NACC1

Summary

NACC1 (nucleus accumbens associated 1, HGNC:20967) is a protein-coding gene on chromosome 19p13.13, encoding Nucleus accumbens-associated protein 1 (Q96RE7). Functions as a transcriptional repressor.

This gene encodes a member of the BTB/POZ protein family. BTB/POZ proteins are involved in several cellular processes including proliferation, apoptosis and transcription regulation. The encoded protein is a transcriptional repressor that plays a role in stem cell self-renewal and pluripotency maintenance. The encoded protein also suppresses transcription of the candidate tumor suppressor Gadd45GIP1, and expression of this gene may play a role in the progression of multiple types of cancer. A pseudogene of this gene is located on the short arm of chromosome 9.

Source: NCBI Gene 112939 — RefSeq curated summary.

At a glance

• Gene–disease (curated): NACC1-related neurodevelopmental disorder with epilepsy, cataracts and episodic irritability (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 1
• Clinical variants (ClinVar): 509 total — 2 pathogenic, 3 likely-pathogenic
• Phenotypes (HPO): 42
• Druggable target: yes
• MANE Select transcript: NM_052876

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:20967
Approved symbol	NACC1
Name	nucleus accumbens associated 1
Location	19p13.13
Locus type	gene with protein product
Status	Approved
Aliases	NAC1, NAC-1, BEND8, BTBD30
Ensembl gene	ENSG00000160877
Ensembl biotype	protein_coding
OMIM	610672
Entrez	112939

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 10 protein_coding

ENST00000292431, ENST00000585663, ENST00000586171, ENST00000700232, ENST00000901702, ENST00000901703, ENST00000901704, ENST00000913331, ENST00000913332, ENST00000913333

RefSeq mRNA: 1 — MANE Select: NM_052876 NM_052876

CCDS: CCDS12294

Canonical transcript exons

ENST00000292431 — 6 exons

Exon	Start	End
ENSE00001055166	13138147	13141147
ENSE00001484140	13118264	13118454
ENSE00002878650	13135200	13136153
ENSE00003979247	13137478	13137575
ENSE00003979249	13136232	13136405
ENSE00003979252	13137271	13137376

Expression profiles

Bgee: expression breadth ubiquitous, 259 present calls, max score 96.99.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 34.5575 / max 257.0700, expressed in 1815 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
174134	30.6589	1815
174131	1.8310	1051
174133	1.5418	950
174135	0.4402	244
174132	0.0857	21

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
pancreatic ductal cell	CL:0002079	96.99	gold quality
nasal cavity epithelium	UBERON:0005384	94.73	gold quality
upper arm skin	UBERON:0004263	93.48	gold quality
stromal cell of endometrium	CL:0002255	92.46	gold quality
left ventricle myocardium	UBERON:0006566	92.02	gold quality
prefrontal cortex	UBERON:0000451	91.78	gold quality
amygdala	UBERON:0001876	90.68	gold quality
kidney epithelium	UBERON:0004819	90.61	gold quality
anterior cingulate cortex	UBERON:0009835	90.46	gold quality
buccal mucosa cell	CL:0002336	90.38	gold quality
decidua	UBERON:0002450	90.36	gold quality
vena cava	UBERON:0004087	90.11	gold quality
ventral tegmental area	UBERON:0002691	89.96	gold quality
cardiac muscle of right atrium	UBERON:0003379	89.86	gold quality
cerebellar vermis	UBERON:0004720	89.84	gold quality
nipple	UBERON:0002030	89.83	gold quality
frontal cortex	UBERON:0001870	89.75	gold quality
putamen	UBERON:0001874	89.70	gold quality
right frontal lobe	UBERON:0002810	89.43	gold quality
epithelium of mammary gland	UBERON:0003244	89.37	gold quality
mammary duct	UBERON:0001765	89.33	gold quality
neocortex	UBERON:0001950	89.30	gold quality
temporal lobe	UBERON:0001871	89.18	gold quality
nucleus accumbens	UBERON:0001882	88.90	gold quality
pylorus	UBERON:0001166	88.70	gold quality
lower esophagus mucosa	UBERON:0035834	88.66	gold quality
dorsal plus ventral thalamus	UBERON:0001897	88.64	gold quality
substantia nigra pars reticulata	UBERON:0001966	88.55	gold quality
midbrain	UBERON:0001891	88.54	gold quality
myocardium	UBERON:0002349	88.44	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	4.00

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

5 targets.

Target	Regulation
AAR2
FOXQ1
GADD45A
GIP
NACC1

Upstream regulators (CollecTRI, top): NACC1, RCOR2

miRNA regulators (miRDB)

161 targeting NACC1, 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-6867-5P	100.00	82.21	3464
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-574-5P	100.00	66.01	989
HSA-MIR-6758-5P	100.00	66.21	1470
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-4425	100.00	67.59	1049
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-10401-5P	99.99	65.79	948
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-2110	99.96	66.68	1930
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-101-3P	99.94	75.03	2230
HSA-MIR-144-3P	99.94	73.98	2698
HSA-MIR-218-5P	99.93	72.22	2103
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-515-5P	99.92	69.82	2343
HSA-MIR-519E-5P	99.92	69.62	2358
HSA-MIR-6783-3P	99.89	67.92	2059
HSA-MIR-1343-3P	99.89	66.78	1815
HSA-MIR-345-3P	99.89	70.23	1421

Literature-anchored findings (GeneRIF, showing 39)

• NAC-1 is a tumor recurrence-associated gene with oncogenic potential; interactions between BTB/POZ domains of NAC-1 proteins are critical to form the discrete NAC-1 nuclear bodies and essential for tumor cell proliferation and survival. (PMID:17130457)
• NAC-1 expression is higher in ovarian carcinoma cells in effusions compared with their solid tumor counterparts. (PMID:17391728)
• NAC-1 contributes to tumor growth and survival by at least inhibiting Gadd45GIP1 expression, which has a tumor suppressor effect in cancer cells. (PMID:17804717)
• NAC-1 may play an important role in cervical carcinomas. (PMID:18347169)
• NAC-1 regulates Taxol resistance in ovarian cancer (PMID:18483383)
• Therefore, we conclude that NAC1 functions as a corepressor for POZ/BTB proteins expressed in the mature CNS. (PMID:19121354)
• NAC-1, a potential stem cell pluripotency factor, contributes to paclitaxel resistance in ovarian cancer by inactivating Gadd45v pathway. (PMID:19305429)
• C-terminal alpha-helix of the Nac1 POZ domain is shorter than that observed in most other POZ-domain transcription factors (PMID:19407373)
• NAC1 is a potential stem cell pluripotency factor expression in normal endometrium, endometrial hyperplasia and endometrial carcinoma (PMID:20372782)
• NAC1 over-expression is critical to the growth and survival of ovarian cancers. Furthermore, they suggest that NAC1 silencing RNA-induced phenotypes depend on the expression status of the targeted cell line. (PMID:20869761)
• Our data suggest that amplification at the ch19p13.2 NACC1 locus, leading to NAC1 overexpression, is one of the molecular genetic alterations associated with early tumor recurrence in ovarian cancer. (PMID:21240255)
• These results indicate that a cell cycle-dependent regulatory mechanism controls NAC1 body formation in the nucleus and suggest that NAC1 body dynamics are associated with mitosis or cytokinesis. (PMID:21301057)
• These data suggest that the acetylation status of CTTN modulated by the NACC1-HDAC6 deacetylation system induces acceleration of melanoma cell migration activity via an actin-dependent cellular process (PMID:21562571)
• NAC1 is identified as a novel regulator of autophagy (PMID:21743489)
• NAC1 overexpression is critical to the growth and survival of cervical carcinomas irrespective of histologic type. (PMID:21889186)
• NAC1 expression was significantly correlated with FASN expression in both OCCC samples and OCCC cell lines. (PMID:22653145)
• Results not only reveal a previously unrecognized function of NAC1, the molecular pathway involved and its impact on pathogenesis of tumor initiation and development, but also identify a novel senescence regulator (PMID:22665267)
• The identification of an NAC1 NLS thus clarifies the mechanism through which NAC1 translocates to the nucleus to regulate the transcription of genes involved in oncogenicity and pluripotency. (PMID:22665369)
• Uterine sarcomas with NAC1 overexpression are clinically the most aggressive, chemoresistant, and radioresistant tumors. (PMID:22993327)
• low expression of NAC1 predicts poor prognosis for patients with pancreatic ductal adenocarcinoma. (PMID:23252869)
• NAC1 is essential and sufficient for activation of FOXQ1 (PMID:24200849)
• strategy for the purification of tethered POZ domains that form forced heterodimers is described, and crystal structures of the heterodimeric POZ domains of Miz1/BCL6 and of Miz1/NAC1 are reported (PMID:25484205)
• NACC1 can be modified by SUMO paralogues, and cooperates with promyelocytic leukemia protein. (PMID:25891951)
• NAC1 has potential as a marker for distinguishing OED from CIS/OSCC (PMID:26172271)
• miR-339-5p inhibits migration and invasion in ovarian cancer by targeting NACC1 and BCL6. miR-339-5p may be a biomarker of metastasis in ovarian cancer; NACC1 had a predictive value for ovarian cancer progression (PMID:26553360)
• NAC1 forms a protein complex to function as a transcriptional regulator in cancer cells (PMID:27424155)
• a mutation in NACC1 causes microcephaly, profound developmental delays and/or intellectual disability, cataracts, severe epilepsy including infantile spasms, irritability, failure to thrive, and stereotypic hand movements (PMID:28132692)
• knockdown of HOXA9 abrogated NAC1induced drug resistance. (PMID:28713930)
• NAC1/ HMGB1 signaling pathway is associated with the epithelial-mesenchymal transition (EMT), invasion, and metastasis of lung cancer cells. (PMID:30373858)
• LINC00319 promotes ovarian cancer progression through upregulating NACC1 expression by restraining miR-423-5p. (PMID:30442370)
• We identified human nucleus accumbens-associated 1 (NAC1), a member of the BTB/POZ family, as a bridge for MAVS and TBK1 that positively regulates the RIG-I-like receptors-mediated induction of type I IFN (PMID:31235549)
• NACC-1 regulates hepatocellular carcinoma cell malignancy and is targeted by miR-760. (PMID:32091103)
• NAC1 attenuates BCL6 negative autoregulation and functions as a BCL6 coactivator of FOXQ1 transcription in cancer cells. (PMID:32412910)
• lncRNA FOXP4AS1 predicts poor prognosis and accelerates the progression of mantle cell lymphoma through the miR4235p/NACC1 pathway. (PMID:33416160)
• Unclassified low grade spindle cell sarcoma with storiform pattern characterized by recurrent novel EWSR1/FUS-NACC1 fusions. (PMID:33859361)
• FUS-induced circRHOBTB3 facilitates cell proliferation via miR-600/NACC1 mediated autophagy response in pancreatic ductal adenocarcinoma. (PMID:34416910)
• Mechanistic insights of NAC1 nuclear export and its role in ovarian cancer resistance to docetaxel. (PMID:37019189)
• An overview of the co-transcription factor NACC1: Beyond its pro-tumor effects. (PMID:38030057)
• Hyperkinetic Movement Disorder Caused by the Recurrent c.892C>T NACC1 Variant. (PMID:38698576)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	nacc1b	ENSDARG00000078238
danio_rerio	nacc1a	ENSDARG00000099164
mus_musculus	Nacc1	ENSMUSG00000001910
rattus_norvegicus	Nacc1	ENSRNOG00000002864

Paralogs (28): ZNF280C (ENSG00000056277), ZBTB25 (ENSG00000089775), PRDM13 (ENSG00000112238), BCL6 (ENSG00000113916), FEZF1 (ENSG00000128610), ZBTB46 (ENSG00000130584), PRDM12 (ENSG00000130711), ZNF280D (ENSG00000137871), NACC2 (ENSG00000148411), FEZF2 (ENSG00000153266), ZBTB7B (ENSG00000160685), BCL6B (ENSG00000161940), GFI1 (ENSG00000162676), GFI1B (ENSG00000165702), ZBTB49 (ENSG00000168826), ZNF280A (ENSG00000169548), ZNF581 (ENSG00000171425), ZNF524 (ENSG00000171443), ZBTB26 (ENSG00000171448), ZBTB21 (ENSG00000173276), ZNF683 (ENSG00000176083), ZBTB33 (ENSG00000177485), ZBTB3 (ENSG00000185670), ZBTB6 (ENSG00000186130), ZBTB14 (ENSG00000198081), ZBTB12 (ENSG00000204366), ZNF580 (ENSG00000213015), ZNF280B (ENSG00000275004)

Protein

Protein identifiers

Nucleus accumbens-associated protein 1 — Q96RE7 (reviewed: Q96RE7)

Alternative names: BTB/POZ domain-containing protein 14B

All UniProt accessions (3): Q96RE7, K7ELC5, K7ENW4

UniProt curated annotations — full annotation on UniProt →

Function. Functions as a transcriptional repressor. Seems to function as a transcriptional corepressor in neuronal cells through recruitment of HDAC3 and HDAC4. Contributes to tumor progression, and tumor cell proliferation and survival. This may be mediated at least in part through repressing transcriptional activity of GADD45GIP1. Required for recruiting the proteasome from the nucleus to the cytoplasm and dendritic spines.

Subunit / interactions. Homooligomer; mediated by the BTB domain. Interacts with HDAC3 and HDAC4. Interacts (via BTB domain) with CUL3, PSMD7 and RCOR1.

Subcellular location. Nucleus. Cytoplasm.

Tissue specificity. Overexpressed in several types of carcinomas including ovarian serous carcinomas. Expression levels positively correlate with tumor recurrence in ovarian serous carcinomas, and intense immunoreactivity in primary ovarian tumors predicts early recurrence. Up-regulated in ovarian carcinomas after chemotherapy, suggesting a role in development of chemotherapy resistance in ovarian cancer.

Disease relevance. Neurodevelopmental disorder with epilepsy, cataracts, feeding difficulties, and delayed brain myelination (NECFM) [MIM:617393] A neurodevelopmental disorder characterized by microcephaly, profound developmental delay, intellectual disability, cataracts, severe epilepsy including infantile spasms, irritability, failure to thrive, and stereotypic hand movements. Brain imaging reveals delayed myelination and cerebral atrophy. The disease is caused by variants affecting the gene represented in this entry.

RefSeq proteins (1): NP_443108* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000210	BTB/POZ_dom	Domain
IPR011333	SKP1/BTB/POZ_sf	Homologous_superfamily
IPR018379	BEN_domain	Domain
IPR050457	ZnFinger_BTB_dom_contain	Family

Pfam: PF00651, PF10523

UniProt features (46 total): helix 12, strand 9, cross-link 8, turn 5, compositionally biased region 4, domain 2, modified residue 2, region of interest 2, chain 1, sequence variant 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
3GA1	X-RAY DIFFRACTION	2.1
4U2N	X-RAY DIFFRACTION	2.3
8YZS	X-RAY DIFFRACTION	2.31
7BV9	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96RE7-F1	64.01	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 (10): 259, 167, 167, 183, 318, 452, 480, 483, 498, 188

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 0 (showing top):

GO Biological Process (5): regulation of transcription by RNA polymerase II (GO:0006357), positive regulation of cell population proliferation (GO:0008284), negative regulation of DNA-templated transcription (GO:0045892), negative regulation of transcription by RNA polymerase II (GO:0000122), regulation of cell population proliferation (GO:0042127)

GO Molecular Function (6): RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), DNA-binding transcription repressor activity, RNA polymerase II-specific (GO:0001227), histone deacetylase binding (GO:0042826), DNA binding (GO:0003677), protein binding (GO:0005515)

GO Cellular Component (5): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cell junction (GO:0030054), nuclear lumen (GO:0031981)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
cellular anatomical structure	3
regulation of DNA-templated transcription	2
transcription by RNA polymerase II	2
cell population proliferation	2
regulation of transcription by RNA polymerase II	2
regulation of cell population proliferation	1
positive regulation of cellular process	1
DNA-templated transcription	1
negative regulation of RNA biosynthetic process	1
negative regulation of DNA-templated transcription	1
regulation of cellular process	1
cis-regulatory region sequence-specific DNA binding	1
chromatin	1
DNA-binding transcription factor activity	1
negative regulation of transcription by RNA polymerase II	1
DNA-binding transcription factor activity, RNA polymerase II-specific	1
DNA-binding transcription repressor activity	1
enzyme binding	1
nucleic acid binding	1
binding	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
intracellular anatomical structure	1
nucleus	1
intracellular organelle lumen	1

Protein interactions and networks

STRING

1506 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NACC1	GADD45GIP1	Q8TAE8	903
NACC1	HDAC4	P56524	741
NACC1	POU5F1	P31359	696
NACC1	SOX2	P48431	685
NACC1	NANOG	Q9H9S0	582
NACC1	PSMD7	P51665	489
NACC1	RCOR1	Q9UKL0	461
NACC1	MORC3	Q14149	449
NACC1	ZBTB17	Q13105	446
NACC1	POLR2C	P19387	437
NACC1	RPL37A	P12751	435
NACC1	COX7C	P15954	433
NACC1	RANBP10	Q6VN20	429
NACC1	SDC1	P18827	427
NACC1	TCHP	Q9BT92	427

IntAct

71 interactions, top by confidence:

A	B	Type	Score
STRN3	STRN	psi-mi:“MI:2364”(proximity)	0.880
CDK8	MED19	psi-mi:“MI:2364”(proximity)	0.850
ZBTB9	NACC1	psi-mi:“MI:0915”(physical association)	0.590
LGALS8	NACC1	psi-mi:“MI:0915”(physical association)	0.560
LSM3	NACC1	psi-mi:“MI:0915”(physical association)	0.560
PRKCI	NACC1	psi-mi:“MI:0915”(physical association)	0.560
UBTFL1	NACC1	psi-mi:“MI:0915”(physical association)	0.560
EHHADH	NACC1	psi-mi:“MI:0915”(physical association)	0.560
PRPF3	NACC1	psi-mi:“MI:0915”(physical association)	0.560
ELOA	NACC1	psi-mi:“MI:0915”(physical association)	0.560
POLR2L	NACC1	psi-mi:“MI:0915”(physical association)	0.560
NACC1	PRPF18	psi-mi:“MI:0915”(physical association)	0.560
NACC1	C8orf33	psi-mi:“MI:0915”(physical association)	0.560
ZNF512B	NACC1	psi-mi:“MI:0915”(physical association)	0.560
MAP3K5	MAP3K6	psi-mi:“MI:0914”(association)	0.550
FOXP3	FOXP2	psi-mi:“MI:0914”(association)	0.530
ZBTB42	MID1	psi-mi:“MI:0914”(association)	0.530
GREM2	ZZEF1	psi-mi:“MI:0914”(association)	0.530
NDUFC2	NDUFS4	psi-mi:“MI:0914”(association)	0.530
ITLN1	HSPA5	psi-mi:“MI:0914”(association)	0.530
FOXA1	NFIC	psi-mi:“MI:0914”(association)	0.350
FOXA2	FOXN2	psi-mi:“MI:0914”(association)	0.350
FOXJ2	TCERG1	psi-mi:“MI:0914”(association)	0.350
RBPJ	SAMD1	psi-mi:“MI:0914”(association)	0.350
Xpo1	IFT56	psi-mi:“MI:0914”(association)	0.350
IFIH1	DDHD2	psi-mi:“MI:0914”(association)	0.350
ITLN1	TIPRL	psi-mi:“MI:0914”(association)	0.350

BioGRID (142): NACC1 (Affinity Capture-MS), NACC1 (Affinity Capture-MS), NACC1 (Affinity Capture-MS), NACC1 (Affinity Capture-MS), NACC1 (Affinity Capture-MS), NACC1 (Affinity Capture-MS), NACC1 (Affinity Capture-MS), NACC1 (Affinity Capture-MS), NACC1 (Affinity Capture-MS), NACC1 (Biochemical Activity), NACC1 (Affinity Capture-Western), NACC1 (Biochemical Activity), NACC1 (Biochemical Activity), NACC1 (Reconstituted Complex), NACC1 (Affinity Capture-MS)

ESM2 similar proteins: A6QPM3, A7X8B3, A7X8B5, A7X8B7, A7X8B9, A7X8C2, A7X8C4, A7X8C7, A7X8C9, A7X8D2, A7X8D4, A7XW16, A7XW20, A7XW25, E9Q3T6, E9Q6W4, J7FCF0, O14512, O42406, O70361, O75626, O95863, O97775, O97952, O97960, P06186, P06401, P07812, P10275, P41182, P41183, Q02085, Q0VDT2, Q3UZD5, Q562B4, Q5IS79, Q5U5Q3, Q60688, Q62233, Q6F2E4

Diamond homologs: A0JN76, A1L2U9, A1YPR0, B1WAZ8, B1WBS3, B1WBU4, B2RXF5, E1B932, G5E8B9, O14867, O15062, O43167, O43298, O88282, O88939, O93567, O95365, O95625, P10074, P28575, P41182, P41183, P52739, P97302, P97303, Q0IH98, Q0IJ29, Q0P4X6, Q0VCJ6, Q13105, Q14526, Q1H9T6, Q1L8W0, Q3B725, Q3B7M1, Q3B7N9, Q3SWU4, Q3ZB90, Q503R4, Q53G59

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
NACC1	“up-regulates activity”	ZBTB14	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 69 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
mRNA Splicing	6	13.4×	8e-04
Processing of Capped Intron-Containing Pre-mRNA	6	10.1×	2e-03
mRNA Splicing - Major Pathway	8	8.9×	8e-04
Diseases of signal transduction by growth factor receptors and second messengers	6	7.0×	8e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	3
Uncertain significance	206
Likely benign	213
Benign	60

Top pathogenic / likely-pathogenic (5)

Variant ID	HGVS	Classification
1700963	NM_052876.4(NACC1):c.385G>A (p.Asp129Asn)	Pathogenic
3340994	NM_052876.4(NACC1):c.1201C>T (p.Arg401Trp)	Pathogenic
1320157	NM_052876.4(NACC1):c.1384G>A (p.Asp462Asn)	Likely pathogenic
2838693	NM_052876.4(NACC1):c.454G>C (p.Gly152Arg)	Likely pathogenic
3375729	NM_052876.4(NACC1):c.1402C>T (p.Arg468Cys)	Likely pathogenic

SpliceAI

1014 predictions. Top by Δscore:

Variant	Effect	Δscore
19:13135177:A:AG	acceptor_gain	1.0000
19:13135178:T:G	acceptor_gain	1.0000
19:13135186:T:TA	acceptor_gain	1.0000
19:13135195:TGCA:T	acceptor_loss	1.0000
19:13135197:CAGCC:C	acceptor_loss	1.0000
19:13135198:A:AC	acceptor_loss	1.0000
19:13135198:A:AG	acceptor_gain	1.0000
19:13135198:AGCC:A	acceptor_gain	1.0000
19:13135199:G:A	acceptor_loss	1.0000
19:13135199:G:GA	acceptor_gain	1.0000
19:13135199:GCC:G	acceptor_gain	1.0000
19:13135199:GCCG:G	acceptor_gain	1.0000
19:13135199:GCCGC:G	acceptor_gain	1.0000
19:13136402:ACAGG:A	donor_loss	1.0000
19:13136403:CAG:C	donor_loss	1.0000
19:13136404:AGGT:A	donor_loss	1.0000
19:13136406:G:GA	donor_loss	1.0000
19:13136407:T:A	donor_loss	1.0000
19:13137269:A:AG	acceptor_gain	1.0000
19:13137270:G:GA	acceptor_gain	1.0000
19:13137372:GACCG:G	donor_gain	1.0000
19:13137373:ACCG:A	donor_gain	1.0000
19:13137374:CCG:C	donor_gain	1.0000
19:13137375:CG:C	donor_gain	1.0000
19:13137376:GG:G	donor_gain	1.0000
19:13137377:G:GG	donor_gain	1.0000
19:13137462:T:G	acceptor_gain	1.0000
19:13137469:T:TA	acceptor_gain	1.0000
19:13137476:A:AG	acceptor_gain	1.0000
19:13137476:AG:A	acceptor_gain	1.0000

AlphaMissense

3475 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:13135257:T:C	L17P	1.000
19:13135266:T:A	L20H	1.000
19:13135266:T:C	L20P	1.000
19:13135275:A:C	Q23P	1.000
19:13135278:G:C	R24P	1.000
19:13135295:T:C	C30R	1.000
19:13135296:G:A	C30Y	1.000
19:13135296:G:T	C30F	1.000
19:13135297:T:G	C30W	1.000
19:13135298:G:C	D31H	1.000
19:13135298:G:T	D31Y	1.000
19:13135299:A:C	D31A	1.000
19:13135299:A:G	D31G	1.000
19:13135299:A:T	D31V	1.000
19:13135308:T:A	V34E	1.000
19:13135314:T:A	V36D	1.000
19:13135328:T:C	F41L	1.000
19:13135329:T:C	F41S	1.000
19:13135330:C:A	F41L	1.000
19:13135330:C:G	F41L	1.000
19:13135335:C:A	A43D	1.000
19:13135337:C:A	H44N	1.000
19:13135337:C:G	H44D	1.000
19:13135337:C:T	H44Y	1.000
19:13135338:A:G	H44R	1.000
19:13135338:A:T	H44L	1.000
19:13135339:C:A	H44Q	1.000
19:13135339:C:G	H44Q	1.000
19:13135350:T:A	L48H	1.000
19:13135350:T:C	L48P	1.000

dbSNP variants (sampled 300 via entrez): RS1000002684 (19:13126063 T>TA), RS1000118341 (19:13125786 C>T), RS1000317587 (19:13115551 A>G,T), RS1000433615 (19:13115278 C>A), RS1000492182 (19:13131829 A>G), RS1000577631 (19:13141061 T>C), RS1000590592 (19:13122648 T>C,G), RS1000781859 (19:13125414 T>C,G), RS1000956700 (19:13136609 T>A), RS1001012611 (19:13124490 C>T), RS1001066191 (19:13125639 C>G,T), RS1001107726 (19:13118582 G>A,C), RS1001292463 (19:13130427 T>G), RS1001481723 (19:13130943 C>G,T), RS1001507609 (19:13122749 G>A,C,T)

Disease associations

OMIM: gene MIM:610672 | disease phenotypes: MIM:617393

GenCC curated gene-disease

Disease	Classification	Inheritance
neurodevelopmental disorder with epilepsy, cataracts, feeding difficulties, and delayed brain myelination	Strong	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
NACC1-related neurodevelopmental disorder with epilepsy, cataracts and episodic irritability	Definitive	AD

Mondo (3): neurodevelopmental disorder with epilepsy, cataracts, feeding difficulties, and delayed brain myelination (MONDO:0044306), neurodevelopmental disorder (MONDO:0700092), microcephaly (MONDO:0001149)

Orphanet (1): Severe neurodevelopmental disorder with feeding difficulties-stereotypic hand movement-bilateral cataract (Orphanet:500545)

HPO phenotypes

42 total (30 of 42 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000252	Microcephaly
HP:0000455	Broad nasal tip
HP:0000518	Cataract
HP:0000733	Motor stereotypy
HP:0000737	Irritability
HP:0001118	Juvenile cataract
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001257	Spasticity
HP:0001263	Global developmental delay
HP:0001288	Gait disturbance
HP:0001344	Absent speech
HP:0001371	Flexion contracture
HP:0001508	Failure to thrive
HP:0002020	Gastroesophageal reflux
HP:0002059	Cerebral atrophy
HP:0002187	Profound intellectual disability
HP:0002188	Delayed CNS myelination
HP:0002360	Sleep disturbance
HP:0002376	Developmental regression
HP:0002421	Poor head control
HP:0002521	Hypsarrhythmia
HP:0002650	Scoliosis
HP:0002870	Obstructive sleep apnea
HP:0003593	Infantile onset
HP:0005484	Secondary microcephaly
HP:0005949	Apneic episodes in infancy
HP:0007359	Focal-onset seizure

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST001762_11	Obesity-related traits	4.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004626	IGFBP-3 measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500
D065886	Neurodevelopmental Disorders	F03.625

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5724631 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases expression	3
Air Pollutants	affects expression, increases abundance, increases expression	2
Dronabinol	increases glycosylation, increases expression	2
aristolochic acid I	increases expression	1
FR900359	decreases phosphorylation	1
TAK-243	decreases sumoylation	1
dicrotophos	increases expression	1
propylparaben	increases expression	1
bisphenol A	increases expression	1
lead acetate	increases expression	1
methylparaben	increases expression	1
cupric chloride	increases expression	1
3-methyladenosine	affects reaction, affects response to substance	1
phenanthrene	decreases expression	1
perfluorodecanoic acid	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
perfluoro-n-nonanoic acid	decreases expression	1
ICG 001	decreases expression	1
NSC 689534	affects binding, decreases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	decreases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Sunitinib	decreases expression	1
Benzo(a)pyrene	affects methylation	1
Chloroquine	affects reaction, affects response to substance	1
Cisplatin	affects response to substance, affects reaction	1
Copper	affects binding, decreases expression	1
Doxorubicin	decreases expression	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1
Estradiol	increases expression	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
CHEMBL5697668	Binding	Inhibition of NACC1 (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

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT02909959	PHASE2	COMPLETED	Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
NCT06081348	PHASE2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06352372	PHASE2	COMPLETED	Safety and Efficacy of tPBM for Epileptiform Activity in Autism
NCT00503191	PHASE1	COMPLETED	NeuroModulation Technique Treatment of Autism
NCT04475848	PHASE1	COMPLETED	A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants
NCT06300398	PHASE1	COMPLETED	IAMA-6 Oral Dose Study in Healthy Adults
NCT01783041	PHASE2/PHASE3	COMPLETED	Effect of Early L-Carnitine Supplementation on Neurodevelopmental Outcomes in Very Preterm Infants
NCT05767385	PHASE2/PHASE3	RECRUITING	Fetal Cerebrovascular Autoregulation in Congenital Heart Disease and Association With Neonatal Neurobehavior
NCT05675098	EARLY_PHASE1	NOT_YET_RECRUITING	Central Nervous System Stimulants and Physical Function in Children With Cerebral Palsy
NCT00783783	Not specified	COMPLETED	CYP2D6 Pharmacogenetics in Risperidone-Treated Children
NCT01778504	Not specified	RECRUITING	Studying Childhood-onset Behavioral, Psychiatric, and Developmental Disorders
NCT01850784	Not specified	UNKNOWN	High Energy Formula Feeding in Infants With Congenital Heart Disease
NCT01922791	Not specified	COMPLETED	Nutrition and Pregnancy Intervention Study
NCT01942525	Not specified	UNKNOWN	Influence of Intrauterine Growth Restriction on Amplitude-integrated EEG in Preterm Infants
NCT02003170	Not specified	COMPLETED	Etiology and Early Diagnosis of Neurodevelopmental Disorders
NCT02118649	Not specified	ACTIVE_NOT_RECRUITING	Enhancing Behavior and Brain Response to Visual Targets Using a Computer Game
NCT02557191	Not specified	TERMINATED	Biomarkers, Neurodevelopment and Preterm Infants
NCT02690675	Not specified	COMPLETED	Iron Supplement Effect on Child Development
NCT02694003	Not specified	COMPLETED	Better Nights, Better Days for Children With Neurodevelopment Disorders
NCT02792894	Not specified	COMPLETED	Family Networks (FaNs) for Children With Developmental Disorders and Delays
NCT02871674	Not specified	UNKNOWN	Good Night Project: Behavioural Sleep Interventions for Children With ADHD: A Randomised Controlled Trial
NCT02887157	Not specified	COMPLETED	Analyzing Retinal Microanatomy in ROP
NCT02898298	Not specified	COMPLETED	Positive Emotion Regulation Training in Children, Adolescents and Young Adults With and Without Developmental Disorder
NCT02912780	Not specified	UNKNOWN	Introduction of Microsystems in a Level 3 Neonatal Intensive Care Unit
NCT03023293	Not specified	COMPLETED	n-3 PUFAs, Irisin and Maternal Glucose Metabolism From Pregnancy to Postpartum
NCT03023644	Not specified	COMPLETED	Improving Neurodevelopmental Outcomes in Children With Congenital Heart Disease: An Intervention Study
NCT03032991	Not specified	UNKNOWN	Early Biomarkers of Neurodevelopment in Offspring of Diabetic Mothers
NCT03088189	Not specified	TERMINATED	Effect of Parental Peri-conceptional Vitamin B12 Supplementation on Infant Neurocognitive Development in Offspring
NCT03096028	Not specified	COMPLETED	Developmental Origins of Mental Health Disorders
NCT03148782	Not specified	COMPLETED	Brain Plasticity Underlying Acquisition of New Organizational Skills in Children-R61 Phase
NCT03172104	Not specified	COMPLETED	Neurobehavioural Development of Infants Born <30 Weeks Gestational Age Between Birth and Five Years of Age
NCT03222375	Not specified	RECRUITING	SQUED™ Series 28.1 Home-use and Treatment of Autowave Reverberator of Autism
NCT03229928	Not specified	COMPLETED	Clinical Testing of a Real-Time Behavior Measurement Tool: Measuring Outcomes for CHAnge
NCT03232489	Not specified	UNKNOWN	Study for the Evaluation of the Feasibility of Applying Advanced MRI Scanning in Pediatric Clinical Practice