NCAPD3

Summary

NCAPD3 (non-SMC condensin II complex subunit D3, HGNC:28952) is a protein-coding gene on chromosome 11q25, encoding Condensin-2 complex subunit D3 (P42695). Regulatory subunit of the condensin-2 complex, a complex which establishes mitotic chromosome architecture and is involved in physical rigidity of the chromatid axis. It is a selective cancer dependency (DepMap: 81.3% of cell lines).

Condensin complexes I and II play essential roles in mitotic chromosome assembly and segregation. Both condensins contain 2 invariant structural maintenance of chromosome (SMC) subunits, SMC2 (MIM 605576) and SMC4 (MIM 605575), but they contain different sets of non-SMC subunits. NCAPD3 is 1 of 3 non-SMC subunits that define condensin II (Ono et al., 2003 [PubMed 14532007]).

Source: NCBI Gene 23310 — RefSeq curated summary.

At a glance

• Gene–disease (curated): microcephaly 22, primary, autosomal recessive (Moderate, GenCC) — +1 more curated relationship
• GWAS associations: 3
• Clinical variants (ClinVar): 382 total — 5 pathogenic, 4 likely-pathogenic
• Phenotypes (HPO): 23
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• Cancer dependency (DepMap): dependent in 81.3% of screened cell lines
• MANE Select transcript: NM_015261

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:28952
Approved symbol	NCAPD3
Name	non-SMC condensin II complex subunit D3
Location	11q25
Locus type	gene with protein product
Status	Approved
Aliases	hCAP-D3, CAP-D3, hHCP-6, KIAA0056, FLJ42888, hcp-6
Ensembl gene	ENSG00000151503
Ensembl biotype	protein_coding
OMIM	609276
Entrez	23310

Gene structure

Transcript identifiers

Ensembl transcripts: 35 — 15 protein_coding, 11 nonsense_mediated_decay, 9 retained_intron

ENST00000525432, ENST00000525964, ENST00000526422, ENST00000526787, ENST00000527944, ENST00000528065, ENST00000530396, ENST00000532445, ENST00000533155, ENST00000534290, ENST00000534532, ENST00000534548, ENST00000685119, ENST00000685324, ENST00000686368, ENST00000687155, ENST00000687480, ENST00000687965, ENST00000688263, ENST00000688672, ENST00000688834, ENST00000689205, ENST00000689387, ENST00000690149, ENST00000690743, ENST00000691025, ENST00000692494, ENST00000693576, ENST00000693663, ENST00000912040, ENST00000912041, ENST00000957779, ENST00000957780, ENST00000957781, ENST00000957782

RefSeq mRNA: 5 — MANE Select: NM_015261 NM_001372065, NM_001372068, NM_001372069, NM_001372070, NM_015261

CCDS: CCDS31723, CCDS91627

Canonical transcript exons

ENST00000534548 — 35 exons

Exon	Start	End
ENSE00001000006	134194665	134194738
ENSE00001000014	134208864	134208951
ENSE00001000023	134192689	134192909
ENSE00001000028	134194016	134194150
ENSE00001099675	134206599	134206732
ENSE00001099676	134202816	134202905
ENSE00001099677	134203142	134203198
ENSE00001099686	134204046	134204171
ENSE00001099690	134203654	134203906
ENSE00001099692	134185335	134185526
ENSE00001099703	134204899	134204971
ENSE00001099709	134184637	134184752
ENSE00001099725	134184903	134185000
ENSE00001099728	134220572	134220726
ENSE00001506057	134216936	134217098
ENSE00002155247	134223863	134223967
ENSE00002159352	134150113	134153052
ENSE00003470897	134181077	134181184
ENSE00003473223	134176307	134176386
ENSE00003490675	134153289	134153363
ENSE00003495019	134209145	134209206
ENSE00003496567	134168469	134168602
ENSE00003512627	134167996	134168195
ENSE00003533858	134158329	134158495
ENSE00003535389	134153140	134153200
ENSE00003548571	134209313	134209477
ENSE00003554002	134157928	134158067
ENSE00003578972	134178634	134178741
ENSE00003592699	134177219	134177457
ENSE00003595144	134157018	134157095
ENSE00003596581	134210270	134210454
ENSE00003631007	134159892	134160074
ENSE00003646040	134168917	134169054
ENSE00003651640	134161781	134161891
ENSE00003653702	134178822	134178936

Expression profiles

Bgee: expression breadth ubiquitous, 226 present calls, max score 90.98.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 18.0955 / max 197.5840, expressed in 1791 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
123258	14.2306	1718
123259	2.0770	1102
123260	1.7878	846

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
sural nerve	UBERON:0015488	90.98	gold quality
secondary oocyte	CL:0000655	90.64	gold quality
ventricular zone	UBERON:0003053	88.96	gold quality
oocyte	CL:0000023	88.09	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	87.87	gold quality
prostate gland	UBERON:0002367	87.83	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	87.56	gold quality
ganglionic eminence	UBERON:0004023	87.56	gold quality
stromal cell of endometrium	CL:0002255	86.39	gold quality
right lobe of liver	UBERON:0001114	86.24	gold quality
left testis	UBERON:0004533	86.21	gold quality
bone marrow cell	CL:0002092	86.20	gold quality
skin of leg	UBERON:0001511	86.15	gold quality
skin of abdomen	UBERON:0001416	86.08	gold quality
bone marrow	UBERON:0002371	85.76	gold quality
adenohypophysis	UBERON:0002196	85.55	gold quality
right testis	UBERON:0004534	85.53	gold quality
tongue squamous epithelium	UBERON:0006919	85.43	gold quality
pituitary gland	UBERON:0000007	85.01	gold quality
right hemisphere of cerebellum	UBERON:0014890	84.96	gold quality
testis	UBERON:0000473	84.92	gold quality
embryo	UBERON:0000922	84.52	gold quality
granulocyte	CL:0000094	84.46	gold quality
cerebellar hemisphere	UBERON:0002245	84.41	gold quality
left lobe of thyroid gland	UBERON:0001120	84.22	gold quality
cerebellar cortex	UBERON:0002129	84.21	gold quality
thymus	UBERON:0002370	84.20	silver quality
zone of skin	UBERON:0000014	84.05	gold quality
hair follicle	UBERON:0002073	84.00	gold quality
tonsil	UBERON:0002372	83.78	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-10596	yes	154.41
E-ANND-3	yes	5.80

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

24 targeting NCAPD3, 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-5692A	100.00	74.40	6850
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-507	99.97	70.11	1915
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-548AT-5P	99.96	70.83	2666
HSA-MIR-557	99.96	70.01	1640
HSA-MIR-338-5P	99.92	72.34	2951
HSA-MIR-3671	99.90	73.04	3897
HSA-MIR-6739-5P	99.80	67.87	2806
HSA-MIR-4668-5P	99.79	70.58	3782
HSA-MIR-320A-3P	99.77	69.73	2107
HSA-MIR-320B	99.77	69.73	2107
HSA-MIR-320C	99.77	69.73	2107
HSA-MIR-320D	99.77	69.73	2107
HSA-MIR-4429	99.77	69.62	2111
HSA-MIR-6733-5P	99.74	67.94	2759
HSA-MIR-6505-5P	99.73	69.25	1595
HSA-MIR-12129	99.72	67.45	1311
HSA-MIR-4328	99.57	71.06	4094
HSA-MIR-3153	99.55	67.59	2337
HSA-MIR-4325	99.49	72.20	1342
HSA-MIR-5683	99.36	68.59	2083
HSA-MIR-555	95.92	65.25	564
HSA-MIR-4734	88.28	63.44	87

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 81.3% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 9)

• The CAP-D3 subunit of the condensin II complex implicated in chromosome assembly and segeregation (PMID:14532007)
• hCAP-D3 is a new biomarker for subtype-1 prostate tumors that improves prognostication. (PMID:18223322)
• We show here that protein phosphatase 2A (PP2A), which interacts with condensin II but not condensin I, plays an essential role in targeting condensin II to chromosomes. (PMID:19915589)
• The initial phase of chromosome condensation requires Cdk1-mediated phosphorylation of the CAP-D3 subunit of condensin II. (PMID:21498573)
• CAP-D3 down-regulates transcription of genes that encode amino acid transporters (SLC7A5 and SLC3A2) to promote bacterial autophagy by colon epithelial cells. (PMID:25701737)
• Condensin II(CAP-D3 and CAP-H2) and GAIT subunits associate with L1 RNA in a co-dependent manner, independent of IFN-gamma. These findings suggest that cooperation between the Condensin II and GAIT complexes may facilitate a novel mechanism of L1 repression, thus contributing to the maintenance of genome stability in somatic cells (PMID:29028794)
• NCAPD2 and NCAPD3 expression levels have been confirmed to be significantly up-regulated in the intestinal mucosa of patients with active ulcerative colitis. In vitro, the data suggested that silencing NACPD2 and NACPD3 could depress the expression of IL-1beta, IL-6 and TNF-alpha. Further, knockdown of NACPD2 and NACPD3 could remarkably suppress IKK nucleation and NF-kappaB volume. (PMID:31885422)
• NCAPD3 promotes prostate cancer progression by up-regulating EZH2 and MALAT1 through STAT3 and E2F1. (PMID:35085770)
• Knockdown of NCAPD3 inhibits the tumorigenesis of non-small cell lung cancer by regulation of the PI3K/Akt pathway. (PMID:38566039)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	ncapd3	ENSDARG00000034773
mus_musculus	Ncapd3	ENSMUSG00000035024
rattus_norvegicus	Ncapd3	ENSRNOG00000008932
drosophila_melanogaster	Cap-D3	FBGN0051989
caenorhabditis_elegans	hcp-6	WBGENE00001833

Paralogs (1): NCAPD2 (ENSG00000010292)

Protein

Protein identifiers

Condensin-2 complex subunit D3 — P42695 (reviewed: P42695)

Alternative names: Non-SMC condensin II complex subunit D3

All UniProt accessions (17): P42695, A0A8I5KR13, A0A8I5KRL1, A0A8I5KT00, A0A8I5KTC8, A0A8I5KTD5, A0A8I5KYN6, A0A8I5QKI5, A0A8I5QKQ4, A0A8I5QKW0, A0A8I5QL00, E9PJM8, E9PKK4, E9PL95, E9PLE0, E9PQA3, G3V1A9

UniProt curated annotations — full annotation on UniProt →

Function. Regulatory subunit of the condensin-2 complex, a complex which establishes mitotic chromosome architecture and is involved in physical rigidity of the chromatid axis. May promote the resolution of double-strand DNA catenanes (intertwines) between sister chromatids. Condensin-mediated compaction likely increases tension in catenated sister chromatids, providing directionality for type II topoisomerase-mediated strand exchanges toward chromatid decatenation. Specifically required for decatenation of centromeric ultrafine DNA bridges during anaphase. Early in neurogenesis, may play an essential role to ensure accurate mitotic chromosome condensation in neuron stem cells, ultimately affecting neuron pool and cortex size.

Subunit / interactions. Component of the condensin-2 complex, which contains the SMC2 and SMC4 heterodimer, and 3 non SMC subunits that probably regulate the complex: NCAPH2, NCAPD3 and NCAPG2. Interacts with BRD4 (isoform B), leading to insulate chromatin from DNA damage response pathway.

Subcellular location. Nucleus.

Disease relevance. Microcephaly 22, primary, autosomal recessive (MCPH22) [MIM:617984] 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.

RefSeq proteins (5): NP_001358994, NP_001358997, NP_001358998, NP_001358999, NP_056076* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR011989	ARM-like	Homologous_superfamily
IPR012371	NCAPD3	Family
IPR016024	ARM-type_fold	Homologous_superfamily
IPR026971	CND1/NCAPD3	Family
IPR032682	Cnd1_C	Domain

Pfam: PF12717

UniProt features (26 total): modified residue 9, region of interest 5, repeat 4, sequence variant 4, compositionally biased region 2, chain 1, coiled-coil region 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
9F5W	ELECTRON MICROSCOPY	7.5

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P42695-F1	73.29	0.29

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 (9): 567, 1329, 1331, 1348, 1357, 1372, 1379, 1382, 1384

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-2299718	Condensation of Prophase Chromosomes

MSigDB gene sets: 243 (showing top): GOBP_CHROMOSOME_ORGANIZATION, WU_APOPTOSIS_BY_CDKN1A_VIA_TP53, SHEPARD_BMYB_MORPHOLINO_UP, GOBP_CHROMOSOME_SEPARATION, AP2_Q3, GOBP_POSITIVE_REGULATION_OF_ORGANELLE_ORGANIZATION, GOBP_CHROMOSOME_CONDENSATION, GOBP_ORGANELLE_FISSION, GOBP_REGULATION_OF_CHROMOSOME_SEGREGATION, GOBP_REGULATION_OF_CELL_CYCLE, GOBP_MITOTIC_NUCLEAR_DIVISION, GOBP_POSITIVE_REGULATION_OF_CELL_CYCLE_PROCESS, GOBP_CHROMOSOME_ORGANIZATION_INVOLVED_IN_MEIOTIC_CELL_CYCLE, GOBP_MITOTIC_CELL_CYCLE, DODD_NASOPHARYNGEAL_CARCINOMA_UP

GO Biological Process (10): mitotic chromosome condensation (GO:0007076), meiotic chromosome condensation (GO:0010032), cell division (GO:0051301), positive regulation of chromosome segregation (GO:0051984), positive regulation of chromosome separation (GO:1905820), positive regulation of chromosome condensation (GO:1905821), nuclear division (GO:0000280), chromatin organization (GO:0006325), chromosome condensation (GO:0030261), nuclear chromosome segregation (GO:0098813)

GO Molecular Function (3): histone binding (GO:0042393), histone H4K20me1 reader activity (GO:0140117), protein binding (GO:0005515)

GO Cellular Component (9): condensed chromosome, centromeric region (GO:0000779), condensed nuclear chromosome (GO:0000794), condensin complex (GO:0000796), nucleoplasm (GO:0005654), pericentric heterochromatin (GO:0005721), membrane (GO:0016020), chromosome, centromeric region (GO:0000775), nucleus (GO:0005634), nuclear lumen (GO:0031981)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Mitotic Prophase	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
chromosome condensation	3
chromosome segregation	2
positive regulation of cell cycle process	2
chromosome, centromeric region	2
condensed chromosome	2
nucleus	2
cellular anatomical structure	2
mitotic sister chromatid segregation	1
mitotic cell cycle	1
mitotic cell cycle process	1
meiotic cell cycle	1
chromosome organization involved in meiotic cell cycle	1
cellular process	1
regulation of chromosome segregation	1
chromosome separation	1
regulation of chromosome separation	1
regulation of chromosome condensation	1
positive regulation of chromosome organization	1
organelle fission	1
cellular component organization	1
chromosome organization	1
protein binding	1
histone H4 reader activity	1
binding	1
nuclear chromosome	1
chromosome	1
protein-containing complex	1
nuclear lumen	1
heterochromatin	1
chromosomal region	1
intracellular membrane-bounded organelle	1
intracellular organelle lumen	1

Protein interactions and networks

STRING

1874 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NCAPD3	NCAPG2	Q86XI2	999
NCAPD3	NCAPH2	Q6IBW4	997
NCAPD3	SMC4	Q9NTJ3	993
NCAPD3	NCAPH	Q15003	908
NCAPD3	NCAPG	Q9BPX3	817
NCAPD3	PHF8	Q9UPP1	796
NCAPD3	NCAPD2	Q15021	768
NCAPD3	H4C16	P02304	689
NCAPD3	RAD21	O60216	668
NCAPD3	MCPH1	Q8NEM0	657
NCAPD3	HCFC1	P51610	655
NCAPD3	TFCP2	Q12800	638
NCAPD3	H4C7	Q99525	627
NCAPD3	SMC3	Q9UQE7	623
NCAPD3	SMC2	O95347	607

IntAct

117 interactions, top by confidence:

A	B	Type	Score
NCAPH2	SMC2	psi-mi:“MI:0915”(physical association)	0.720
NCAPD3	NCAPH2	psi-mi:“MI:0915”(physical association)	0.720
EPHA1	EXOC5	psi-mi:“MI:0914”(association)	0.530
CXCR4	TMEM120B	psi-mi:“MI:0914”(association)	0.530
LDLRAD4	WWP2	psi-mi:“MI:0914”(association)	0.530
RIC3	ATP9A	psi-mi:“MI:0914”(association)	0.530
DGCR2	HOXD13	psi-mi:“MI:0914”(association)	0.530
	NCAPD3	psi-mi:“MI:0407”(direct interaction)	0.520
NCAPD3	EPRS1	psi-mi:“MI:0915”(physical association)	0.500
EPRS1	NCAPD3	psi-mi:“MI:0915”(physical association)	0.500
NCAPD3	GAPDH	psi-mi:“MI:0915”(physical association)	0.500
vpu	SCAMP3	psi-mi:“MI:0914”(association)	0.460
NCAPD3	PLEC	psi-mi:“MI:0915”(physical association)	0.400
Smc4	SMC2	psi-mi:“MI:0914”(association)	0.350
Ssna1	NCAPD3	psi-mi:“MI:0914”(association)	0.350
NES	RPL10	psi-mi:“MI:0914”(association)	0.350
XRCC3	DERL1	psi-mi:“MI:0914”(association)	0.350
Ncapg2		psi-mi:“MI:0914”(association)	0.350
NCAPD3	SMC2	psi-mi:“MI:0914”(association)	0.350
FOXG1	TCERG1	psi-mi:“MI:0914”(association)	0.350
FOXL1	IFRD1	psi-mi:“MI:0914”(association)	0.350
RIPK4	VWA8	psi-mi:“MI:0914”(association)	0.350
HSCB	RBP5	psi-mi:“MI:0914”(association)	0.350
	SMC2	psi-mi:“MI:0914”(association)	0.350
BCL2L14		psi-mi:“MI:0914”(association)	0.350
CD74		psi-mi:“MI:0914”(association)	0.350
P2RY6	ESYT2	psi-mi:“MI:0914”(association)	0.350

BioGRID (211): TEKT1 (Two-hybrid), NCAPD3 (Affinity Capture-RNA), NCAPD3 (Affinity Capture-RNA), NCAPD3 (Affinity Capture-RNA), NCAPD3 (Affinity Capture-MS), NCAPD3 (Affinity Capture-MS), NCAPD3 (Affinity Capture-MS), NCAPD3 (Affinity Capture-MS), NCAPD3 (Affinity Capture-MS), NCAPD3 (Affinity Capture-MS), NCAPD3 (Affinity Capture-MS), NCAPD3 (Affinity Capture-MS), CLTB (Co-fractionation), NCAPD3 (Co-fractionation), NCAPD3 (Co-fractionation)

ESM2 similar proteins: A0JP94, A1A5F2, A1EC95, A2BID5, A9JRI0, E7FAW3, E7FBU4, E9PVA8, F4HRS2, F4IP13, K8ERU3, O35095, O43299, P42695, P49815, P49816, Q08CY4, Q0DJS1, Q28205, Q2KJ97, Q3U829, Q3UHQ6, Q5JWR5, Q5PRF0, Q5R5R2, Q5SPP5, Q5ZIG0, Q61037, Q640K1, Q642P2, Q68F70, Q6AI08, Q6GN08, Q6GPP1, Q6P1G0, Q6ZNJ1, Q6ZQA0, Q6ZQK0, Q7T006, Q7ZY56

Diamond homologs: P42695, Q6GN08, Q6ZQK0, Q15021, Q8K2Z4

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
NCAPD3	“form complex”	“Condensin II”	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	5
Likely pathogenic	4
Uncertain significance	253
Likely benign	57
Benign	21

Top pathogenic / likely-pathogenic (9)

Variant ID	HGVS	Classification
1032666	NM_015261.3(NCAPD3):c.3278_3281del (p.Lys1093fs)	Pathogenic
4278373	NM_015261.3(NCAPD3):c.2675-1G>A	Pathogenic
524197	NM_015261.3(NCAPD3):c.1783del (p.Val595fs)	Pathogenic
524198	NM_015261.3(NCAPD3):c.382+14A>G	Pathogenic
524199	NM_015261.3(NCAPD3):c.3458A>C (p.Glu1153Ala)	Pathogenic
3064698	NM_015261.3(NCAPD3):c.4388+1G>A	Likely pathogenic
3065840	NM_015261.3(NCAPD3):c.3229C>T (p.Gln1077Ter)	Likely pathogenic
3355483	NM_015261.3(NCAPD3):c.3278_3279del (p.Lys1093fs)	Likely pathogenic
4849486	NM_015261.3(NCAPD3):c.1273del (p.Arg425fs)	Likely pathogenic

SpliceAI

5701 predictions. Top by Δscore:

Variant	Effect	Δscore
11:134153138:A:AC	donor_gain	1.0000
11:134153139:C:CC	donor_gain	1.0000
11:134153199:CT:C	acceptor_gain	1.0000
11:134153201:C:CC	acceptor_gain	1.0000
11:134153360:CTCT:C	acceptor_gain	1.0000
11:134153362:CT:C	acceptor_gain	1.0000
11:134157016:A:AC	donor_gain	1.0000
11:134157017:C:CC	donor_gain	1.0000
11:134157094:CA:C	acceptor_gain	1.0000
11:134157096:C:CC	acceptor_gain	1.0000
11:134157926:AC:A	donor_gain	1.0000
11:134157927:CC:C	donor_gain	1.0000
11:134159887:CCTA:C	donor_loss	1.0000
11:134159888:CTAC:C	donor_loss	1.0000
11:134159889:TACC:T	donor_loss	1.0000
11:134159890:A:AG	donor_loss	1.0000
11:134159891:C:G	donor_loss	1.0000
11:134160072:CTC:C	acceptor_gain	1.0000
11:134160073:TC:T	acceptor_gain	1.0000
11:134160073:TCCTG:T	acceptor_loss	1.0000
11:134160074:CC:C	acceptor_gain	1.0000
11:134160075:C:CC	acceptor_gain	1.0000
11:134160075:CTG:C	acceptor_loss	1.0000
11:134160076:T:G	acceptor_loss	1.0000
11:134161775:CCTTA:C	donor_loss	1.0000
11:134161776:CTTA:C	donor_loss	1.0000
11:134161777:TTAC:T	donor_loss	1.0000
11:134161778:TA:T	donor_loss	1.0000
11:134161779:A:AC	donor_gain	1.0000
11:134161779:AC:A	donor_gain	1.0000

AlphaMissense

9871 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:134203743:A:T	V460D	0.997
11:134177226:A:G	L1005P	0.996
11:134168507:C:G	R1112P	0.995
11:134176371:A:G	W1013R	0.995
11:134176371:A:T	W1013R	0.995
11:134177337:A:G	L968P	0.995
11:134203740:C:G	R461P	0.995
11:134203896:C:G	R409P	0.995
11:134161842:A:G	L1208P	0.994
11:134177256:C:G	R995P	0.994
11:134192876:A:G	W620R	0.994
11:134192876:A:T	W620R	0.994
11:134204149:C:G	R371P	0.994
11:134168555:C:G	R1096P	0.992
11:134168981:A:G	C1059R	0.991
11:134169037:A:G	L1040P	0.991
11:134177244:A:G	L999P	0.991
11:134177457:C:T	G928D	0.991
11:134203728:A:G	L465P	0.991
11:134204150:G:T	R371S	0.991
11:134160004:A:G	L1252P	0.990
11:134177235:A:G	L1002P	0.990
11:134177360:G:C	N960K	0.990
11:134177360:G:T	N960K	0.990
11:134177367:C:G	R958P	0.990
11:134203732:C:G	A464P	0.990
11:134203759:C:G	D455H	0.990
11:134161785:A:G	L1227P	0.989
11:134177280:A:G	L987P	0.989
11:134185417:A:G	W719R	0.989

dbSNP variants (sampled 300 via entrez): RS1000040961 (11:134154479 C>CA,CG,CT), RS1000041907 (11:134217190 A>C,G,T), RS1000042481 (11:134152110 G>A,C), RS1000073378 (11:134170118 G>A,T), RS1000117265 (11:134220934 C>A,T), RS1000237259 (11:134202765 G>A,T), RS1000249515 (11:134170423 A>C,G), RS1000255881 (11:134164772 G>A,C), RS1000299539 (11:134163078 G>A), RS1000305315 (11:134196848 C>T), RS1000371883 (11:134174240 G>A), RS1000404893 (11:134208197 C>T), RS1000407532 (11:134205258 G>A), RS1000408796 (11:134189667 T>G), RS1000424286 (11:134174488 CATATATATATACAT>C)

Disease associations

OMIM: gene MIM:609276 | disease phenotypes: MIM:617984

GenCC curated gene-disease

Disease	Classification	Inheritance
microcephaly 22, primary, autosomal recessive	Moderate	Autosomal recessive
autosomal recessive primary microcephaly	Supportive	Autosomal recessive

Mondo (3): microcephaly 22, primary, autosomal recessive (MONDO:0054805), intellectual disability (MONDO:0001071), autosomal recessive primary microcephaly (MONDO:0016660)

Orphanet (1): NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

23 total (23 of 23 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000076	Vesicoureteral reflux
HP:0000122	Unilateral renal agenesis
HP:0000219	Thin upper lip vermilion
HP:0000252	Microcephaly
HP:0000340	Sloping forehead
HP:0000582	Upslanted palpebral fissure
HP:0001250	Seizure
HP:0001263	Global developmental delay
HP:0001274	Agenesis of corpus callosum
HP:0001302	Pachygyria
HP:0001347	Hyperreflexia
HP:0001510	Growth delay
HP:0001518	Small for gestational age
HP:0002119	Ventriculomegaly
HP:0002282	Gray matter heterotopia
HP:0002509	Limb hypertonia
HP:0003103	Abnormal cortical bone morphology
HP:0003593	Infantile onset
HP:0004322	Short stature
HP:0007333	Hypoplasia of the frontal lobes
HP:0010864	Severe intellectual disability
HP:0011343	Moderate global developmental delay

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST000098_2	Cognitive test performance	6.000000e-06
GCST002701_37	Verbal declarative memory	2.000000e-06
GCST009391_1324	Metabolite levels	9.000000e-06

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0003926	neuropsychological test
EFO:0004874	memory performance
EFO:0006805	word list delayed recall measurement
EFO:0010519	pantothenic acid measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
C579935	Autosomal Recessive Primary Microcephaly (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5724763 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 1,538 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1232461	MOLIBRESIB	2	1,538

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

ChEMBL bioactivities

1 potent at pChembl≥5 of 1 total, top 1 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.17	IC50	670	nM	MOLIBRESIB

PubChem BioAssay actives

1 with measured affinity, of 6 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
2-[(4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]-N-ethylacetamide	2178807: Inhibition of NCAPD3 (unknown origin) incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	ic50	0.6700	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases expression	3
Aflatoxin B1	decreases methylation, increases expression	2
FR900359	decreases phosphorylation	1
triphenyl phosphate	affects expression	1
propionaldehyde	decreases expression	1
bisphenol A	decreases expression	1
arsenite	affects binding, decreases reaction	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
cobaltous chloride	decreases expression	1
sulindac sulfide	decreases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
coumarin	decreases phosphorylation	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
perfluoro-n-nonanoic acid	decreases expression	1
AM 251	decreases expression	1
K 7174	decreases expression	1
ICG 001	increases expression	1
abrine	decreases expression	1
NSC 689534	affects binding, decreases expression	1
Dasatinib	decreases expression	1
Temozolomide	increases expression	1
Sunitinib	decreases expression	1
Fulvestrant	increases methylation	1
Acetaminophen	increases expression	1
Air Pollutants	decreases expression, increases abundance	1
Caffeine	decreases phosphorylation	1
Carbamazepine	affects expression	1
Cisplatin	decreases expression, decreases reaction	1

ChEMBL screening assays

6 unique, capped per target: 6 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5697537	Binding	Inhibition of NCAPD3 (unknown origin) assessed as fold change at 10 uM incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia. — Nature

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B1Y8	Abcam HeLa NCAPD3 KO	Cancer cell line	Female

Clinical trials (associated diseases)

197 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)
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
NCT01988623	Not specified	COMPLETED	Pivotal Response Treatment for Individuals With Intellectual Disabilities
NCT02099773	Not specified	COMPLETED	Support Staff-client Interactions With Augmentative and Alternative Communication
NCT02136849	Not specified	COMPLETED	Inter-regional Project of the Great Western Exploration Approach for Exome Molecular Causes Severe Intellectual Disability Isolated or Syndromic
NCT02225041	Not specified	COMPLETED	Sedation Strategy and Cognitive Outcome After Critical Illness in Early Childhood
NCT02414438	Not specified	COMPLETED	Establishing the Clinical Utility of First StepDx PLUS and NextStepDx PLUS Study
NCT02451761	Not specified	COMPLETED	Apparently Balanced Chromosomal Translocation/ Next-generation Sequencing/ Intellectual Disability
NCT02461420	Not specified	ACTIVE_NOT_RECRUITING	Mapping the Genotype, Phenotype, and Natural History of Phelan-McDermid Syndrome
NCT02461459	Not specified	ACTIVE_NOT_RECRUITING	Autism Spectrum Disorder (ASD) and Intellectual Disability (ID) Determinants in Tuberous Sclerosis Complex (TSC)
NCT02486081	Not specified	COMPLETED	Development and Application-Smart Football for Movement Evaluation and Training in the Special Education Population
NCT02504502	Not specified	COMPLETED	Enhancing Genomic Laboratory Reports to Enhance Communication and Empower Patients
NCT02513277	Not specified	COMPLETED	Diabetes Screening & Prevention for People With Learning (Intellectual) Disabilities:STOP Diabetes Study
NCT02561754	Not specified	COMPLETED	Weight Management for Adolescents With IDD
NCT02591446	Not specified	COMPLETED	Transcranial Magnetic Stimulation Studies in Autism Spectrum Disorders
NCT02714868	Not specified	COMPLETED	Evaluation of Project TEAM (Teens Making Environmental and Activity Modifications)
NCT02721394	Not specified	UNKNOWN	FCT With Young Children With ID in the UK: A Feasibility Project V.1
NCT02746614	Not specified	COMPLETED	Psychomotor Therapy Effects in Adaptive Behavior and Motor Proficiency in Intellectual Disability
NCT02836405	Not specified	COMPLETED	TMS for the Investigation of Brain Plasticity in Autism Spectrum Disorders