ADAM28

Summary

ADAM28 (ADAM metallopeptidase domain 28, HGNC:206) is a protein-coding gene on chromosome 8p21.2, encoding Disintegrin and metalloproteinase domain-containing protein 28 (Q9UKQ2). May play a role in the adhesive and proteolytic events that occur during lymphocyte emigration or may function in ectodomain shedding of lymphocyte surface target proteins, such as FASL and CD40L.

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 is a lymphocyte-expressed ADAM protein. This gene is present in a gene cluster with other members of the ADAM family on chromosome 8. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 10863 — RefSeq curated summary.

At a glance

• GWAS associations: 23
• Clinical variants (ClinVar): 309 total — 30 pathogenic, 4 likely-pathogenic
• Phenotypes (HPO): 1
• MANE Select transcript: NM_014265

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:206
Approved symbol	ADAM28
Name	ADAM metallopeptidase domain 28
Location	8p21.2
Locus type	gene with protein product
Status	Approved
Aliases	eMDCII, MDC-Lm, MDC-Ls, ADAM23
Ensembl gene	ENSG00000042980
Ensembl biotype	protein_coding
OMIM	606188
Entrez	10863

Gene structure

Transcript identifiers

Ensembl transcripts: 17 — 9 protein_coding, 3 protein_coding_CDS_not_defined, 3 retained_intron, 2 nonsense_mediated_decay

ENST00000265769, ENST00000437154, ENST00000518326, ENST00000518516, ENST00000518737, ENST00000520448, ENST00000520665, ENST00000521110, ENST00000521629, ENST00000523236, ENST00000523379, ENST00000523440, ENST00000699027, ENST00000904758, ENST00000904759, ENST00000904760, ENST00000950408

RefSeq mRNA: 3 — MANE Select: NM_014265 NM_001304351, NM_014265, NM_021777

CCDS: CCDS34865, CCDS47830

Canonical transcript exons

ENST00000265769 — 23 exons

Exon	Start	End
ENSE00002135305	24354384	24359014
ENSE00003459949	24311361	24311437
ENSE00003464512	24310163	24310241
ENSE00003473786	24294069	24294195
ENSE00003489355	24309894	24309970
ENSE00003494517	24331150	24331327
ENSE00003500274	24299974	24300077
ENSE00003506101	24326554	24326635
ENSE00003539258	24323834	24324003
ENSE00003550052	24332660	24332749
ENSE00003570811	24339466	24339568
ENSE00003577519	24341598	24341757
ENSE00003585641	24335446	24335641
ENSE00003587937	24343101	24343181
ENSE00003604181	24351232	24351310
ENSE00003605690	24351987	24352052
ENSE00003612648	24353770	24353832
ENSE00003613913	24349864	24349972
ENSE00003630787	24343506	24343584
ENSE00003630840	24320236	24320307
ENSE00003631933	24313388	24313580
ENSE00003633429	24329985	24330115
ENSE00003693517	24321218	24321289

Expression profiles

Bgee: expression breadth ubiquitous, 253 present calls, max score 99.56.

FANTOM5 (CAGE): breadth broad, TPM avg 8.0001 / max 418.3473, expressed in 585 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
87940	4.0896	481
87941	1.7893	393
87942	1.2060	313
87939	0.3782	156
87945	0.2925	31
87943	0.1784	66
87947	0.0347	9
87946	0.0314	9

Top tissues by expression

294 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
corpus epididymis	UBERON:0004359	99.56	gold quality
nasal cavity epithelium	UBERON:0005384	97.25	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	97.21	gold quality
gall bladder	UBERON:0002110	96.19	gold quality
pancreatic ductal cell	CL:0002079	96.01	gold quality
right uterine tube	UBERON:0001302	95.63	gold quality
nasal cavity mucosa	UBERON:0001826	95.46	gold quality
epithelium of nasopharynx	UBERON:0001951	95.25	gold quality
mucosa of paranasal sinus	UBERON:0005030	94.63	gold quality
bronchial epithelial cell	CL:0002328	93.66	gold quality
vermiform appendix	UBERON:0001154	93.21	gold quality
epithelium of bronchus	UBERON:0002031	93.17	gold quality
pylorus	UBERON:0001166	92.77	gold quality
bronchus	UBERON:0002185	92.67	gold quality
spleen	UBERON:0002106	92.26	gold quality
caecum	UBERON:0001153	91.56	gold quality
lymph node	UBERON:0000029	91.53	gold quality
stomach	UBERON:0000945	91.38	gold quality
body of stomach	UBERON:0001161	91.33	gold quality
colonic epithelium	UBERON:0000397	90.86	gold quality
pituitary gland	UBERON:0000007	90.58	gold quality
rectum	UBERON:0001052	90.51	gold quality
small intestine Peyer’s patch	UBERON:0003454	90.13	gold quality
caput epididymis	UBERON:0004358	89.57	gold quality
tonsil	UBERON:0002372	89.25	gold quality
cardia of stomach	UBERON:0001162	89.24	gold quality
adenohypophysis	UBERON:0002196	89.21	gold quality
minor salivary gland	UBERON:0001830	89.07	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	89.05	gold quality
small intestine	UBERON:0002108	87.47	gold quality

Single-cell (SCXA)

Detected in 14 experiment(s), a significant marker in 13.

Experiment	Marker?	Max mean expression
E-MTAB-9906	yes	1335.87
E-GEOD-70580	yes	505.26
E-CURD-122	yes	109.22
E-CURD-88	yes	51.80
E-HCAD-35	yes	41.23
E-GEOD-84465	yes	38.64
E-MTAB-9067	yes	28.89
E-MTAB-9467	yes	22.55
E-HCAD-25	yes	20.89
E-MTAB-9221	yes	18.26
E-HCAD-4	yes	18.08
E-MTAB-9801	yes	7.92
E-HCAD-30	no	620.56
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 33)

• ADAM8, ADAM15, and ADAM28, but not ADAM17, catalyzed ectodomain shedding of CD23, the low affinity IgE receptor. (PMID:12777399)
• data demonstrate for the first time that ADAM28 is overexpressed and activated in human non-small cell lung carcinomas, and suggest the possibility that ADAM28 plays a role in cell proliferation and progression of the human lung carcinomas (PMID:16052521)
• ADAM28 is overexpressed in an activated form in breast carcinoma cells and suggest ADAM28 is involved in cell proliferation through enhanced bioavailability of IGF-I released from the IGF-I/IGFBP-3 complex by IGFBP-3 cleavage in breast carcinomas. (PMID:17047053)
• ADAM28s promotes PSGL-1/P-selectin-mediated leukocyte rolling adhesion to endothelial cells and subsequent infiltration into tissue spaces through interaction with PSGL-1 (PMID:17597069)
• Report essential role of ADAM28 in regulating the proliferation and differentiation of human dental papilla mesenchymal cells. (PMID:18690470)
• These results indicate that ADAM28 participates in proteoglycan degradation. (PMID:19527685)
• overexpression of A disintegrin and metalloproteinase 28 was increased according to its histologic grade in conventional chondrosarcoma and could be one of the helpful tools in distinguishing between low-grade chondrosarcoma and enchondroma. (PMID:19896699)
• High ADAM28 in serum is associated with non-small-cell lung cancers. (PMID:20112342)
• was able to effectively manipulate the proliferation, apoptosis, and differentiation of human periodontal ligament stem cells (PMID:20450360)
• Upregulation of ADAM28 is associated with asbestos-related lung adenocarcinomas. (PMID:20544843)
• These data provide the first evidence that CTGF is a novel substrate of ADAM28 and suggest that ADAM28 may promote VEGF(165)-induced angiogenesis in the breast carcinomas by the CTGF digestion in the CTGF/VEGF(165) complex. (PMID:20971063)
• It plays a role in cancer cell proliferation, invasion and metastasis. (review) (PMID:21077327)
• ADAM28 might actively participate in manipulating the proliferation, differentiation, and apoptosis of human dental pulp stem cells (HDPSCs). (PMID:21329817)
• ADAM28 showed significant differences compared with normal individuals, so it may be a biomarker of bladder cancer. (PMID:21782798)
• Study shows using proteomics that ADAM28 may be used as a possible biomarker of bladder cancer. (PMID:21913264)
• ADAM28 cleaves and inactivates proapoptotic VWF in carcinoma cells and enhances lung metastasis probably by promoting carcinoma cell survival within the blood vessels. (PMID:22636800)
• Human ADAM28 expression levels were positively correlated with parameters of the metabolic syndrome. (PMID:23010875)
• The change of ADAM28 and IGFBP-3 gene expression is present in the normal tissue in overweight/obese patients with colorectal cancer only, and the observed variability of ADAM28 and IGFBP-3 expression may be an initial process of cancer proliferation (PMID:23527725)
• Sequence analysis of ADAM28 genes did not reveal any putative mutations for hyperostosis cranialis interna to chromosome 8p21 (PMID:23640157)
• High ADAM28 expression is associated with B-Cell Chronic Lymphocytic Leukemia. (PMID:23643150)
• Src is an inducer of ADAM28 gene expression through the MEK/extracellular signal-regulated kinase and PI3K/mammalian target of rapamycin pathways. (PMID:24007880)
• The results of this study suggest that these proteins play important roles in pulmonary inflammatory reactions elicited against etiological viral agents. (PMID:25453333)
• The data demonstrate that ADAM28 is expressed by epithelial cells of several normal organs, and suggest that ADAM28 plays a role in cell survival by suppression of C1q-induced cytotoxicity in bronchial epithelial cells. (PMID:26918856)
• miR-552 is an oncomir able to promote CRC metastasis in part through a mechanism of targeting ADAM28. (PMID:27661126)
• ADAM28 is overexpressed in primary human prostate tumor biopsies, and it promotes human prostate cancer cell proliferation and migration. (PMID:27749584)
• Within placental villi, ADAM28 mRNA levels were highest in HLA-G(+) column trophoblasts, and consistent with this, ADAM28 was preferentially localized to HLA-G(+) trophoblasts within distal anchoring columns and decidual tissue. (PMID:28623976)
• There is a relationship between the serum level of ADAM28 and the degree of the colonic cancer clinical stage. (PMID:29254295)
• ADAM28 regulates the growth and dissemination of acute myeloid leukemia through IGFBP-3 degradation and IGF-I-induced cell proliferation. (PMID:30429106)
• Study demonstrates that ADAM28 is overexpressed in pancreatic cancer, and closely involved in the regulation of gemcitabine resistance. Overexpression of ADAM28 is a novel prognostic biomarker in pancreatic cancer. (PMID:31602160)
• ADAM28: Another ambivalent protease in cancer. (PMID:32861707)
• [Construction of ADAM28 shRNA interference vector and its inhibitory effect on human periodontal ligament stem cells]. (PMID:33543212)
• ADAM28 from both endothelium and gastric cancer cleaves von Willebrand Factor to eliminate von Willebrand Factor-induced apoptosis of gastric cancer cells. (PMID:33675784)
• LncRNA NEAT1 induces autophagy through the miR-128-3p/ADAM28 axis to suppress apoptosis of nonsmall-cell lung cancer. (PMID:36054559)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	adam28	ENSDARG00000035514
mus_musculus	Adam28	ENSMUSG00000014725
rattus_norvegicus	Adam28	ENSRNOG00000014518
drosophila_melanogaster	kuz	FBGN0259984
caenorhabditis_elegans	sup-17	WBGENE00006324

Paralogs (20): ADAM22 (ENSG00000008277), ADAM7 (ENSG00000069206), ADAM11 (ENSG00000073670), ADAM2 (ENSG00000104755), ADAM23 (ENSG00000114948), ADAM20 (ENSG00000134007), ADAMDEC1 (ENSG00000134028), ADAM30 (ENSG00000134249), ADAM19 (ENSG00000135074), ADAM10 (ENSG00000137845), ADAM21 (ENSG00000139985), ADAM15 (ENSG00000143537), ADAM12 (ENSG00000148848), ADAM33 (ENSG00000149451), ADAM8 (ENSG00000151651), ADAM17 (ENSG00000151694), ADAM29 (ENSG00000168594), ADAM9 (ENSG00000168615), ADAM18 (ENSG00000168619), ADAM32 (ENSG00000197140)

Protein

Protein identifiers

Disintegrin and metalloproteinase domain-containing protein 28 — Q9UKQ2 (reviewed: Q9UKQ2)

Alternative names: Epididymal metalloproteinase-like, disintegrin-like, and cysteine-rich protein II, Metalloproteinase-like, disintegrin-like, and cysteine-rich protein L

All UniProt accessions (7): A0A384NKT9, A0A8V8TMM6, E5RGY1, E5RJQ1, Q9UKQ2, H0YBG8, H0YBQ8

UniProt curated annotations — full annotation on UniProt →

Function. May play a role in the adhesive and proteolytic events that occur during lymphocyte emigration or may function in ectodomain shedding of lymphocyte surface target proteins, such as FASL and CD40L. May be involved in sperm maturation.

Subcellular location. Cell membrane Secreted.

Tissue specificity. Expressed predominantly in secondary lymphoid tissues, such as lymph node, spleen, small intestine, stomach, colon, appendix and trachea. The lymphocyte population is responsible for expression of this protein in these tissues. Isoform 2 is expressed preferentially in spleen.

Post-translational modifications. Pro-domain removal and maturation may be, at least in part, autocatalytic.

Cofactor. Binds 1 zinc ion per subunit.

Domain organisation. 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.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9UKQ2-1	1, MDC-LM	yes
Q9UKQ2-2	2, MDC-LS

RefSeq proteins (3): NP_001291280, NP_055080, NP_068547 (=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 (47 total): sequence variant 12, disulfide bond 7, glycosylation site 5, binding site 4, compositionally biased region 3, domain 3, topological domain 2, splice variant 2, sequence conflict 2, signal peptide 1, propeptide 1, short sequence motif 1, active site 1, chain 1, transmembrane region 1, region of interest 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UKQ2-F1	75.56	0.38

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): 340

Ligand- & substrate-binding residues (4): 169 (in inhibited form); 339; 343; 349

Disulfide bonds (7): 315–394, 354–378, 356–361, 465–485, 629–639, 633–645, 647–656

Glycosylation sites (5): 268, 275, 557, 602, 628

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 392 (showing top): WALLACE_PROSTATE_CANCER_RACE_UP, YAGI_AML_WITH_INV_16_TRANSLOCATION, GOMF_METALLOPEPTIDASE_ACTIVITY, GOBP_RESPONSE_TO_PEPTIDE, RACCACAR_AML_Q6, TAKADA_GASTRIC_CANCER_COPY_NUMBER_DN, MEF2_02, AP2_Q3, GOBP_MALE_GAMETE_GENERATION, MODULE_205, ONKEN_UVEAL_MELANOMA_UP, chr8p21, RHEIN_ALL_GLUCOCORTICOID_THERAPY_UP, IRF1_Q6, MODULE_210

GO Biological Process (2): proteolysis (GO:0006508), spermatogenesis (GO:0007283)

GO Molecular Function (7): metalloendopeptidase activity (GO:0004222), metallopeptidase activity (GO:0008237), immunoglobulin receptor binding (GO:0034987), metal ion binding (GO:0046872), protein binding (GO:0005515), peptidase activity (GO:0008233), hydrolase activity (GO:0016787)

GO Cellular Component (5): extracellular region (GO:0005576), mitochondrion (GO:0005739), plasma membrane (GO:0005886), cell surface (GO:0009986), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
protein metabolic process	1
developmental process involved in reproduction	1
male gamete generation	1
endopeptidase activity	1
metallopeptidase activity	1
peptidase activity	1
signaling receptor binding	1
cation binding	1
binding	1
hydrolase activity	1
catalytic activity, acting on a protein	1
catalytic activity	1
cytoplasm	1
intracellular membrane-bounded organelle	1
membrane	1
cell periphery	1

Protein interactions and networks

STRING

898 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ADAM28	LGI1	O95970	994
ADAM28	ADAM22	Q9P0K1	888
ADAM28	LGI3	Q8N145	688
ADAM28	KCNA1	Q09470	637
ADAM28	DLG4	P78352	570
ADAM28	ITGA4	P13612	569
ADAM28	LGI2	Q8N0V4	567
ADAM28	DLG2	Q15700	471
ADAM28	ITGB1	P05556	451
ADAM28	CNTNAP2	Q9UHC6	447
ADAM28	LGI4	Q8N135	431
ADAM28	ZDBF2	Q9HCK1	417
ADAM28	PRNP	P04156	404
ADAM28	ADAM12	O43184	394
ADAM28	TEDDM1	Q5T9Z0	377

IntAct

6 interactions, top by confidence:

A	B	Type	Score
PLAU	ADAM28	psi-mi:“MI:0915”(physical association)	0.560
	TBKBP1	psi-mi:“MI:0914”(association)	0.350
	AURKA	psi-mi:“MI:0914”(association)	0.350
ADAM28	PLAU	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (8): ADAM28 (Synthetic Growth Defect), ADAM28 (Affinity Capture-MS), ADAM28 (Synthetic Lethality), PLAU (Two-hybrid), ADAM28 (Positive Genetic), ADAM28 (Proximity Label-MS), ADAM28 (Proximity Label-MS), ADAM28 (Proximity Label-MS)

ESM2 similar proteins: F8VQ03, O15072, O15204, O35227, O77780, P58397, P59509, P59510, P70505, P97776, P97857, Q1EHB3, Q28475, Q28478, Q28483, Q28660, Q3TTE0, Q5BK84, Q60411, Q60472, Q60718, Q60813, Q63180, Q63202, Q68SA9, Q811B3, Q811Q4, Q8C9W3, Q8K410, Q8N2E2, Q8R534, Q8TC27, Q8TE59, Q99965, Q9H2U9, Q9JI76, Q9JLN6, Q9R0X2, Q9R157, Q9R158

Diamond homologs: A0A0B4U9L8, A0A6B7FMR5, A2CJE2, A2CJE3, A2CJE4, A3R0T9, A4PBQ9, A8QL48, A8QL49, A8QL59, B8K1W0, C0LZJ5, C5H5D1, C5H5D2, C5H5D3, C5H5D4, C5H5D5, C5H5D6, C9E1R8, C9E1S0, D3TTC1, D3TTC2, D5LMJ3, D6PXE8, D8VNS0, F8RKV9, F8RKW0, F8RKW1, F8S108, G5EFD5, J3S829, J3S830, J3SDW6, J3SDW8, O35227, O35674, O42138, O43184, O77780, O88839

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	30
Likely pathogenic	4
Uncertain significance	202
Likely benign	24
Benign	3

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1341975	GRCh37/hg19 8p21.3-21.2(chr8:19779604-26531980)x4	Pathogenic
146786	GRCh38/hg38 8p23.3-21.2(chr8:241605-24656971)x3	Pathogenic
148741	GRCh38/hg38 8p23.3-11.23(chr8:226452-38021728)x3	Pathogenic
150733	GRCh38/hg38 8p23.1-11.23(chr8:11851113-37216333)x3	Pathogenic
150985	GRCh38/hg38 8p23.1-11.22(chr8:12729023-39235934)x3	Pathogenic
151133	GRCh38/hg38 8p23.1-11.22(chr8:7141697-38695546)x3	Pathogenic
1707427	GRCh37/hg19 8p23.3-12(chr8:158048-30187456)x1	Pathogenic
219026	GRCh37/hg19 8p21.3-12(chr8:20478546-28986438)x3	Pathogenic
253392	GRCh37/hg19 8p23.1-21.2(chr8:12580132-26774307)x3	Pathogenic
2579268	GRCh38/hg38 8p23.1-12(chr8:12721809-30183737)x1	Pathogenic
2684526	GRCh37/hg19 8p23.1-11.23(chr8:11945856-37902453)x3	Pathogenic
2684528	GRCh37/hg19 8p23.1-11.22(chr8:12560782-38748763)x3	Pathogenic
3063019	GRCh37/hg19 8p21.2-12(chr8:23754939-30219110)x1	Pathogenic
32400	GRCh38/hg38 8p23.3-21.1(chr8:2475295-27504279)x1	Pathogenic
3391900	GRCh37/hg19 8p23.3-21.2(chr8:158049-24812752)x1	Pathogenic
395720	GRCh37/hg19 8p22-21.2(chr8:13091530-24483615)	Pathogenic
4279133	GRCh37/hg19 8p23.2-21.2(chr8:6194677-25015979)x1	Pathogenic
442982	GRCh37/hg19 8p23.1-12(chr8:12528482-33684786)x3	Pathogenic
443715	GRCh37/hg19 8p23.1-12(chr8:11945855-34875355)x3	Pathogenic
4682718	GRCh37/hg19 8p23.3-21.2(chr8:158049-26626500)x1	Pathogenic
563552	GRCh37/hg19 8p23.1-21.2(chr8:8770948-27079636)x3	Pathogenic
563553	GRCh37/hg19 8p23.3-21.2(chr8:1825200-24533193)x3	Pathogenic
563554	GRCh37/hg19 8p23.1-12(chr8:12552775-35935825)x3	Pathogenic
59163	GRCh38/hg38 2q33.3(chr2:206391900-207078994)x3	Pathogenic
59735	GRCh38/hg38 8p23.3-12(chr8:96310-30614703)x3	Pathogenic
59763	GRCh38/hg38 8p23.1-11.23(chr8:12609975-37892000)x3	Pathogenic
59767	GRCh38/hg38 8p23.1-12(chr8:12750796-29445409)x3	Pathogenic
686366	GRCh37/hg19 8p21.3-21.2(chr8:22442548-27369334)x1	Pathogenic
686595	GRCh37/hg19 8p21.2(chr8:23501519-24907990)x1	Pathogenic
688470	GRCh37/hg19 8p21.3-21.2(chr8:21662847-24199218)x1	Pathogenic

SpliceAI

4183 predictions. Top by Δscore:

Variant	Effect	Δscore
8:24321216:A:AG	acceptor_gain	1.0000
8:24321217:G:GG	acceptor_gain	1.0000
8:24323832:A:AG	acceptor_gain	1.0000
8:24323833:G:GG	acceptor_gain	1.0000
8:24323833:GCTTT:G	acceptor_gain	1.0000
8:24323996:T:G	donor_gain	1.0000
8:24326550:GCAG:G	acceptor_loss	1.0000
8:24326552:A:AG	acceptor_gain	1.0000
8:24326552:A:G	acceptor_loss	1.0000
8:24326553:G:GG	acceptor_gain	1.0000
8:24326553:GA:G	acceptor_gain	1.0000
8:24326631:TTCAG:T	donor_loss	1.0000
8:24326632:TCAG:T	donor_loss	1.0000
8:24326633:CAGGT:C	donor_loss	1.0000
8:24326634:AGGTC:A	donor_loss	1.0000
8:24326635:GGTC:G	donor_loss	1.0000
8:24326637:T:G	donor_loss	1.0000
8:24329976:T:G	acceptor_gain	1.0000
8:24329977:A:AG	acceptor_gain	1.0000
8:24330112:TGAGG:T	donor_loss	1.0000
8:24330113:GAGGT:G	donor_loss	1.0000
8:24330114:AGG:A	donor_loss	1.0000
8:24330115:GGTG:G	donor_loss	1.0000
8:24330116:GTG:G	donor_loss	1.0000
8:24330117:T:A	donor_loss	1.0000
8:24332659:GGAAT:G	acceptor_gain	1.0000
8:24332745:GCCAA:G	donor_gain	1.0000
8:24332750:G:GG	donor_gain	1.0000
8:24339447:T:A	acceptor_gain	1.0000
8:24341596:A:AG	acceptor_gain	1.0000

AlphaMissense

5212 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
8:24330093:T:A	C361S	0.997
8:24330093:T:C	C361R	0.997
8:24330094:G:C	C361S	0.997
8:24330095:T:G	C361W	0.997
8:24331170:T:G	F375C	0.997
8:24330094:G:A	C361Y	0.996
8:24330101:G:A	M363I	0.996
8:24330101:G:C	M363I	0.996
8:24330101:G:T	M363I	0.996
8:24331169:T:C	F375L	0.996
8:24331171:C:A	F375L	0.996
8:24331171:C:G	F375L	0.996
8:24331172:A:C	S376R	0.996
8:24331174:T:A	S376R	0.996
8:24331174:T:G	S376R	0.996
8:24330078:T:A	C356S	0.995
8:24330078:T:C	C356R	0.995
8:24330079:G:C	C356S	0.995
8:24323882:T:A	W257R	0.994
8:24323882:T:C	W257R	0.994
8:24330024:G:C	A338P	0.994
8:24331181:A:C	S379R	0.994
8:24331183:C:A	S379R	0.994
8:24331183:C:G	S379R	0.994
8:24323884:G:C	W257C	0.993
8:24323884:G:T	W257C	0.993
8:24330094:G:T	C361F	0.993
8:24331170:T:C	F375S	0.993
8:24330027:C:G	H339D	0.992
8:24330080:T:G	C356W	0.992

dbSNP variants (sampled 300 via entrez): RS1000042342 (8:24338556 A>T), RS1000057438 (8:24322726 C>T), RS1000112655 (8:24331441 G>A,T), RS1000122396 (8:24293198 T>C), RS1000185033 (8:24340958 A>G), RS1000263464 (8:24296024 A>G), RS1000278795 (8:24295080 A>T), RS1000332137 (8:24294596 A>C,G), RS1000379929 (8:24296283 G>A,T), RS1000399394 (8:24329063 A>G,T), RS1000519020 (8:24339778 A>G), RS1000536153 (8:24322450 A>T), RS1000585886 (8:24333544 T>C), RS1000657259 (8:24334984 G>A,C), RS1000659540 (8:24340043 T>C)

Disease associations

OMIM: gene MIM:606188 | disease phenotypes:

GenCC curated gene-disease

Mondo (1): microcephaly (MONDO:0001149)

Orphanet (0):

HPO phenotypes

1 total (1 of 1 shown, HPO-id order):

HPO	Term
HP:0000252	Microcephaly

GWAS associations

23 associations (top):

Study	Trait	p-value
GCST000817_164	Height	2.000000e-09
GCST001567_11	Bipolar disorder and schizophrenia	9.000000e-06
GCST002783_252	Body mass index	4.000000e-07
GCST002783_431	Body mass index	2.000000e-07
GCST003177_16	Childhood body mass index	3.000000e-08
GCST003478_5	Hair greying	4.000000e-06
GCST003995_26	Tonsillectomy	5.000000e-09
GCST004904_254	Body mass index	6.000000e-09
GCST005014_90	Tonsillectomy	5.000000e-09
GCST005984_33	Glomerular filtration rate	1.000000e-12
GCST005985_51	Creatinine levels	9.000000e-12
GCST005986_11	Blood urea nitrogen levels	4.000000e-09
GCST006585_2051	Blood protein levels	2.000000e-40
GCST007733_14	Serum uric acid levels	3.000000e-08
GCST007844_4	Ankylosing spondylitis	8.000000e-08
GCST007876_129	Estimated glomerular filtration rate	3.000000e-34
GCST008154_77	Trunk fat mass	7.000000e-06
GCST008155_11	Waist-hip ratio	7.000000e-06
GCST008478_10	Neurological blood protein biomarker levels	2.000000e-14
GCST008478_9	Neurological blood protein biomarker levels	3.000000e-17
GCST010142_77	Fish- and plant-related diet	2.000000e-08
GCST012226_754	Waist circumference adjusted for body mass index	6.000000e-13
GCST90020029_838	Waist circumference adjusted for body mass index	3.000000e-12

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0004340	body mass index
EFO:0007924	tonsillectomy risk measurement
EFO:0004761	uric acid measurement
EFO:0004343	waist-hip ratio
EFO:0008111	diet measurement
EFO:0007789	BMI-adjusted waist circumference

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — M12: Astacin/Adamalysin

CTD chemical–gene interactions

40 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases methylation, increases expression	6
Benzo(a)pyrene	affects expression, affects methylation, increases expression	3
Panobinostat	affects cotreatment, increases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Aflatoxin B1	decreases methylation, increases methylation	2
p-Chloromercuribenzoic Acid	affects cotreatment, increases expression	2
trichostatin A	increases expression	1
perfluorooctanoic acid	increases expression	1
benzo(e)pyrene	increases methylation	1
mercuric bromide	increases expression, affects cotreatment	1
CGP 52608	affects binding, increases reaction	1
2-palmitoylglycerol	increases expression	1
entinostat	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, increases expression	1
bisphenol S	decreases methylation	1
Zoledronic Acid	increases expression	1
Acetaminophen	increases expression	1
Air Pollutants	increases abundance, increases expression	1
Calcitriol	decreases expression	1
Carbamazepine	affects expression	1
Succimer	affects cotreatment, increases expression	1
Estradiol	affects cotreatment, decreases expression	1
Gold	increases expression	1
Methapyrilene	increases methylation	1
N-Nitrosopyrrolidine	increases expression	1
Oxygen	increases expression	1
Phthalic Acids	decreases methylation	1
Progesterone	affects cotreatment, decreases expression	1

Clinical trials (associated diseases)

17 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT05518188	PHASE1/PHASE2	RECRUITING	Melpida: Recombinant Adeno-associated Virus (serotype 9) Encoding a Codon Optimized Human AP4M1 Transgene (hAP4M1opt)
NCT00001639	Not specified	COMPLETED	Evaluation of Patients With Unresolved Chromosome Abnormalities
NCT01151462	Not specified	WITHDRAWN	Postnatal HCMV Infection in Very Preterm Infants. Implications, Morbidity, Growth and Neurodevelopmental Outcomes.
NCT01565005	Not specified	COMPLETED	Microcephaly Genetic Deficiency in Neural Progenitors
NCT02510170	Not specified	COMPLETED	Fetal and Maternal Head Circumference During Pregnancy in Israeli Population
NCT02741882	Not specified	COMPLETED	Zika and Microcephaly: Case-control Study
NCT02943304	Not specified	COMPLETED	Neurodevelopment Outcome of Newborns Exposed to Zika Virus (ZIKV) in Utero
NCT03255369	Not specified	UNKNOWN	Vertical Exposure to Zika Virus and Its Consequences for Child Neurodevelopment (ZIKVIRUSIFF)
NCT03325946	Not specified	RECRUITING	The FBRI VTC Neuromotor Research Clinic
NCT03330600	Not specified	COMPLETED	Efficacy of Aquatic Physiotherapy in Children With Microcephaly by Zika Virus Congenital Syndrome
NCT03548779	Not specified	COMPLETED	North Carolina Genomic Evaluation by Next-generation Exome Sequencing, 2
NCT03651687	Not specified	COMPLETED	Guangzhou Surveillance and Clinical Study in Microcephaly (GSCSM)
NCT03922594	Not specified	TERMINATED	Surveillance of Zika-related Microcephaly in Sub-Saharan Africa and Asia
NCT04816175	Not specified	COMPLETED	Intensive Therapy for Children With Microcephaly, Hyperkinetic Movements, or Global Developmental Delay
NCT05322980	Not specified	COMPLETED	Summary of Infants Weighing 500 Grams or Less
NCT06019182	Not specified	RECRUITING	MEHMO Natural History and Biomarkers
NCT06566066	Not specified	RECRUITING	Register for Patients With Thyroid Hormone Resistance.