ANKLE2

Summary

ANKLE2 (ankyrin repeat and LEM domain containing 2, HGNC:29101) is a protein-coding gene on chromosome 12q24.33, encoding Ankyrin repeat and LEM domain-containing protein 2 (Q86XL3). Involved in mitotic nuclear envelope reassembly by promoting dephosphorylation of BAF/BANF1 during mitotic exit. It is a common-essential gene (DepMap: required in 100.0% of cancer cell lines).

This gene encodes a member of the LEM family of inner nuclear membrane proteins. The encoded protein functions as a mitotic regulator through postmitotic formation of the nuclear envelope. Mutations in this gene cause morphology defects in the nuclear envelope and BAF hyperphosphorylation.

Source: NCBI Gene 23141 — RefSeq curated summary.

At a glance

• Gene–disease (curated): microcephaly 16, primary, autosomal recessive (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 4
• Clinical variants (ClinVar): 390 total — 8 pathogenic, 6 likely-pathogenic
• Phenotypes (HPO): 36
• Cancer dependency (DepMap): dependent in 100.0% of screened cell lines (common-essential)
• MANE Select transcript: NM_015114

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:29101
Approved symbol	ANKLE2
Name	ankyrin repeat and LEM domain containing 2
Location	12q24.33
Locus type	gene with protein product
Status	Approved
Aliases	LEMD7, Lem4
Ensembl gene	ENSG00000176915
Ensembl biotype	protein_coding
OMIM	616062
Entrez	23141

Gene structure

Transcript identifiers

Ensembl transcripts: 12 — 5 retained_intron, 4 protein_coding, 2 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000357997, ENST00000439231, ENST00000505031, ENST00000535036, ENST00000538591, ENST00000538766, ENST00000539605, ENST00000542282, ENST00000542374, ENST00000542657, ENST00000545623, ENST00000546061

RefSeq mRNA: 1 — MANE Select: NM_015114 NM_015114

CCDS: CCDS41869

Canonical transcript exons

ENST00000357997 — 13 exons

Exon	Start	End
ENSE00001645663	132754675	132755133
ENSE00002301519	132761618	132761832
ENSE00003598480	132741419	132741485
ENSE00003598990	132748138	132748331
ENSE00003620785	132734385	132734575
ENSE00003623169	132735406	132735512
ENSE00003648807	132743154	132743276
ENSE00003652753	132736893	132737065
ENSE00003691263	132747832	132748020
ENSE00003693000	132728032	132728163
ENSE00003716293	132750643	132750849
ENSE00003719725	132725503	132727443
ENSE00003733567	132729679	132730270

Expression profiles

Bgee: expression breadth ubiquitous, 289 present calls, max score 96.52.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 22.9933 / max 398.8839, expressed in 1816 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
134234	21.2662	1816
134235	1.7219	1207
134230	0.0051	1

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
stromal cell of endometrium	CL:0002255	96.52	gold quality
left testis	UBERON:0004533	96.37	gold quality
right testis	UBERON:0004534	95.96	gold quality
sural nerve	UBERON:0015488	95.45	gold quality
lower esophagus mucosa	UBERON:0035834	95.28	gold quality
skin of leg	UBERON:0001511	94.74	gold quality
skin of abdomen	UBERON:0001416	94.68	gold quality
right adrenal gland cortex	UBERON:0035827	94.37	gold quality
testis	UBERON:0000473	94.16	gold quality
left adrenal gland	UBERON:0001234	94.08	gold quality
right adrenal gland	UBERON:0001233	94.04	gold quality
mucosa of stomach	UBERON:0001199	93.99	gold quality
left adrenal gland cortex	UBERON:0035825	93.89	gold quality
small intestine Peyer’s patch	UBERON:0003454	93.86	gold quality
left uterine tube	UBERON:0001303	93.44	gold quality
upper lobe of left lung	UBERON:0008952	93.44	gold quality
body of uterus	UBERON:0009853	93.25	gold quality
right ovary	UBERON:0002118	93.23	gold quality
ventricular zone	UBERON:0003053	93.23	gold quality
right uterine tube	UBERON:0001302	93.21	gold quality
adrenal gland	UBERON:0002369	93.20	gold quality
metanephros cortex	UBERON:0010533	93.20	gold quality
esophagus mucosa	UBERON:0002469	93.16	gold quality
minor salivary gland	UBERON:0001830	93.08	gold quality
left ovary	UBERON:0002119	93.08	gold quality
granulocyte	CL:0000094	93.07	gold quality
adult organism	UBERON:0007023	93.07	gold quality
ectocervix	UBERON:0012249	92.87	gold quality
adrenal cortex	UBERON:0001235	92.83	gold quality
endocervix	UBERON:0000458	92.66	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	8.03
E-ENAD-27	no	3.95

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

68 targeting ANKLE2, 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-3120-5P	100.00	65.56	965
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-4715-3P	99.98	66.03	670
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-146A-5P	99.96	68.93	988
HSA-MIR-146B-5P	99.96	69.13	977
HSA-MIR-7153-5P	99.94	68.89	1006
HSA-MIR-3143	99.93	71.96	3104
HSA-MIR-205-3P	99.92	69.92	3165
HSA-MIR-589-3P	99.91	69.62	2088
HSA-MIR-9902	99.89	69.15	2250
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057
HSA-MIR-548E-5P	99.89	72.73	4486
HSA-MIR-3180-5P	99.82	69.12	2422
HSA-MIR-4799-5P	99.82	70.60	2663
HSA-MIR-6885-3P	99.75	70.36	3187
HSA-MIR-187-5P	99.74	70.26	1404
HSA-MIR-580-3P	99.67	69.23	1841
HSA-MIR-1303	99.65	69.77	1662
HSA-MIR-6757-3P	99.63	66.88	1089
HSA-MIR-4663	99.62	65.33	957
HSA-MIR-4743-3P	99.62	68.12	2095

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 100.0% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 6)

• By coordinating VRK-1- and PP2A-mediated signaling on BAF, Lem4 and LEM-4L (Y55F3BR.8) controls postmitotic nuclear envelope formation in a function conserved from worms to humans. (PMID:22770216)
• ANKLE2 acetylation at K302 and phosphorylation at S662 are dynamically regulated throughout the cell cycle by SIRT2 and are essential for normal nuclear envelope reassembly. (PMID:27875273)
• Absence of ANKLE2 severely compromises the post mitotic re-association of the nuclear proteins BAF, LAP2alpha and LaminA to chromosomes. These defects give rise to a strong mechanical instability of the nuclear envelope in telophase and to a chromosomal instability leading to increased number of hyperploid cells. (PMID:29254732)
• LEM4 represents a prognostic marker and an attractive target for breast cancer therapeutics. (PMID:30301939)
• that NS4A, ANKLE2, VRK1, and LLGL1 define a pathway impinging on asymmetric determinants of neural stem cell division (PMID:31735666)
• ANKLE2-related microcephaly: A variable microcephaly syndrome resembling Zika infection. (PMID:35871307)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	ankle2	ENSDARG00000035607
mus_musculus	Ankle2	ENSMUSG00000029501
rattus_norvegicus	Ankle2	ENSRNOG00000060144
drosophila_melanogaster	Ankle2	FBGN0028343
caenorhabditis_elegans		WBGENE00021945

Protein

Protein identifiers

Ankyrin repeat and LEM domain-containing protein 2 — Q86XL3 (reviewed: Q86XL3)

Alternative names: LEM domain-containing protein 4

All UniProt accessions (3): F5H1D4, F5H6J0, Q86XL3

UniProt curated annotations — full annotation on UniProt →

Function. Involved in mitotic nuclear envelope reassembly by promoting dephosphorylation of BAF/BANF1 during mitotic exit. Coordinates the control of BAF/BANF1 dephosphorylation by inhibiting VRK1 kinase and promoting dephosphorylation of BAF/BANF1 by protein phosphatase 2A (PP2A), thereby facilitating nuclear envelope assembly. May regulate nuclear localization of VRK1 in non-dividing cells. It is unclear whether it acts as a real PP2A regulatory subunit or whether it is involved in recruitment of the PP2A complex. Involved in brain development.

Subunit / interactions. Interacts with BAF/BANF1. Interacts with protein phosphatase 2A (PP2A) components PPP2C (PPP2CA or PPP2CB) and PPP2R1A. (Microbial infection) May interact with non-structural protein 4A/NS4A from Zika virus strains Mr-766 or French Polynesia 10087PF/2013; the interaction may inhibit ANKLE2 function and contribute to defects in brain development, such as microcephaly.

Subcellular location. Endoplasmic reticulum membrane.

Disease relevance. Microcephaly 16, primary, autosomal recessive (MCPH16) [MIM:616681] A form of microcephaly, a disease defined as a head circumference more than 3 standard deviations below the age, sex and ethnically matched mean. Brain weight is markedly reduced and the cerebral cortex is disproportionately small. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the ANKLE2 family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q86XL3-1	1	yes
Q86XL3-2	2
Q86XL3-3	3

RefSeq proteins (1): NP_055929* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002110	Ankyrin_rpt	Repeat
IPR003887	LEM_dom	Domain
IPR011015	LEM/LEM-like_dom_sf	Homologous_superfamily
IPR011320	RNase_H1_N	Domain
IPR035006	LEM_ANKL2	Domain
IPR036770	Ankyrin_rpt-contain_sf	Homologous_superfamily
IPR037056	RNase_H1_N_sf	Homologous_superfamily
IPR056237	ANKLE2_3rd	Domain

Pfam: PF00023, PF01693, PF03020, PF24567

UniProt features (42 total): sequence variant 13, modified residue 10, sequence conflict 7, splice variant 3, topological domain 2, region of interest 2, chain 1, transmembrane region 1, domain 1, repeat 1, compositionally biased region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q86XL3-F1	65.14	0.25

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 (10): 268, 488, 496, 512, 528, 662, 804, 896, 914, 259

Function

Pathways and Gene Ontology

Reactome pathways

13 pathways

ID	Pathway
R-HSA-2995383	Initiation of Nuclear Envelope (NE) Reformation
R-HSA-9013404	RAC2 GTPase cycle
R-HSA-9013408	RHOG GTPase cycle
R-HSA-162582	Signal Transduction
R-HSA-1640170	Cell Cycle
R-HSA-194315	Signaling by Rho GTPases
R-HSA-2555396	Mitotic Metaphase and Anaphase
R-HSA-2995410	Nuclear Envelope (NE) Reassembly
R-HSA-68882	Mitotic Anaphase
R-HSA-68886	M Phase
R-HSA-69278	Cell Cycle, Mitotic
R-HSA-9012999	RHO GTPase cycle
R-HSA-9716542	Signaling by Rho GTPases, Miro GTPases and RHOBTB3

MSigDB gene sets: 252 (showing top): GOBP_NUCLEAR_MEMBRANE_REASSEMBLY, GOBP_REGULATION_OF_PHOSPHORYLATION, GOBP_MEMBRANE_BIOGENESIS, GOBP_ORGANELLE_FISSION, GOBP_NUCLEUS_ORGANIZATION, LI_WILMS_TUMOR_VS_FETAL_KIDNEY_1_DN, GOBP_NEGATIVE_REGULATION_OF_PHOSPHORUS_METABOLIC_PROCESS, GOBP_MITOTIC_NUCLEAR_DIVISION, PYEON_CANCER_HEAD_AND_NECK_VS_CERVICAL_UP, GOBP_ENDOMEMBRANE_SYSTEM_ORGANIZATION, GOBP_MITOTIC_CELL_CYCLE, DODD_NASOPHARYNGEAL_CARCINOMA_UP, GOBP_NUCLEAR_ENVELOPE_ORGANIZATION, GOBP_MEMBRANE_ORGANIZATION, ZHANG_BREAST_CANCER_PROGENITORS_UP

GO Biological Process (8): mitotic nuclear membrane reassembly (GO:0007084), central nervous system development (GO:0007417), negative regulation of phosphorylation (GO:0042326), negative regulation of apoptotic process (GO:0043066), regulation of catalytic activity (GO:0050790), cell division (GO:0051301), nervous system development (GO:0007399), nuclear membrane reassembly (GO:0031468)

GO Molecular Function (4): protein kinase inhibitor activity (GO:0004860), protein phosphatase regulator activity (GO:0019888), protein phosphatase 2A binding (GO:0051721), protein binding (GO:0005515)

GO Cellular Component (3): endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-10 pathways:

Category	Pathways
RHO GTPase cycle	2
Nuclear Envelope (NE) Reassembly	1
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1
M Phase	1
Mitotic Anaphase	1
Mitotic Metaphase and Anaphase	1
Cell Cycle, Mitotic	1
Cell Cycle	1
Signaling by Rho GTPases	1
Signal Transduction	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
system development	2
protein phosphatase binding	2
mitotic cell cycle	1
nuclear membrane reassembly	1
mitotic nuclear membrane organization	1
nervous system development	1
phosphorylation	1
regulation of phosphorylation	1
negative regulation of phosphate metabolic process	1
apoptotic process	1
regulation of apoptotic process	1
negative regulation of programmed cell death	1
catalytic activity	1
regulation of molecular function	1
cellular process	1
membrane assembly	1
nuclear membrane organization	1
protein kinase activity	1
kinase inhibitor activity	1
protein kinase regulator activity	1
phosphoprotein phosphatase activity	1
phosphatase regulator activity	1
binding	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1478 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ANKLE2	VRK1	Q99986	713
ANKLE2	ANKLE1	Q8NAG6	700
ANKLE2	ZNF335	Q9H4Z2	683
ANKLE2	LEMD2	Q8NC56	669
ANKLE2	BANF1	O75531	666
ANKLE2	LEMD3	Q9Y2U8	640
ANKLE2	BANF2	Q9H503	615
ANKLE2	WDR62	O43379	612
ANKLE2	EMD	P50402	595
ANKLE2	CEP135	Q66GS9	588
ANKLE2	MCPH1	Q8NEM0	577
ANKLE2	SASS6	Q6UVJ0	559
ANKLE2	CPAP	Q9HC77	553
ANKLE2	TRAPPC14	Q8WVR3	523
ANKLE2	CEP152	O94986	523

IntAct

146 interactions, top by confidence:

A	B	Type	Score
BCL2	BCL2L11	psi-mi:“MI:0914”(association)	0.930
BCL2L11	BCL2	psi-mi:“MI:0914”(association)	0.930
PPP2R1A	STRN	psi-mi:“MI:0914”(association)	0.880
PPP2R1A	STRN	psi-mi:“MI:2364”(proximity)	0.880
ANKLE2	PPP2R1A	psi-mi:“MI:0914”(association)	0.850
PPP2CB	STRN	psi-mi:“MI:0914”(association)	0.790
RFXANK	RFXAP	psi-mi:“MI:0914”(association)	0.780
PPP2CB	CEP43	psi-mi:“MI:0914”(association)	0.730
STAC	YWHAE	psi-mi:“MI:0914”(association)	0.730
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
PPP2R1A	PPFIA3	psi-mi:“MI:0914”(association)	0.670
GLMN	FKBP5	psi-mi:“MI:0914”(association)	0.640
INSR	PIK3R2	psi-mi:“MI:2364”(proximity)	0.570
OSMR	JAK1	psi-mi:“MI:0914”(association)	0.560
ANKLE2	EDC4	psi-mi:“MI:0915”(physical association)	0.560
ANKLE2	vrk-1	psi-mi:“MI:0407”(direct interaction)	0.560
KCNA5	TMEM223	psi-mi:“MI:0914”(association)	0.530
CNGA3	C2CD2L	psi-mi:“MI:0914”(association)	0.530
ATP6V0A2	B4GALT3	psi-mi:“MI:0914”(association)	0.530
GHITM	CCNB2	psi-mi:“MI:0914”(association)	0.530
GLMN	CUL1	psi-mi:“MI:0914”(association)	0.530
SLC30A2	RER1	psi-mi:“MI:0914”(association)	0.530
IL4R	RHOBTB3	psi-mi:“MI:0914”(association)	0.530
TMEM9	ESYT2	psi-mi:“MI:0914”(association)	0.530

BioGRID (293): ANKLE2 (Affinity Capture-MS), ANKLE2 (Affinity Capture-MS), ANKLE2 (Affinity Capture-MS), ANKLE2 (Affinity Capture-MS), ANKLE2 (Affinity Capture-MS), ANKLE2 (Affinity Capture-MS), ANKLE2 (Proximity Label-MS), ANKLE2 (Proximity Label-MS), ANKLE2 (Proximity Label-MS), ANKLE2 (Proximity Label-MS), ANKLE2 (Affinity Capture-MS), ANKLE2 (Affinity Capture-MS), ANKLE2 (Affinity Capture-MS), ANKLE2 (Affinity Capture-MS), ANKLE2 (Affinity Capture-MS)

ESM2 similar proteins: A0A1L8HBI7, A0A1L8HJK9, A0A1L8HTT5, A6NP61, A8T6P4, C0SPG1, C3VD30, F1N4E5, K7SGN7, O35144, O35253, O70240, O88406, O88566, Q15554, Q1XFL1, Q3ZC82, Q4KLH3, Q5HZN9, Q5JTV8, Q5PQX1, Q5R7A3, Q62315, Q68DK7, Q6P1H6, Q6PDM1, Q6PG95, Q6ZPF3, Q76N89, Q7T3T8, Q7T3T9, Q7T3U0, Q7TNY7, Q7TP65, Q7TSX9, Q80SU3, Q80VM8, Q86XL3, Q8IVF5, Q8K3I4

Diamond homologs: H2KZB2, Q7TP65, Q86XL3, Q8MQX9, Q6P1H6

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
ANKLE2	down-regulates	VRK1

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 194 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
Cyclin A/B1/B2 associated events during G2/M transition	5	13.0×	7e-03
Intrinsic Pathway for Apoptosis	5	12.3×	7e-03
Degradation of beta-catenin by the destruction complex	6	8.7×	8e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	8
Likely pathogenic	6
Uncertain significance	182
Likely benign	84
Benign	71

Top pathogenic / likely-pathogenic (14)

Variant ID	HGVS	Classification
1425930	NC_000012.11:g.(?133236030)(133676672_?)del	Pathogenic
144295	GRCh38/hg38 12q24.33(chr12:132576614-133191400)x1	Pathogenic
144761	GRCh38/hg38 12q24.33(chr12:131650542-133191400)x1	Pathogenic
2443910	NM_015114.3(ANKLE2):c.706C>T (p.Arg236Ter)	Pathogenic
2443912	NM_015114.3(ANKLE2):c.1891+1701_2615+14delinsA	Pathogenic
3244416	NC_000012.11:g.(?133248873)(133501664_?)del	Pathogenic
3339785	NC_000012.11:g.(133319863_133324417)(133338419?)del	Pathogenic
930179	NM_015114.3(ANKLE2):c.1870C>T (p.Arg624Ter)	Pathogenic
218246	NM_015114.3(ANKLE2):c.1717C>G (p.Leu573Val)	Likely pathogenic
3254693	NM_015114.3(ANKLE2):c.2495C>G (p.Ser832Ter)	Likely pathogenic
3389621	NM_015114.3(ANKLE2):c.1701-2A>G	Likely pathogenic
4845688	NM_015114.3(ANKLE2):c.1508_1518del (p.Ala503fs)	Likely pathogenic
635194	NM_015114.3(ANKLE2):c.601G>T (p.Gly201Trp)	Likely pathogenic
985174	NM_015114.3(ANKLE2):c.941G>A (p.Arg314Gln)	Likely pathogenic

SpliceAI

3185 predictions. Top by Δscore:

Variant	Effect	Δscore
12:132727440:CCAA:C	acceptor_gain	1.0000
12:132727441:CAAC:C	acceptor_gain	1.0000
12:132727444:C:CC	acceptor_gain	1.0000
12:132728028:ATAC:A	donor_loss	1.0000
12:132728029:TACCT:T	donor_loss	1.0000
12:132728030:A:AC	donor_gain	1.0000
12:132728030:ACCTC:A	donor_loss	1.0000
12:132728031:C:CC	donor_gain	1.0000
12:132728031:C:CG	donor_loss	1.0000
12:132728031:CCT:C	donor_gain	1.0000
12:132728159:CCTCT:C	acceptor_gain	1.0000
12:132728160:CTCT:C	acceptor_gain	1.0000
12:132728160:CTCTC:C	acceptor_gain	1.0000
12:132728161:TCTC:T	acceptor_gain	1.0000
12:132728162:CT:C	acceptor_gain	1.0000
12:132728163:TC:T	acceptor_loss	1.0000
12:132728164:C:CC	acceptor_gain	1.0000
12:132728164:CTAGA:C	acceptor_loss	1.0000
12:132728172:CACAA:C	acceptor_gain	1.0000
12:132728174:C:CT	acceptor_gain	1.0000
12:132728175:A:T	acceptor_gain	1.0000
12:132728176:A:AC	acceptor_gain	1.0000
12:132728176:A:C	acceptor_gain	1.0000
12:132734380:CTTA:C	donor_loss	1.0000
12:132734381:TTACC:T	donor_loss	1.0000
12:132734382:TA:T	donor_loss	1.0000
12:132734383:A:AC	donor_gain	1.0000
12:132734384:C:CC	donor_gain	1.0000
12:132734384:CCAGA:C	donor_gain	1.0000
12:132735393:AG:A	donor_gain	1.0000

AlphaMissense

6113 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:132748238:C:G	R314P	0.999
12:132747851:A:G	L404P	0.998
12:132747989:G:T	A358D	0.998
12:132748003:G:C	N353K	0.998
12:132748003:G:T	N353K	0.998
12:132748151:G:T	P343H	0.998
12:132748178:C:G	R334P	0.998
12:132748181:G:T	P333H	0.998
12:132748241:A:G	L313P	0.998
12:132748253:A:G	L309P	0.998
12:132750770:A:C	F240L	0.998
12:132750770:A:T	F240L	0.998
12:132750772:A:G	F240L	0.998
12:132735491:A:G	W539R	0.997
12:132735491:A:T	W539R	0.997
12:132743251:G:T	A419D	0.997
12:132747857:A:G	L402P	0.997
12:132747986:G:T	A359D	0.997
12:132747992:A:T	V357D	0.997
12:132748158:C:G	D341H	0.997
12:132748172:A:G	L336P	0.997
12:132748183:G:C	N332K	0.997
12:132748183:G:T	N332K	0.997
12:132748268:G:T	P304H	0.997
12:132750743:A:C	F249L	0.997
12:132750743:A:T	F249L	0.997
12:132750745:A:G	F249L	0.997
12:132750753:G:T	A246D	0.997
12:132750754:C:G	A246P	0.997
12:132750837:A:T	V218D	0.997

dbSNP variants (sampled 300 via entrez): RS1000055366 (12:132757917 G>A), RS1000121981 (12:132729235 C>T), RS1000208821 (12:132742504 T>A), RS1000282258 (12:132749670 C>T), RS1000297366 (12:132729737 T>C), RS1000336818 (12:132759515 ATATATG>A), RS1000359860 (12:132759116 C>T), RS1000432444 (12:132737517 C>A,G), RS1000625434 (12:132756593 C>A,T), RS1000701294 (12:132747103 C>G,T), RS1000775466 (12:132755600 G>A), RS1000830769 (12:132752032 G>A), RS1000912649 (12:132741078 A>G), RS1000924427 (12:132751821 G>A), RS1000965900 (12:132746123 C>T)

Disease associations

OMIM: gene MIM:616062 | disease phenotypes: MIM:616681, MIM:603896

GenCC curated gene-disease

Disease	Classification	Inheritance
microcephaly 16, primary, autosomal recessive	Strong	Autosomal recessive
autosomal recessive primary microcephaly	Supportive	Autosomal recessive

Mondo (5): microcephaly 16, primary, autosomal recessive (MONDO:0014730), microcephaly (MONDO:0001149), intellectual disability (MONDO:0001071), leukoencephalopathy with vanishing white matter (MONDO:0800448), autosomal recessive primary microcephaly (MONDO:0016660)

Orphanet (4): Autosomal recessive primary microcephaly (Orphanet:2512), CACH syndrome (Orphanet:135), Ovarioleukodystrophy (Orphanet:99853), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

36 total (30 of 36 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000028	Cryptorchidism
HP:0000076	Vesicoureteral reflux
HP:0000122	Unilateral renal agenesis
HP:0000194	Open mouth
HP:0000219	Thin upper lip vermilion
HP:0000252	Microcephaly
HP:0000340	Sloping forehead
HP:0000347	Micrognathia
HP:0000501	Glaucoma
HP:0000506	Telecanthus
HP:0000508	Ptosis
HP:0000582	Upslanted palpebral fissure
HP:0001034	Hypermelanotic macule
HP:0001181	Adducted thumb
HP:0001250	Seizure
HP:0001257	Spasticity
HP:0001263	Global developmental delay
HP:0001274	Agenesis of corpus callosum
HP:0001302	Pachygyria
HP:0001347	Hyperreflexia
HP:0001510	Growth delay
HP:0002119	Ventriculomegaly
HP:0002282	Gray matter heterotopia
HP:0002307	Drooling
HP:0002510	Spastic tetraplegia
HP:0003103	Abnormal cortical bone morphology
HP:0003577	Congenital onset
HP:0004322	Short stature
HP:0004325	Decreased body weight

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST001491_3	Immune response to smallpox vaccine (IL-6)	3.000000e-07
GCST010002_179	Refractive error	1.000000e-12
GCST010988_507	Adult body size	4.000000e-08
GCST90002388_443	Lymphocyte count	4.000000e-10

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004645	response to vaccine
EFO:0004587	lymphocyte count

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
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.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Arsenic	affects methylation, affects cotreatment, increases abundance, increases expression	2
Benzo(a)pyrene	affects methylation, increases expression	2
Nickel	increases expression	2
Tobacco Smoke Pollution	increases expression	2
Aflatoxin B1	increases expression, increases methylation	2
FR900359	affects phosphorylation	1
sodium arsenite	affects cotreatment, increases abundance, increases expression	1
cobaltous chloride	increases expression	1
manganese chloride	increases abundance, increases expression, affects cotreatment	1
benzo(e)pyrene	increases methylation	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression	1
di-n-butylphosphoric acid	affects expression	1
corosolic acid	increases expression	1
abrine	increases expression	1
bromovanin	decreases expression	1
jinfukang	affects cotreatment, decreases expression	1
Fulvestrant	increases methylation	1
Acetaminophen	increases expression	1
Caffeine	decreases phosphorylation	1
Cisplatin	affects cotreatment, decreases expression	1
Estradiol	affects cotreatment, increases expression	1
Ivermectin	decreases expression	1
Lipopolysaccharides	affects response to substance, increases expression	1
Manganese	increases expression, affects cotreatment, increases abundance	1
Methapyrilene	increases methylation	1
Potassium Dichromate	decreases expression	1
Ribonucleotides	affects binding	1
Smoke	decreases expression	1
Thiram	increases expression	1
Tretinoin	decreases expression	1

Clinical trials (associated diseases)

218 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