions by confidence (×1000):

| Protein A | Protein B | Partner UniProt | Score |
| --- | --- | --- | --- |
| ADAM21 | OR2T27 | Q8NH04 | 387 |
| ADAM21 | MAGEB6B | A0A0J9YX57 | 380 |
| ADAM21 | TEKTIP1 | A6NCJ1 | 360 |
| ADAM21 | TEX55 | Q96M34 | 359 |
| ADAM21 | ADAMTSL5 | Q6ZMM2 | 345 |
| ADAM21 | COX16 | Q9P0S2 | 344 |
| ADAM21 | FAM228A | Q86W67 | 323 |
| ADAM21 | A0A087WYV9 | A0A087WYV9 | 322 |
| ADAM21 | SYNJ2BP | P57105 | 307 |
| ADAM21 | WDR48 | Q8TAF3 | 307 |
| ADAM21 | SUSD6 | Q92537 | 300 |
| ADAM21 | DCAF5 | Q96JK2 | 295 |
| ADAM21 | ADAMTSL2 | Q86TH1 | 292 |
| ADAM21 | CNBD2 | Q96M20 | 289 |
| ADAM21 | SIAH1 | Q8IUQ4 | 288 |

#### IntAct

Human interaction partners of ADAM21 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

5 partners by confidence:

| Partner | Interaction type | MIscore | Records |
| --- | --- | --- | --- |
| CNR2 | physical association | 0.560 | 3 |
| SGTA | physical association | 0.560 | 3 |
| PLXNA2 | association | 0.530 | 2 |
| FGA | physical association | 0.400 | 1 |
| PLXNB2 | association | 0.350 | 1 |

**BioGRID (83 interactions; top human partners by supporting records):** VEGFB (Affinity Capture-MS; 3 records), ACTA2 (Affinity Capture-MS; 2 records), CANX (Affinity Capture-MS; 2 records), CCPG1 (Affinity Capture-MS; 2 records), CHSY3 (Affinity Capture-MS; 2 records), DHFRL1 (Affinity Capture-MS; 2 records), EGFL7 (Affinity Capture-MS; 2 records), HLA-B (Affinity Capture-MS; 2 records), ITGB5 (Affinity Capture-MS; 2 records), LCLAT1 (Affinity Capture-MS; 2 records), LRFN3 (Affinity Capture-MS; 2 records), LRP10 (Affinity Capture-MS; 2 records), LRRC3 (Affinity Capture-MS; 2 records), MANF (Affinity Capture-MS; 2 records), PCSK1N (Affinity Capture-MS; 2 records)

## Disease & clinical

### Genetic variants

**Variant evidence for ADAM21:** [114 ClinVar records](#clinvar) (0 pathogenic / likely pathogenic); [2 GWAS associations](#gwas-assoc).

#### ClinVar

114 variants total. Per-class counts are floors (≥ shown; pagination cap):

| Classification | Count (floor) |
| --- | --- |
| Pathogenic | 0 |
| Likely pathogenic | 0 |
| Uncertain significance | 99 |
| Likely benign | 9 |
| Benign | 0 |

#### SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 19 predictions of 36):

| Position(s) | Effect | Δscore | Sites |
| --- | --- | --- | --- |
| 14:70452264–70452265 | donor_loss | 0.9900 | 5 |
| 14:70457347–70457348 | acceptor_loss | 0.9400 | 6 |
| 14:70455260 | donor_gain | 0.9100 |  |
| 14:70457336 | acceptor_loss | 0.9100 |  |
| 14:70457342 | acceptor_loss | 0.9000 |  |
| 14:70457351 | acceptor_gain | 0.7600 |  |
| 14:70455256 | donor_gain | 0.6500 |  |
| 14:70457346 | acceptor_loss | 0.6500 |  |
| 14:70457352 | acceptor_gain | 0.5200 |  |
| 14:70457469 | acceptor_gain | 0.4500 |  |

#### AlphaMissense

760 missense substitutions predicted likely pathogenic (of 4,811 scored), across 202 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

| Residue | Likely-pathogenic substitutions | Mean am_pathogenicity | Max am_pathogenicity |
| --- | --- | --- | --- |
| M365 | 9 | 0.788 | 0.961 |
| H341 | 8 | 0.797 | 0.907 |
| H345 | 8 | 0.762 | 0.893 |
| D472 | 8 | 0.758 | 0.817 |
| C662 | 7 | 0.913 | 0.958 |
| C653 | 7 | 0.905 | 0.950 |
| C651 | 7 | 0.899 | 0.948 |
| C639 | 7 | 0.892 | 0.943 |
| F375 | 7 | 0.877 | 0.964 |
| C471 | 7 | 0.871 | 0.939 |
| C560 | 7 | 0.861 | 0.920 |
| C477 | 7 | 0.860 | 0.939 |
| C645 | 7 | 0.859 | 0.933 |
| C613 | 7 | 0.857 | 0.927 |
| C502 | 7 | 0.848 | 0.910 |
| C619 | 7 | 0.848 | 0.913 |
| C451 | 7 | 0.847 | 0.917 |
| C446 | 7 | 0.841 | 0.898 |
| C553 | 7 | 0.839 | 0.932 |
| C452 | 7 | 0.837 | 0.899 |

### HPA cancer prognostics

**RNA cancer specificity:** Not detected

### Disease associations

**OMIM:** gene `MIM:603713` | disease phenotypes: 

#### GWAS associations

2 associations:

| Study | Trait | p-value |
| --- | --- | --- |
| GCST004362_1 | Plasma estrone levels in resected estrogen-receptor positive breast cancer | 1e-6 |
| GCST012137_5 | Motor coordination | 2e-6 |

#### EFO canonical traits (from GWAS)

2 canonical traits:

| EFO ID | Trait name |
| --- | --- |
| EFO:0007970 | estrone measurement |
| EFO:0010749 | motor function measurement |

## Drugs & pharmacology

### Drug and pharmacology data

**Is drug target: no**

**PharmGKB:** 1 entry (CPIC guideline: no)

#### GtoPdb / IUPHAR curated pharmacology

*(IUPHAR/BPS Guide to Pharmacology — expert-curated)*

**Target class:** enzyme — *M12: Astacin/Adamalysin*

#### CTD chemical–gene interactions

17 total (human), top 17 by PubMed support.

| Chemical | Actions (top 5) | PubMed papers |
| --- | --- | --- |
| sodium arsenite | decreases expression, increases expression | 2 |
| Benzo(a)pyrene | decreases expression, increases methylation | 2 |
| testosterone enanthate | affects expression | 1 |
| propionaldehyde | increases expression | 1 |
| bisphenol A | decreases methylation | 1 |
| 2,4,5,2',4',5'-hexachlorobiphenyl | increases expression | 1 |
| sulforaphane | increases expression | 1 |
| butyraldehyde | decreases expression | 1 |
| S-(1,2-dichlorovinyl)cysteine | affects response to substance, increases expression | 1 |
| 2,2',4,4'-tetrabromodiphenyl ether | increases expression | 1 |
| Cadmium | decreases expression, increases abundance | 1 |
| Lipopolysaccharides | affects response to substance, increases expression | 1 |
| Tobacco Smoke Pollution | increases expression | 1 |
| Valproic Acid | decreases methylation | 1 |
| Aflatoxin B1 | decreases methylation | 1 |
| Antirheumatic Agents | decreases expression | 1 |
| Cadmium Chloride | decreases expression, increases abundance | 1 |

#### Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.

## Related Atlas pages

*No linked Atlas pages yet — the cross-entity mesh grows as the corpus expands.*