SPOCK1

Summary

SPOCK1 (SPARC (osteonectin), cwcv and kazal like domains proteoglycan 1, HGNC:11251) is a protein-coding gene on chromosome 5q31.2, encoding Testican-1 (Q08629). May play a role in cell-cell and cell-matrix interactions.

This gene encodes the protein core of a seminal plasma proteoglycan containing chondroitin- and heparan-sulfate chains. The protein’s function is unknown, although similarity to thyropin-type cysteine protease-inhibitors suggests its function may be related to protease inhibition.

Source: NCBI Gene 6695 — RefSeq curated summary.

At a glance

• GWAS associations: 9
• Clinical variants (ClinVar): 72 total
• Phenotypes (HPO): 1
• MANE Select transcript: NM_004598

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11251
Approved symbol	SPOCK1
Name	SPARC (osteonectin), cwcv and kazal like domains proteoglycan 1
Location	5q31.2
Locus type	gene with protein product
Status	Approved
Aliases	testican-1
Ensembl gene	ENSG00000152377
Ensembl biotype	protein_coding
OMIM	602264
Entrez	6695

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 6 protein_coding_CDS_not_defined, 3 protein_coding, 1 retained_intron

ENST00000394945, ENST00000503916, ENST00000505690, ENST00000508642, ENST00000509293, ENST00000509978, ENST00000510405, ENST00000510689, ENST00000515091, ENST00000635347

RefSeq mRNA: 1 — MANE Select: NM_004598 NM_004598

CCDS: CCDS4191

Canonical transcript exons

ENST00000394945 — 11 exons

Exon	Start	End
ENSE00001004926	137067715	137067829
ENSE00001520079	136975298	136978844
ENSE00001520082	137499179	137499326
ENSE00003467026	136988422	136988643
ENSE00003533637	136985140	136985202
ENSE00003548873	137140580	137140694
ENSE00003594531	137267010	137267055
ENSE00003608323	136992484	136992600
ENSE00003612709	137498373	137498558
ENSE00003615496	137112435	137112561
ENSE00003645231	136979332	136979469

Expression profiles

Bgee: expression breadth ubiquitous, 273 present calls, max score 99.48.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 60.7450 / max 1076.1930, expressed in 1319 samples.

FANTOM5 promoters (12 alternative TSS)

Promoter ID	TPM avg	Samples expressed
63633	59.6610	1316
63631	0.3872	182
63632	0.2802	166
63614	0.1514	9
63611	0.0952	29
63622	0.0439	20
63625	0.0354	7
63615	0.0259	3
63613	0.0253	3
63616	0.0176	4

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
stromal cell of endometrium	CL:0002255	99.48	gold quality
lateral nuclear group of thalamus	UBERON:0002736	99.16	gold quality
decidua	UBERON:0002450	98.91	gold quality
postcentral gyrus	UBERON:0002581	98.69	gold quality
Brodmann (1909) area 46	UBERON:0006483	98.57	gold quality
orbitofrontal cortex	UBERON:0004167	98.42	gold quality
parietal lobe	UBERON:0001872	98.33	gold quality
cerebellar cortex	UBERON:0002129	98.27	gold quality
cerebellar hemisphere	UBERON:0002245	98.26	gold quality
cerebellum	UBERON:0002037	98.13	gold quality
superior frontal gyrus	UBERON:0002661	97.84	gold quality
right hemisphere of cerebellum	UBERON:0014890	97.64	gold quality
entorhinal cortex	UBERON:0002728	97.59	gold quality
inferior olivary complex	UBERON:0002127	97.38	gold quality
pons	UBERON:0000988	97.32	gold quality
Brodmann (1909) area 9	UBERON:0013540	97.25	gold quality
CA1 field of hippocampus	UBERON:0003881	97.22	gold quality
renal glomerulus	UBERON:0000074	97.17	gold quality
metanephric glomerulus	UBERON:0004736	97.15	gold quality
dorsal plus ventral thalamus	UBERON:0001897	97.11	gold quality
cardiac muscle of right atrium	UBERON:0003379	97.09	gold quality
Brodmann (1909) area 23	UBERON:0013554	96.91	gold quality
Ammon’s horn	UBERON:0001954	96.89	gold quality
prefrontal cortex	UBERON:0000451	96.88	gold quality
cortical plate	UBERON:0005343	96.75	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	96.73	gold quality
corpus callosum	UBERON:0002336	96.58	gold quality
middle temporal gyrus	UBERON:0002771	96.36	gold quality
adult organism	UBERON:0007023	96.36	gold quality
occipital lobe	UBERON:0002021	96.30	gold quality

Single-cell (SCXA)

Detected in 11 experiment(s), a significant marker in 10.

Experiment	Marker?	Max mean expression
E-GEOD-84465	yes	1389.39
E-MTAB-6678	yes	826.20
E-GEOD-137537	yes	624.86
E-ENAD-27	yes	144.25
E-CURD-119	yes	29.65
E-MTAB-10287	yes	15.87
E-CURD-114	yes	11.94
E-GEOD-81608	yes	8.31
E-HCAD-10	yes	3.84
E-CURD-11	no	57.10
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): E2F1, MAFB, PRDM1, RUNX2

miRNA regulators (miRDB)

227 targeting SPOCK1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-12118	100.00	65.88	1270
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-6758-5P	100.00	66.21	1470
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-3162-3P	100.00	65.37	363
HSA-MIR-4481	100.00	66.42	1669
HSA-MIR-6748-5P	100.00	65.81	1057
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-6798-5P	100.00	65.77	699
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-6759-5P	99.99	66.54	785
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-511-3P	99.99	68.85	1467
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-19A-3P	99.98	75.33	2762

Literature-anchored findings (GeneRIF, showing 40)

• Significant overexpression of osteonectin mRNA is associated with pancreatic cancer (PMID:16596217)
• SPOCK gene underlies variation of age at menarche (PMID:19282985)
• In the present study, we showed that SPOCK1 could inhibit apoptosis and promote cancer invasion. (PMID:23022495)
• Testican-1-induced EMT signaling. (PMID:23873022)
• this study showed that SPOCK1 is a novel metastasis related biomarker in lung cancer and may be new diagnostic and therapeutic target for lung cancer. (PMID:24134845)
• SPOCK1 activates PI3K/Akt signaling. (PMID:25623055)
• These results suggest that up-regulation of SPOCK1 in ESCC induces EMT, thus promotes migration and invasion in ESCC cells. (PMID:26077618)
• Collectively, altered expression of PKP1 and SPOCK1 appears to be a frequent and critical event in prostate cancer (PMID:26138584)
• SPOCK1 is highly expressed in ovarian cancer.SPOCK1 contributes to ovarian cancer development and metastasis. (PMID:26638890)
• This study suggests that SPOCK1 promotes proliferation, migration and invasion in glioma cells by activating PI3K/AKT and Wnt/beta-catenin pathways, which provides a potential theoretical basis for clinical treatment of glioma. (PMID:27108836)
• findings suggest that SPOCK1 is a critical mediator of tumor growth and metastasis in prostate cancer (PMID:27486308)
• a novel TGF-beta-induced myoepithelial marker and enhanced invasion in breast cancer cells and correlated with poor prognosis (PMID:27626636)
• SPOCK1 expression is significantly up-regulated in colorectal cancer tissues and associated with tumor size and stage. SPOCK1 stimulates the PI3K/AKT signaling pathway to inhibit cell apoptosis and promote tumor growth. (PMID:27889608)
• Transcriptomic analysis of EPCR-silenced tumors unveiled an effect mediated by matricellular SPOCK1/testican 1. SPOCK1 silencing suppressed in vitro 3D growth. SPOCK1 ablation decreased orthotopic tumor growth and reduced metastatic osteolytic tumors. High SPOCK1 levels were also associated with poor clinical outcome in a subset of breast cancer patients. (PMID:28103946)
• Knockdown of SPOCK1 inhibits the proliferation. (PMID:28281964)
• Functional assessment in cocultures demonstrated that SPOCK1 strongly affects the composition of the extracellular collagen matrix and by doing so, enables invasive tumor cell growth in Pancreatic ductal adenocarcinoma. (PMID:28486750)
• High SPOCK1 expression is associated with castration-resistant prostate cancer. (PMID:28534948)
• Our results suggested that microRNA-129-5p could directly specifically suppress SPOCK1, which might be one of the potential mechanisms in inhibiting cell processes including viability, proliferation, cell mitosis, migration, and invasiveness of gastric cancer cells. (PMID:28653880)
• downregulation of both strands of pre-miR-150 and overexpression of SPOCK1 are involved in esophageal squamous cell carcinoma (ESCC). pathogenesis. The involvement of passenger strand miRNAs in the regulation of cancer cell aggressiveness is a novel concept in RNA research (PMID:28659612)
• is significantly upregulated in osteosarcoma tissue. (PMID:28869894)
• The elevated SPOCK1 expression is closely correlated with cancer metastasis and patient survival, and SPOCK1 promotes the invasion and metastasis of gastric cancer through Slug-mediated epithelial-mesenchymal transition. (PMID:28940639)
• Overexpression of SPOCK1was confirmed in head and neck squamous cell carcinoma clinical specimens. Overexpression of SPOCK1 contributes to the aggressive nature of HNSCC. (PMID:29233721)
• Testican-1 blood level is related to the severity of sepsis and Testican-1 could be used as a biomarker to determine the severity of sepsis. (PMID:29315764)
• expression of SPOCK1 served as a tumor promoter, possibly through the Wnt/beta-catenin signaling pathway in NSCLC; targeting SPOCK1 could be a potential therapeutic strategy in NSCLC (PMID:29461591)
• SPOCK1 overexpression promoted proliferation and invasion, and restrained apoptosis of hepatocellular carcinoma (HCC) cells. MiR-139-5p, miR-940 and miR-193a-5p inhibited HCC development through targeting SPOCK1. (PMID:30710422)
• SPOCK1 contributes to the third-generation EGFR tyrosine kinase inhibitors resistance in lung cancer. (PMID:30825234)
• A potential prognostic marker and therapeutic target: SPOCK1 promotes the proliferation, metastasis, and apoptosis of pancreatic ductal adenocarcinoma cells. (PMID:31478239)
• SPOCK1 is a novel inducer of epithelial to mesenchymal transition in drug-induced gingival overgrowth. (PMID:32555336)
• SPOCK1 induces adipose tissue maturation: New insights into the function of SPOCK1 in metabolism. (PMID:33012508)
• Knockdown of Long Noncoding RNA Urothelial Carcinoma-Associated 1 Represses Gallbladder Cancer Advancement by Regulating SPOCK1 Expression Through Sponging miR-613. (PMID:33090888)
• SPOCK1/SIX1axis promotes breast cancer progression by activating AKT/mTOR signaling. (PMID:33293473)
• The Central Region of Testican-2 Forms a Compact Core and Promotes Cell Migration. (PMID:33321927)
• Long non-coding RNA TTN antisense RNA 1 facilitates hepatocellular carcinoma progression via regulating miR-139-5p/SPOCK1 axis. (PMID:33517826)
• SPOCK1 promotes the proliferation and migration of colon cancer cells by regulating the NF-kappaB pathway and inducing EMT. (PMID:33884883)
• Multiomic analysis of the function of SPOCK1 across cancers: an integrated bioinformatics approach. (PMID:34156309)
• SPOCK1 promotes metastasis in pancreatic cancer via NF-kappaB-dependent epithelial-mesenchymal transition by interacting with IkappaB-alpha. (PMID:34855159)
• Expression and Potential Prognostic Value of SOX9, MCL-1 and SPOCK1 in Gastric Adenocarcinoma. (PMID:35221802)
• SPOCK1 silencing decreases 5-FU resistance through PRRX1 in colorectal cancer. (PMID:35462225)
• SPOCK1 and POSTN are valuable prognostic biomarkers and correlate with tumor immune infiltrates in colorectal cancer. (PMID:36611136)
• Proteoglycan SPOCK1 as a Poor Prognostic Marker Promotes Malignant Progression of Clear Cell Renal Cell Carcinoma via Triggering the Snail/Slug-MMP-2 Axis-Mediated Epithelial-to-Mesenchymal Transition. (PMID:36766694)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	spock1	ENSDARG00000074644
mus_musculus	Spock1	ENSMUSG00000056222
rattus_norvegicus	Spock1	ENSRNOG00000012747
drosophila_melanogaster	Cow	FBGN0039054
caenorhabditis_elegans		WBGENE00016918

Paralogs (3): SPOCK2 (ENSG00000107742), SPOCK3 (ENSG00000196104), KIAA1210 (ENSG00000250423)

Protein

Protein identifiers

Testican-1 — Q08629 (reviewed: Q08629)

Alternative names: Protein SPOCK

All UniProt accessions (3): Q08629, D6RAM7, D6RB21

UniProt curated annotations — full annotation on UniProt →

Function. May play a role in cell-cell and cell-matrix interactions. May contribute to various neuronal mechanisms in the central nervous system.

Subcellular location. Secreted. Extracellular space. Extracellular matrix.

Post-translational modifications. O-glycosylated. Glycosaminoglycan that contains chondroitin sulfate and heparan sulfate.

RefSeq proteins (1): NP_004589* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000716	Thyroglobulin_1	Domain
IPR002350	Kazal_dom	Domain
IPR011992	EF-hand-dom_pair	Homologous_superfamily
IPR019577	SPARC/Testican_Ca-bd-dom	Domain
IPR036058	Kazal_dom_sf	Homologous_superfamily
IPR036857	Thyroglobulin_1_sf	Homologous_superfamily

Pfam: PF00086, PF07648, PF10591

UniProt features (19 total): disulfide bond 8, glycosylation site 3, sequence conflict 2, domain 2, signal peptide 1, chain 1, region of interest 1, compositionally biased region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q08629-F1	63.80	0.02

Functional residue map

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

Disulfide bonds (8): 91–107, 136–166, 139–159, 148–180, 313–337, 348–355, 357–376, 86–97

Glycosylation sites (3): 228, 383, 388

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 259 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_BRAIN_TUMORAL_MACROPHAGE_UP, GSE18804_SPLEEN_MACROPHAGE_VS_TUMORAL_MACROPHAGE_UP, MODULE_52, BERTUCCI_MEDULLARY_VS_DUCTAL_BREAST_CANCER_DN, BROWNE_HCMV_INFECTION_8HR_UP, KAAB_HEART_ATRIUM_VS_VENTRICLE_UP, AAGCCAT_MIR135A_MIR135B, ASTON_MAJOR_DEPRESSIVE_DISORDER_DN, GOBP_GROWTH, LINDGREN_BLADDER_CANCER_CLUSTER_3_DN, GOBP_NEUROGENESIS, COLIN_PILOCYTIC_ASTROCYTOMA_VS_GLIOBLASTOMA_UP, BRUECKNER_TARGETS_OF_MIRLET7A3_DN, GOBP_NEGATIVE_REGULATION_OF_CELLULAR_COMPONENT_ORGANIZATION, GOBP_NEGATIVE_REGULATION_OF_CELL_SUBSTRATE_ADHESION

GO Biological Process (8): regulation of cell growth (GO:0001558), neuron migration (GO:0001764), cell adhesion (GO:0007155), nervous system development (GO:0007399), negative regulation of cell-substrate adhesion (GO:0010812), negative regulation of neuron projection development (GO:0010977), central nervous system neuron differentiation (GO:0021953), neurogenesis (GO:0022008)

GO Molecular Function (8): serine-type endopeptidase inhibitor activity (GO:0004867), cysteine-type endopeptidase inhibitor activity (GO:0004869), extracellular matrix structural constituent (GO:0005201), calcium ion binding (GO:0005509), collagen binding (GO:0005518), metalloendopeptidase inhibitor activity (GO:0008191), extracellular matrix binding (GO:0050840), protein binding (GO:0005515)

GO Cellular Component (8): obsolete extracellular space (GO:0005615), cytoplasm (GO:0005737), postsynaptic density (GO:0014069), sarcoplasm (GO:0016528), extracellular matrix (GO:0031012), neuromuscular junction (GO:0031594), node of Ranvier (GO:0033268), extracellular region (GO:0005576)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
endopeptidase inhibitor activity	3
cellular anatomical structure	3
binding	2
cell growth	1
regulation of growth	1
regulation of cellular component organization	1
cell migration	1
generation of neurons	1
cellular process	1
system development	1
negative regulation of cell adhesion	1
regulation of cell-substrate adhesion	1
cell-substrate adhesion	1
regulation of neuron projection development	1
neuron projection development	1
negative regulation of cell projection organization	1
central nervous system development	1
neuron differentiation	1
nervous system development	1
cell differentiation	1
serine-type endopeptidase activity	1
cysteine-type endopeptidase activity	1
structural molecule activity	1
extracellular matrix	1
metal ion binding	1
protein-containing complex binding	1
metalloendopeptidase activity	1
intracellular anatomical structure	1
asymmetric synapse	1
postsynaptic specialization	1
cytoplasm	1
external encapsulating structure	1
synapse	1
main axon	1

Protein interactions and networks

STRING

1238 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SPOCK1	SPARC	P09486	851
SPOCK1	MMP16	P51512	797
SPOCK1	FST	P19883	770
SPOCK1	TG	P01266	724
SPOCK1	MMP14	P50281	614
SPOCK1	MMP2	P08253	501
SPOCK1	SMOC1	Q9H4F8	500
SPOCK1	CHD1L	Q86WJ1	496
SPOCK1	EGR1	P18146	492
SPOCK1	MMP1	P03956	481
SPOCK1	ARHGEF9	O43307	466
SPOCK1	SPARCL1	Q14515	448
SPOCK1	PDGFRA	P16234	439
SPOCK1	PLAUR	Q03405	435
SPOCK1	IL9	P15248	430

IntAct

10 interactions, top by confidence:

A	B	Type	Score
SPOCK1	BCL2L13	psi-mi:“MI:0915”(physical association)	0.560
SPOCK1	CREB3L1	psi-mi:“MI:0915”(physical association)	0.560
Gtf2e2	CASC3	psi-mi:“MI:0914”(association)	0.350
Gpr158	AGRN	psi-mi:“MI:0914”(association)	0.350
SPOCK1	BCL2L13	psi-mi:“MI:0915”(physical association)	0.000
SPOCK1	CREB3L1	psi-mi:“MI:0915”(physical association)	0.000
TNF	SPOCK1	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (11): SPOCK1 (Affinity Capture-MS), SPOCK1 (Affinity Capture-MS), SPOCK1 (Two-hybrid), CREB3L1 (Two-hybrid), SPOCK1 (Affinity Capture-MS), SPOCK1 (Proximity Label-MS), SPOCK1 (Reconstituted Complex), SPOCK1 (Cross-Linking-MS (XL-MS)), SPOCK1 (Affinity Capture-MS), SPOCK1 (Affinity Capture-MS), SPOCK1 (Affinity Capture-RNA)

ESM2 similar proteins: A0A0F7YYX3, A0A0K8R726, A0A0K8RK34, A0A1L4BJ46, A0A5C1ZW08, A0A5C1ZXT8, A0A5C2A2T2, B5DEL3, B6DCK1, B6DCK9, B6DCL6, C0HKG1, C5DVG0, E2AX35, E9PVB5, G1CWH5, O70514, O76061, O88452, O97561, P0C8E8, P0C8L9, P0DN48, P17322, P18301, P42579, P52823, P58239, P58911, P85831, P86899, Q08629, Q14512, Q4R6V5, Q5RAT2, Q5Y4U3, Q62288, Q802A9, Q8BJ83, Q8GV50

Diamond homologs: A0A1D0C023, B3F211, B5DFC9, P04233, P04441, P10247, P10493, P31226, P81439, P84032, Q08629, Q14112, Q62288, Q8BKV0, Q8BLY1, Q8CD91, Q92563, Q9ER58, Q9H3U7, Q9H4F8, A0A1D5PUP4, A0JP86, A2ASQ1, A3KN33, A5YT95, E9Q7X7, G4V4G1, G5ECE3, O00468, O00634, O09118, O15230, O62650, O75094, O75445, O88280, O94813, O95631, O95633, O95980

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	53
Likely benign	6
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

5465 predictions. Top by Δscore:

Variant	Effect	Δscore
5:136988416:CCTTA:C	donor_loss	1.0000
5:136988417:CTTA:C	donor_loss	1.0000
5:136988419:TA:T	donor_loss	1.0000
5:136988420:ACCT:A	donor_gain	1.0000
5:136988421:CCT:C	donor_gain	1.0000
5:136988421:CCTC:C	donor_gain	1.0000
5:136988423:T:TA	donor_gain	1.0000
5:136988472:T:TA	donor_gain	1.0000
5:136988640:AACC:A	acceptor_gain	1.0000
5:136988641:ACC:A	acceptor_gain	1.0000
5:136988642:CC:C	acceptor_gain	1.0000
5:136988642:CCC:C	acceptor_gain	1.0000
5:136988642:CCCT:C	acceptor_loss	1.0000
5:136988643:CC:C	acceptor_gain	1.0000
5:136988644:C:CA	acceptor_loss	1.0000
5:136988644:C:CC	acceptor_gain	1.0000
5:136988645:T:G	acceptor_loss	1.0000
5:136992482:A:AC	donor_gain	1.0000
5:136992482:ACTGC:A	donor_gain	1.0000
5:136992483:C:CC	donor_gain	1.0000
5:136992483:CT:C	donor_gain	1.0000
5:136992483:CTG:C	donor_gain	1.0000
5:136992483:CTGCC:C	donor_gain	1.0000
5:136992597:CAGG:C	acceptor_gain	1.0000
5:136992600:GC:G	acceptor_loss	1.0000
5:136992601:C:CA	acceptor_loss	1.0000
5:136992601:C:CC	acceptor_gain	1.0000
5:137066774:TAA:T	donor_gain	1.0000
5:137066775:AAA:A	donor_gain	1.0000
5:137067714:CCA:C	donor_gain	1.0000

AlphaMissense

2921 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:136979393:C:A	W356C	1.000
5:136979393:C:G	W356C	1.000
5:136979395:A:G	W356R	1.000
5:136979395:A:T	W356R	1.000
5:136979451:C:G	C337S	1.000
5:136979452:A:T	C337S	1.000
5:136988444:G:C	C302W	1.000
5:136988445:C:G	C302S	1.000
5:136988446:A:G	C302R	1.000
5:136988446:A:T	C302S	1.000
5:136988447:C:A	W301C	1.000
5:136988447:C:G	W301C	1.000
5:136988449:A:G	W301R	1.000
5:136988449:A:T	W301R	1.000
5:136988487:C:T	C288Y	1.000
5:136988559:A:G	L264P	1.000
5:136988591:G:C	F253L	1.000
5:136988591:G:T	F253L	1.000
5:136988592:A:C	F253C	1.000
5:136988592:A:G	F253S	1.000
5:136988593:A:G	F253L	1.000
5:136988597:C:A	W251C	1.000
5:136988597:C:G	W251C	1.000
5:136988615:G:C	C245W	1.000
5:136988616:C:G	C245S	1.000
5:136988616:C:T	C245Y	1.000
5:136988617:A:G	C245R	1.000
5:136988617:A:T	C245S	1.000
5:136992561:A:G	L210P	1.000
5:137140607:C:G	C107S	1.000

dbSNP variants (sampled 300 via entrez): RS1000000681 (5:137102412 C>T), RS1000007305 (5:137013439 T>A,C), RS1000008198 (5:137057917 A>C), RS1000008550 (5:137355974 G>A), RS1000022552 (5:137132875 T>C), RS1000031225 (5:137144243 G>C,T), RS1000037521 (5:137042270 A>G), RS1000045420 (5:137399987 AT>A), RS1000055691 (5:137229055 A>G), RS1000055808 (5:137002351 T>C), RS1000059639 (5:137141336 G>C), RS1000063127 (5:137454179 A>G), RS1000066430 (5:137271101 A>T), RS1000070296 (5:137399771 T>A), RS1000072830 (5:137233404 G>A,C)

Disease associations

OMIM: gene MIM:602264 | 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

9 associations (top):

Study	Trait	p-value
GCST002104_20	Bronchopulmonary dysplasia	9.000000e-06
GCST002818_1	HIV-1 susceptibility	3.000000e-06
GCST003262_296	Post bronchodilator FEV1	9.000000e-07
GCST003264_1095	Post bronchodilator FEV1/FVC ratio	4.000000e-06
GCST004123_1	Mathematical ability	6.000000e-10
GCST006295_13	Response to quetiapine in schizophrenia	7.000000e-06
GCST008152_79	Weight	2.000000e-06
GCST008158_102	Body mass index	2.000000e-06
GCST009391_1125	Metabolite levels	5.000000e-06

EFO canonical traits (7, from GWAS)

EFO ID	Trait name
EFO:0000180	HIV-1 infection
EFO:0004314	forced expiratory volume
EFO:0004713	FEV/FVC ratio
EFO:0004875	mathematical ability
EFO:0004338	body weight
EFO:0004340	body mass index
EFO:0010523	phosphoglyceric acid measurement

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)

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases methylation, affects cotreatment, increases expression, affects expression, decreases expression	8
sodium arsenite	increases expression, affects methylation, decreases expression, increases abundance	4
Estradiol	affects cotreatment, decreases expression, increases expression	3
bisphenol A	increases expression, affects cotreatment	2
cobaltous chloride	increases expression, decreases reaction, decreases expression	2
Air Pollutants	decreases expression, increases abundance	2
Benzo(a)pyrene	affects methylation, increases methylation	2
Cisplatin	affects cotreatment, decreases expression, increases reaction	2
Smoke	decreases expression, increases abundance, increases expression	2
Tetrachlorodibenzodioxin	affects cotreatment, decreases expression, affects expression	2
Cadmium Chloride	increases expression	2
aristolochic acid I	decreases expression	1
TAK-243	increases sumoylation	1
trichostatin A	increases expression	1
zinc chloride	decreases reaction, increases expression	1
ochratoxin A	increases acetylation, increases expression	1
benzo(e)pyrene	increases methylation	1
aflatoxin B2	increases methylation	1
nickel sulfate	increases expression	1
beta-methylcholine	affects expression	1
perfluorooctane sulfonic acid	increases expression	1
chloropicrin	decreases expression	1
entinostat	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	increases expression, affects cotreatment	1
2,2’,4,4’,5-brominated diphenyl ether	increases expression	1
abrine	increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
enzalutamide	decreases expression	1
bisphenol S	decreases methylation	1
jinfukang	decreases expression, increases reaction	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.