ASPM

Summary

ASPM (assembly factor for spindle microtubules, HGNC:19048) is a protein-coding gene on chromosome 1q31.3, encoding Abnormal spindle-like microcephaly-associated protein (Q8IZT6). Involved in mitotic spindle regulation and coordination of mitotic processes. It is a selective cancer dependency (DepMap: 21.4% of cell lines).

This gene is the human ortholog of the Drosophila melanogaster ‘abnormal spindle’ gene (asp), which is essential for normal mitotic spindle function in embryonic neuroblasts. Studies in mouse also suggest a role of this gene in mitotic spindle regulation, with a preferential role in regulating neurogenesis. Mutations in this gene are associated with microcephaly primary type 5. Multiple transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 259266 — RefSeq curated summary.

At a glance

• Gene–disease (curated): autosomal recessive primary microcephaly (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 4
• Clinical variants (ClinVar): 2,226 total — 263 pathogenic, 67 likely-pathogenic
• Phenotypes (HPO): 44
• Cancer dependency (DepMap): dependent in 21.4% of screened cell lines
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_018136

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:19048
Approved symbol	ASPM
Name	assembly factor for spindle microtubules
Location	1q31.3
Locus type	gene with protein product
Status	Approved
Aliases	Calmbp1, ASP, FLJ10517, FLJ10549
Ensembl gene	ENSG00000066279
Ensembl biotype	protein_coding
OMIM	605481
Entrez	259266

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 5 protein_coding, 3 retained_intron, 1 nonsense_mediated_decay

ENST00000294732, ENST00000367408, ENST00000367409, ENST00000679766, ENST00000680112, ENST00000680265, ENST00000680710, ENST00000681879, ENST00000913989

RefSeq mRNA: 2 — MANE Select: NM_018136 NM_001206846, NM_018136

CCDS: CCDS1389, CCDS55672

Canonical transcript exons

ENST00000367409 — 28 exons

Exon	Start	End
ENSE00000468981	197093052	197093261
ENSE00000791068	197094084	197094180
ENSE00000791069	197091907	197092056
ENSE00000791071	197090196	197090388
ENSE00000791072	197089930	197090084
ENSE00000791073	197088256	197088432
ENSE00000791074	197086803	197086972
ENSE00000999409	197095998	197096164
ENSE00001067760	197122159	197122301
ENSE00001067766	197117789	197117983
ENSE00001067767	197132285	197132352
ENSE00001067770	197121915	197122043
ENSE00001067777	197125046	197125191
ENSE00001067780	197128490	197128665
ENSE00001067783	197129187	197129317
ENSE00001067786	197129915	197130056
ENSE00001277893	197100431	197105185
ENSE00001277906	197139767	197139871
ENSE00001277916	197142331	197143810
ENSE00001277921	197143957	197144100
ENSE00001277977	197122388	197122595
ENSE00001277986	197124110	197124331
ENSE00001277993	197124870	197124955
ENSE00001278060	197090850	197091041
ENSE00001419954	197135096	197135242
ENSE00003588360	197133350	197133595
ENSE00003842522	197146141	197146669
ENSE00003847628	197084127	197084426

Expression profiles

Bgee: expression breadth ubiquitous, 176 present calls, max score 95.77.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 11.5251 / max 235.4156, expressed in 1277 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
16494	10.1487	1239
16495	0.6391	407
16493	0.5360	342
16492	0.1569	55
16491	0.0197	2
16489	0.0127	2
16490	0.0120	2

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
oocyte	CL:0000023	95.77	gold quality
ventricular zone	UBERON:0003053	95.57	gold quality
secondary oocyte	CL:0000655	93.51	gold quality
trabecular bone tissue	UBERON:0002483	93.27	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	91.06	gold quality
buccal mucosa cell	CL:0002336	90.15	silver quality
embryo	UBERON:0000922	89.58	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	89.06	gold quality
ganglionic eminence	UBERON:0004023	88.88	gold quality
bone marrow	UBERON:0002371	85.53	gold quality
oral cavity	UBERON:0000167	83.44	gold quality
thymus	UBERON:0002370	80.90	gold quality
bone marrow cell	CL:0002092	79.12	gold quality
stromal cell of endometrium	CL:0002255	78.39	gold quality
jejunal mucosa	UBERON:0000399	78.25	gold quality
gingival epithelium	UBERON:0001949	77.32	gold quality
mucosa of sigmoid colon	UBERON:0004993	77.08	gold quality
esophagus squamous epithelium	UBERON:0006920	77.06	gold quality
colonic mucosa	UBERON:0000317	76.98	gold quality
adrenal tissue	UBERON:0018303	76.95	gold quality
gingiva	UBERON:0001828	76.47	gold quality
amniotic fluid	UBERON:0000173	76.07	gold quality
cartilage tissue	UBERON:0002418	75.45	gold quality
tongue squamous epithelium	UBERON:0006919	74.56	gold quality
vermiform appendix	UBERON:0001154	73.87	gold quality
germinal epithelium of ovary	UBERON:0001304	73.79	gold quality
lower esophagus mucosa	UBERON:0035834	73.77	gold quality
epithelium of esophagus	UBERON:0001976	73.50	gold quality
squamous epithelium	UBERON:0006914	73.36	gold quality
epithelium of nasopharynx	UBERON:0001951	72.83	gold quality

Single-cell (SCXA)

Detected in 17 experiment(s), a significant marker in 15.

Experiment	Marker?	Max mean expression
E-GEOD-75140	yes	1634.88
E-MTAB-11121	yes	1099.52
E-MTAB-10485	yes	861.73
E-HCAD-56	yes	861.02
E-MTAB-10290	yes	770.20
E-MTAB-8271	yes	522.74
E-MTAB-10018	yes	401.56
E-MTAB-6911	yes	351.72
E-MTAB-8495	yes	263.03
E-MTAB-8530	yes	261.32
E-HCAD-6	yes	253.48
E-MTAB-10855	yes	206.43
E-MTAB-6678	yes	10.37
E-ANND-3	yes	6.76
E-CURD-88	yes	3.99

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

1 targets.

Target	Regulation
BRCA1	Activation

Upstream regulators (CollecTRI, top): BRCA1, FOXJ1, FOXO1, FOXO3

miRNA regulators (miRDB)

9 targeting ASPM, 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-3646	100.00	73.56	5283
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4307	99.82	70.45	3374
HSA-MIR-425-5P	99.59	67.67	900
HSA-MIR-1252-3P	99.55	67.71	2862
HSA-MIR-10522-5P	99.26	68.50	2087
HSA-MIR-3613-5P	98.40	68.91	604
HSA-MIR-382-5P	96.71	65.90	762

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map DepMap (CRISPR cell-line fitness): dependent in 21.4% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• Similar to aspm of Drosophila. Regulates brain size by regulating mitotic spindle activity in neuronal progenitor cells. (PMID:12355089)
• microcephalin and ASPM determine the size of the human brain (PMID:12571366)
• identification of all 19 mutations in a cohort of 23 consanguineous families with autosomal recessive primary microcephaly (PMID:14574646)
• evolutionary selection of specific segments of the ASPM sequence strongly relates to differences in cerebral cortical size (PMID:15045028)
• ASPM mutations is associated with microcephaly (PMID:15355437)
• ASPM is localized in the spindle poles during mitosis. This finding suggests that MCPH is the consequence of an impairment in mitotic spindle regulation in cortical progenitors due to mutations in ASPM. (PMID:15972725)
• ASPM may be involved in mitotic spindle function, possibly, through regulation of BRCA1 (PMID:16123590)
• We thus expand the clinical spectrum of ASPM mutations by showing that they can occur in patients with seizures and that the history of seizures alone should not necessarily preclude the diagnosis of primary microcephaly. (PMID:16141009)
• findings show that one genetic variant of ASPM in humans arose merely about 5800 years ago and has since swept to high frequency under strong positive selection (PMID:16151010)
• The study found no evidence that the selected alleles of MCPH1 and ASPM were associated with increases or decreases in brain volume. (PMID:16687438)
• ASPM inhibition by siRNA-mediated knockdown inhibits tumor cell proliferation and neural stem cell proliferation, supporting ASPM as a potential molecular target in glioblastoma (PMID:17090670)
• Studies using 2393 subjects do not support a detectable association between the recent adaptive evolution of either ASPM or Microcephalin and changes in IQ. (PMID:17220170)
• no relationship was found between polymorphisms of brain regulator gene ASPM and any general mental ability, head circumference and social intelligence (PMID:17251122)
• A GFP-tagged fragment of the N-terminus of ASPM localizes to centrosomes and spindle poles, while a GFP-tagged fragment of the C-terminus localizes to midbodies. (PMID:17534152)
• that phenotypes other than brain size may have been selected for in ASPM and MCPH1 variants during evolution of modern humans. (PMID:17566767)
• The latest ASPM variant arising about 6000 years ago somewhere in the Middle East may be connected with alphabetical writing. (PMID:17604569)
• four novel sequence variants (Y1712X, I1717X, Y3353X, R3244X) were detected and all were predicted to be protein truncating. (PMID:17849285)
• This is the first report suggesting that the suppression of Aspm by IR could be the initial molecular target leading to the future microcephaly formation. (PMID:18331833)
• the neuronal depletion associated with the ASPM defect predominantly affects the anterior cortex (PMID:18452193)
• Increase in ASPM mRNA and protein expression is associated with malignant gliomas (PMID:18636190)
• ASPM has a role in vascular invasion, early recurrence, and poor prognosis of hepatocellular carcinoma (PMID:18676753)
• NS5A protein down-regulates the expression of spindle gene Aspm through PKR-p38 signaling pathway (PMID:18728014)
• Study confirms that mutations in ASPM are the most common cause of MCPH, that ASPM mutations are restricted to individuals with an MCPH phenotype, and that ASPM testing in primary microcephaly is clinically useful. (PMID:19028728)
• Compound heterozygous ASPM mutations associated with microcephaly and simplified cortical gyration in a consanguineous Algerian family are reported. (PMID:19332161)
• in this study of microcephaly families there was found compound heterozygosity in 10% of families with microcephaly caused by ASPM. (PMID:19353628)
• We provide a detailed description of features associated with ASPM mutations. Borderline microcephaly at birth, borderline-normal intellectual efficiency, and brain malformations can occur in ASPM-related primary hereditary microcephaly. (PMID:19770472)
• identified mutations that extended the body of evidence implicating the ASPM gene in the pathogenesis of human hereditary primary microcephaly. (PMID:19808985)
• All medulloblastoma samples overexpressed ASPM gene more than 40-fold (PMID:20694558)
• ASPM splice site mutation results in the expression of a novel variant protein lacking a tripeptide motif, a minimal alteration that correlates with a dramatic decrease in ASPM spindle pole localisation. (PMID:21044324)
• We conclude that the common variations we measured in the 4 microcephaly genes, ASPM, MCPH1, CDK5RAP2, and CENPJ, do not affect the risk of Alzheimer disease (PMID:21297427)
• ASPM interacts with Angelman syndrome protein UBE3A (PMID:21633703)
• Study links Angelman syndrome protein UBE3A to ASPM, centrosome and mitosis. (PMID:21633703)
• Results show for the first time that ASPM is required for efficient non-homologous end-joining in mammalian cells. (PMID:21923303)
• the association between the recently derived allele of ASPM is likely to be specific and is tied to higher level brain functions in the temporal cortex related to human communication. (PMID:22529908)
• Data indicate frameshift and stop mutation leading to truncations (c.3796G > T, p.E1266X and c.7815_7816del, p.E2605fs) in the ASPM gene unexpectedly found on chromosome 1 in apparent X-linked microcephalic intellectual deficit patients. (PMID:22823409)
• Identification of a novel ASPM mutation in a family with primary microcephaly. (PMID:22989186)
• ASPM mutations in primary autosomal recessive microcephaly patients in ethnically diverse patients (PMID:23611254)
• Autosomal recessive inheritance due to consanguinity caused microcephaly with attention deficit disorder and mental retardation. (PMID:23887221)
• ASPM promotes aggressiveness of pancreatic ductal adenocarcinoma (PDAC) by maintaining Wnt-beta-catenin signaling and stem cell features of PDAC cells. (PMID:23896173)
• microcephalin and ASPM expression are deregulated in epithelial ovarian cancer progression (PMID:24830737)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	aspm	ENSDARG00000103754
mus_musculus	Aspm	ENSMUSG00000033952
rattus_norvegicus	Aspm	ENSRNOG00000012318
drosophila_melanogaster	asp	FBGN0000140

Paralogs (7): MICALL1 (ENSG00000100139), EHBP1 (ENSG00000115504), GAS2 (ENSG00000148935), MICALL2 (ENSG00000164877), EHBP1L1 (ENSG00000173442), GAS2L1 (ENSG00000185340), SMTNL1 (ENSG00000214872)

Protein

Protein identifiers

Abnormal spindle-like microcephaly-associated protein — Q8IZT6 (reviewed: Q8IZT6)

Alternative names: Abnormal spindle protein homolog

All UniProt accessions (4): Q8IZT6, A0A7P0T8U9, A0A7P0Z491, A0A7P0Z4R7

UniProt curated annotations — full annotation on UniProt →

Function. Involved in mitotic spindle regulation and coordination of mitotic processes. The function in regulating microtubule dynamics at spindle poles including spindle orientation, astral microtubule density and poleward microtubule flux seems to depend on the association with the katanin complex formed by KATNA1 and KATNB1. Enhances the microtubule lattice severing activity of KATNA1 by recruiting the katanin complex to microtubules. Can block microtubule minus-end growth and reversely this function can be enhanced by the katanin complex. May have a preferential role in regulating neurogenesis.

Subunit / interactions. Interacts with KATNA1 and KATNB1; katanin complex formation KATNA1:KATNB1 is required for the association.

Subcellular location. Cytoplasm. Cytoskeleton. Spindle. Nucleus.

Disease relevance. Microcephaly 5, primary, autosomal recessive (MCPH5) [MIM:608716] A disease defined as a head circumference more than 3 standard deviations below the age-related mean. Brain weight is markedly reduced and the cerebral cortex is disproportionately small. Despite this marked reduction in size, the gyral pattern is relatively well preserved, with no major abnormality in cortical architecture. Affected individuals have mild to severe intellectual disability. Primary microcephaly is further defined by the absence of other syndromic features or significant neurological deficits due to degenerative brain disorder. The disease is caused by variants affecting the gene represented in this entry.

Isoforms (2)

UniProt ID	Names	Canonical?
Q8IZT6-1	1	yes
Q8IZT6-2	2

RefSeq proteins (2): NP_001193775, NP_060606* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000048	IQ_motif_EF-hand-BS	Binding_site
IPR001715	CH_dom	Domain
IPR011989	ARM-like	Homologous_superfamily
IPR013783	Ig-like_fold	Homologous_superfamily
IPR016024	ARM-type_fold	Homologous_superfamily
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR031549	ASH	Domain
IPR036872	CH_dom_sf	Homologous_superfamily
IPR051185	ASPM	Family

Pfam: PF00307, PF00612, PF15780

UniProt features (72 total): domain 41, sequence variant 12, modified residue 7, region of interest 4, sequence conflict 3, compositionally biased region 2, chain 1, coiled-coil region 1, splice variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

No AlphaFold model available for Q8IZT6 — AlphaFold DB does not currently provide models for proteins above ~3000 aa.

Functional residue map

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

Post-translational modifications (7): 280, 283, 367, 392, 425, 605, 1103

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 0 (showing top):

GO Biological Process (21): neuron migration (GO:0001764), positive regulation of neuroblast proliferation (GO:0002052), spindle organization (GO:0007051), spermatogenesis (GO:0007283), asymmetric cell division (GO:0008356), male gonad development (GO:0008584), forebrain neuroblast division (GO:0021873), cerebral cortex development (GO:0021987), negative regulation of neuron differentiation (GO:0045665), negative regulation of asymmetric cell division (GO:0045769), oogenesis (GO:0048477), developmental growth (GO:0048589), regulation of meiotic cell cycle (GO:0051445), spindle localization (GO:0051653), maintenance of centrosome location (GO:0051661), positive regulation of canonical Wnt signaling pathway (GO:0090263), meiotic spindle assembly (GO:0090306), neuronal stem cell population maintenance (GO:0097150), neuroblast proliferation (GO:0007405), brain development (GO:0007420), cell division (GO:0051301)

GO Molecular Function (2): calmodulin binding (GO:0005516), protein binding (GO:0005515)

GO Cellular Component (12): nucleus (GO:0005634), cytoplasm (GO:0005737), centrosome (GO:0005813), apical plasma membrane (GO:0016324), midbody (GO:0030496), microtubule minus-end (GO:0036449), meiotic spindle (GO:0072687), mitotic spindle pole (GO:0097431), spindle pole (GO:0000922), spindle (GO:0005819), cytoskeleton (GO:0005856), microtubule (GO:0005874)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
generation of neurons	2
cell cycle process	2
spindle	2
microtubule cytoskeleton	2
intracellular membraneless organelle	2
cell migration	1
neuroblast proliferation	1
positive regulation of neurogenesis	1
regulation of neuroblast proliferation	1
positive regulation of neural precursor cell proliferation	1
microtubule cytoskeleton organization	1
developmental process involved in reproduction	1
male gamete generation	1
cell division	1
gonad development	1
development of primary male sexual characteristics	1
forebrain generation of neurons	1
neuroblast division	1
pallium development	1
anatomical structure development	1
neuron differentiation	1
negative regulation of cell differentiation	1
regulation of neuron differentiation	1
asymmetric cell division	1
regulation of asymmetric cell division	1
negative regulation of cell division	1
germ cell development	1
female gamete generation	1
developmental process	1
growth	1
meiotic cell cycle	1
regulation of cell cycle	1
regulation of reproductive process	1
organelle localization	1
centrosome localization	1
maintenance of organelle location	1
positive regulation of Wnt signaling pathway	1
canonical Wnt signaling pathway	1
regulation of canonical Wnt signaling pathway	1

Protein interactions and networks

STRING

2584 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ASPM	MCPH1	Q8NEM0	988
ASPM	WDR62	O43379	951
ASPM	STIL	Q15468	943
ASPM	CDK5RAP2	Q96SN8	932
ASPM	CPAP	Q9HC77	927
ASPM	CEP152	O94986	894
ASPM	TOP2A	P11388	804
ASPM	CENPF	P49454	802
ASPM	DLGAP5	Q15398	799
ASPM	KIF20A	O95235	766
ASPM	CEP63	Q96MT8	765
ASPM	PDHA2	P29803	761
ASPM	HYDIN	Q4G0P3	752
ASPM	KIF15	Q9NS87	743
ASPM	BUB1	O43683	741

IntAct

160 interactions, top by confidence:

A	B	Type	Score
CDK4	CCND3	psi-mi:“MI:0914”(association)	0.980
SPC24	NDC80	psi-mi:“MI:0914”(association)	0.920
ODAD1	HGS	psi-mi:“MI:0914”(association)	0.850
TUBGCP5	TUBG1	psi-mi:“MI:0914”(association)	0.840
EID1	FBXO21	psi-mi:“MI:0914”(association)	0.650
NEUROG3	GXYLT2	psi-mi:“MI:0914”(association)	0.640
SDF4	ACAD11	psi-mi:“MI:0914”(association)	0.640
NIPAL1	ESYT2	psi-mi:“MI:0914”(association)	0.640
ASPM	KATNB1	psi-mi:“MI:0403”(colocalization)	0.580
OS9	AGRN	psi-mi:“MI:0914”(association)	0.530
DKK3	NME4	psi-mi:“MI:0914”(association)	0.530
IARS2	GAK	psi-mi:“MI:0914”(association)	0.530
COPS7B	ZZEF1	psi-mi:“MI:0914”(association)	0.530
PEX19	FAM20B	psi-mi:“MI:0914”(association)	0.530
MYL2	MYL5	psi-mi:“MI:0914”(association)	0.530
TRAFD1	ACAD11	psi-mi:“MI:0914”(association)	0.530
GPN3	POLR3A	psi-mi:“MI:0914”(association)	0.530
FOXJ1	PEX14	psi-mi:“MI:0914”(association)	0.530
MOAP1	PNMA8A	psi-mi:“MI:0914”(association)	0.530
CREB3	MYO9A	psi-mi:“MI:0914”(association)	0.530
DNAJB8	DNAJB6	psi-mi:“MI:0914”(association)	0.530

BioGRID (205): ASPM (Affinity Capture-MS), ASPM (Affinity Capture-MS), ASPM (Affinity Capture-MS), ASPM (Affinity Capture-MS), ASPM (Affinity Capture-MS), ASPM (Affinity Capture-MS), ASPM (Affinity Capture-MS), ASPM (Affinity Capture-MS), ASPM (Affinity Capture-MS), ASPM (Affinity Capture-MS), ASPM (Affinity Capture-MS), PSMD8 (Co-fractionation), ASPM (Affinity Capture-MS), CALU (Affinity Capture-MS), CENPB (Affinity Capture-MS)

ESM2 similar proteins: A0A0G2L7I0, A0A1L8G2K9, A0A1P8AW69, A5D979, A8K979, B3H578, B4R4H1, D3ZVU1, F4HTH8, F4HXQ7, F4I8S3, F6UH96, G3X912, O64571, P0DKJ8, P62283, P62285, P62286, P62287, P62288, P62289, P62290, P62293, P62294, Q0IGK1, Q2PS26, Q56NI9, Q5QGU6, Q60GC1, Q6DJS0, Q6DRC5, Q6NYJ3, Q6PF04, Q7ZXG4, Q8BMI4, Q8BP27, Q8CIB9, Q8IZT6, Q8N4S0, Q94F87

Diamond homologs: P62283, P62284, P62285, P62286, P62287, P62288, P62289, P62290, P62291, P62292, P62293, P62294, P62295, P62296, P62297, Q8C170, Q8CJ27, Q8IZT6, Q9VC45, Q9Z1N3, B2RTY4, E7F3F0, P11531

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
ASPM	“up-regulates quantity by expression”	BRCA1	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 185 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
SPOP-mediated proteasomal degradation of PD-L1(CD274)	6	12.8×	1e-03
Ubiquitin-dependent degradation of Cyclin D	5	12.4×	3e-03
AUF1 (hnRNP D0) binds and destabilizes mRNA	5	11.6×	3e-03
Hh mutants are degraded by ERAD	5	11.3×	3e-03
Degradation of DVL	5	11.1×	3e-03
Defective CFTR causes cystic fibrosis	5	10.3×	5e-03
Degradation of CRY and PER proteins	5	10.3×	5e-03
MAPK6/MAPK4 signaling	8	10.2×	4e-04

GO biological processes:

GO term	Partners	Fold	FDR
protein folding	9	5.7×	8e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

2226 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	263
Likely pathogenic	67
Uncertain significance	1016
Likely benign	491
Benign	73

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1012239	NM_018136.5(ASPM):c.1789C>T (p.Arg597Ter)	Pathogenic
1029675	NM_018136.5(ASPM):c.6994C>T (p.Arg2332Ter)	Pathogenic
1029678	NM_018136.5(ASPM):c.9659G>A (p.Trp3220Ter)	Pathogenic
1072719	NM_018136.5(ASPM):c.1615_1616del (p.Glu539fs)	Pathogenic
1073107	NM_018136.5(ASPM):c.9789T>G (p.Tyr3263Ter)	Pathogenic
1076360	NC_000001.10:g.(?196918585)(197742062_?)del	Pathogenic
1172591	NM_018136.5(ASPM):c.727C>T (p.Arg243Ter)	Pathogenic
1180742	NM_018136.5(ASPM):c.1592_1595del (p.Val531fs)	Pathogenic
1180743	NM_018136.5(ASPM):c.6047_6053del (p.His2015_Leu2016insTer)	Pathogenic
1180803	NM_018136.5(ASPM):c.1694del (p.Ser565fs)	Pathogenic
1202983	NM_018136.5(ASPM):c.4414C>T (p.Gln1472Ter)	Pathogenic
1279935	NM_018136.5(ASPM):c.8141del (p.Ala2714fs)	Pathogenic
1320079	NM_018136.5(ASPM):c.2760+1G>A	Pathogenic
1320080	NM_018136.5(ASPM):c.9641T>A (p.Leu3214Ter)	Pathogenic
1323512	NM_018136.5(ASPM):c.2581dup (p.Ile861fs)	Pathogenic
1323515	NM_018136.5(ASPM):c.4451_4455del (p.Tyr1484fs)	Pathogenic
1323525	NM_018136.5(ASPM):c.9874C>T (p.Gln3292Ter)	Pathogenic
1323530	NM_018136.5(ASPM):c.434del (p.Lys145fs)	Pathogenic
1338429	NM_018136.5(ASPM):c.4612C>T (p.Arg1538Ter)	Pathogenic
1338478	NM_018136.5(ASPM):c.4381C>T (p.Gln1461Ter)	Pathogenic
1339592	NM_018136.5(ASPM):c.10055_10056insGG (p.Ile3352fs)	Pathogenic
1373394	NM_018136.5(ASPM):c.2093del (p.Lys698fs)	Pathogenic
1385962	NM_018136.5(ASPM):c.1801del (p.Arg601fs)	Pathogenic
1395316	NM_018136.5(ASPM):c.7105C>T (p.Gln2369Ter)	Pathogenic
1396776	NM_018136.5(ASPM):c.275_290del (p.Ser92fs)	Pathogenic
1451719	NM_018136.5(ASPM):c.6708T>A (p.Tyr2236Ter)	Pathogenic
1451816	NM_018136.5(ASPM):c.8892G>A (p.Trp2964Ter)	Pathogenic
1451824	NM_018136.5(ASPM):c.7049T>A (p.Leu2350Ter)	Pathogenic
1452144	NM_018136.5(ASPM):c.77dup (p.Ala28fs)	Pathogenic
1453107	NM_018136.5(ASPM):c.6307_6308del (p.Val2103fs)	Pathogenic

SpliceAI

3625 predictions. Top by Δscore:

Variant	Effect	Δscore
1:197086798:CTTA:C	donor_loss	1.0000
1:197086799:TTA:T	donor_loss	1.0000
1:197086801:A:AC	donor_gain	1.0000
1:197086802:C:CA	donor_loss	1.0000
1:197086802:C:CC	donor_gain	1.0000
1:197086968:ACATC:A	acceptor_gain	1.0000
1:197086969:CATC:C	acceptor_gain	1.0000
1:197086969:CATCC:C	acceptor_gain	1.0000
1:197086971:TC:T	acceptor_gain	1.0000
1:197086972:CC:C	acceptor_gain	1.0000
1:197086973:C:CA	acceptor_loss	1.0000
1:197086973:C:CC	acceptor_gain	1.0000
1:197088254:A:AC	donor_gain	1.0000
1:197088255:C:CC	donor_gain	1.0000
1:197088255:CA:C	donor_gain	1.0000
1:197088255:CAGA:C	donor_gain	1.0000
1:197088429:CATA:C	acceptor_gain	1.0000
1:197088433:C:CC	acceptor_gain	1.0000
1:197088434:T:C	acceptor_gain	1.0000
1:197089973:T:TA	donor_gain	1.0000
1:197090192:TAACC:T	donor_loss	1.0000
1:197090193:AAC:A	donor_loss	1.0000
1:197090195:C:CT	donor_loss	1.0000
1:197090207:AAGG:A	donor_gain	1.0000
1:197090237:T:C	donor_gain	1.0000
1:197090385:ATGC:A	acceptor_gain	1.0000
1:197090386:TGCC:T	acceptor_loss	1.0000
1:197090387:GCC:G	acceptor_loss	1.0000
1:197090388:CC:C	acceptor_loss	1.0000
1:197090388:CCT:C	acceptor_gain	1.0000

AlphaMissense

22901 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:197132305:A:G	W823R	0.995
1:197132305:A:T	W823R	0.995
1:197144070:A:G	W110R	0.994
1:197144070:A:T	W110R	0.994
1:197135186:A:G	W695R	0.993
1:197135186:A:T	W695R	0.993
1:197124145:A:G	W1119R	0.992
1:197124145:A:T	W1119R	0.992
1:197132301:A:G	L824P	0.990
1:197129248:G:T	A900D	0.989
1:197129983:C:G	R854P	0.989
1:197132289:A:G	L828P	0.989
1:197135153:A:G	W706R	0.989
1:197135153:A:T	W706R	0.989
1:197125104:A:C	N1008K	0.988
1:197125104:A:T	N1008K	0.988
1:197132298:C:G	R825P	0.988
1:197132346:C:G	R809P	0.988
1:197133362:A:G	W803R	0.988
1:197133362:A:T	W803R	0.988
1:197133472:C:G	R766P	0.988
1:197133473:G:T	R766S	0.988
1:197090198:A:G	L3276P	0.987
1:197122252:A:C	N1216K	0.987
1:197122252:A:T	N1216K	0.987
1:197144069:C:G	W110S	0.987
1:197146172:A:G	F89S	0.987
1:197122006:A:G	L1260P	0.986
1:197122546:A:G	L1147P	0.986
1:197122564:C:T	G1141D	0.986

dbSNP variants (sampled 300 via entrez): RS1000007118 (1:197089158 T>C), RS1000041576 (1:197086133 T>C), RS1000079322 (1:197129676 C>A), RS1000181150 (1:197085175 A>T), RS1000233469 (1:197095887 A>T), RS1000236368 (1:197116761 C>T), RS1000249927 (1:197136381 G>A), RS1000263017 (1:197093374 A>C), RS1000286704 (1:197110831 T>C,G), RS1000340145 (1:197120781 T>C), RS1000433228 (1:197134095 A>G), RS1000564133 (1:197096314 T>C), RS1000620757 (1:197125469 GAGAA>G), RS1000644749 (1:197109193 G>A,C), RS1000662167 (1:197123675 C>T)

Disease associations

OMIM: gene MIM:605481 | disease phenotypes: MIM:608716, MIM:600105, MIM:613835, MIM:251200, MIM:620806, MIM:617468, MIM:208150, MIM:607432

GenCC curated gene-disease

Disease	Classification	Inheritance
autosomal recessive primary microcephaly	Definitive	Autosomal recessive
microcephaly 5, primary, autosomal recessive	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
autosomal recessive primary microcephaly	Definitive	AR

Mondo (12): microcephaly 5, primary, autosomal recessive (MONDO:0012106), retinitis pigmentosa 12 (MONDO:0010818), Leber congenital amaurosis 8 (MONDO:0013453), microcephaly (MONDO:0001149), congenital nervous system disorder (MONDO:0002320), autosomal recessive primary microcephaly (MONDO:0016660), developmental and epileptic encephalopathy 116 (MONDO:0970945), intellectual disability (MONDO:0001071), microcephaly 1, primary, autosomal recessive (MONDO:0009617), arthrogryposis multiplex congenita (MONDO:0015168), fetal akinesia deformation sequence 1 (MONDO:0100101), lissencephaly spectrum disorders (MONDO:0018838)

Orphanet (8): Autosomal recessive primary microcephaly (Orphanet:2512), Leber congenital amaurosis (Orphanet:65), Retinitis pigmentosa (Orphanet:791), Arthrogryposis multiplex congenita (Orphanet:1037), Fetal akinesia deformation sequence (Orphanet:994), Lissencephaly (Orphanet:48471), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658), Premature chromosome condensation with microcephaly and intellectual disability (Orphanet:52183)

HPO phenotypes

44 total (30 of 44 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000076	Vesicoureteral reflux
HP:0000122	Unilateral renal agenesis
HP:0000218	High palate
HP:0000219	Thin upper lip vermilion
HP:0000252	Microcephaly
HP:0000286	Epicanthus
HP:0000340	Sloping forehead
HP:0000341	Narrow forehead
HP:0000347	Micrognathia
HP:0000365	Hearing impairment
HP:0000520	Proptosis
HP:0000582	Upslanted palpebral fissure
HP:0000718	Aggressive behavior
HP:0000750	Delayed speech and language development
HP:0000752	Hyperactivity
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001263	Global developmental delay
HP:0001270	Motor delay
HP:0001274	Agenesis of corpus callosum
HP:0001302	Pachygyria
HP:0001321	Cerebellar hypoplasia
HP:0001347	Hyperreflexia
HP:0001510	Growth delay
HP:0002079	Hypoplasia of the corpus callosum
HP:0002119	Ventriculomegaly
HP:0002179	Opisthotonus
HP:0002282	Gray matter heterotopia
HP:0002472	Small cerebral cortex

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST001899_1	Age-related macular degeneration	1.000000e-16
GCST002479_5	Lupus nephritis in systemic lupus erythematosus	5.000000e-06
GCST005187_2	Matrix metalloproteinase-8 levels	2.000000e-35
GCST007989_3	Facial morphology traits (63 three-dimensional facial segments)	3.000000e-19

MeSH disease descriptors (7)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D054082	Lissencephaly	C10.500.507.450.499; C16.131.666.507.450.499
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500
C579935	Autosomal Recessive Primary Microcephaly (supp.)
C565384	Microcephaly, Primary Autosomal Recessive, 1 (supp.)
C563871	Microcephaly, Primary Autosomal Recessive, 5 (supp.)
C563999	Retinitis Pigmentosa 12 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	4
bisphenol A	increases expression, affects expression, decreases expression	3
sodium arsenite	decreases expression, increases abundance, increases expression	3
Estradiol	increases expression	3
Valproic Acid	decreases expression	3
Cyclosporine	decreases expression	3
Cadmium Chloride	decreases expression, increases expression	3
trichostatin A	affects cotreatment, decreases expression	2
Acetaminophen	decreases expression, increases expression	2
Air Pollutants	decreases expression, increases abundance	2
Cisplatin	decreases expression, increases reaction	2
Coumestrol	affects reaction, affects cotreatment, increases expression	2
Doxorubicin	decreases expression	2
Polychlorinated Biphenyls	affects expression, increases expression	2
Tobacco Smoke Pollution	decreases expression	2
Aflatoxin B1	affects expression, decreases expression	2
Genistein	affects expression, increases expression	2
Particulate Matter	decreases expression, increases abundance, affects cotreatment	2
aristolochic acid I	decreases expression	1
FR900359	affects phosphorylation	1
TAK-243	increases sumoylation	1
dicrotophos	decreases expression	1
geldanamycin	increases expression	1
triphenyl phosphate	affects expression	1
propionaldehyde	decreases expression	1
beta-lapachone	decreases expression	1
o,p’-DDT	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
boron nitride	decreases expression	1
cobaltous chloride	decreases expression	1

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_SD67	HAP1 ASPM (-) 1	Cancer cell line	Male
CVCL_XL61	HAP1 ASPM (-) 2	Cancer cell line	Male
CVCL_XL62	HAP1 ASPM (-) 3	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
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.
NCT03479476	PHASE2/PHASE3	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome
NCT02616796	PHASE1/PHASE2	COMPLETED	Effects of Social Gaze Training on Brain and Behavior in Fragile X Syndrome
NCT06860672	EARLY_PHASE1	RECRUITING	Clinical Trial of the Dual Vector Base Editor for the Treatment of the CHD3-R1025W Mutation
NCT00597948	Not specified	COMPLETED	Healthy Lifestyles for People With Intellectual Disabilities
NCT01087320	Not specified	RECRUITING	Genome Medical Sequencing for Gene Discovery
NCT01652963	Not specified	UNKNOWN	Picture-based Computerised Assessment and Training of Cognitive Behaviour Therapy Skills
NCT01695395	Not specified	COMPLETED	Mental Health Care Provision for Adults With Intellectual Disability and a Mental Disorder
NCT01867554	Not specified	COMPLETED	Research and Characterization of New Genes Involved in Intellectual Disability
NCT01915381	Not specified	COMPLETED	Improving Adherence Healthy Lifestyle With a Smartphone Application Based on Adults With Intellectual Disabilities