ENC1

Summary

ENC1 (ectodermal-neural cortex 1, HGNC:3345) is a protein-coding gene on chromosome 5q13.3, encoding Ectoderm-neural cortex protein 1 (O14682). Actin-binding protein involved in the regulation of neuronal process formation and in differentiation of neural crest cells.

This gene encodes a member of the kelch-related family of actin-binding proteins. The encoded protein plays a role in the oxidative stress response as a regulator of the transcription factor Nrf2, and expression of this gene may play a role in malignant transformation. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene.

Source: NCBI Gene 8507 — RefSeq curated summary.

At a glance

• GWAS associations: 5
• Clinical variants (ClinVar): 41 total — 1 pathogenic
• GTEx eGene: eQTL in 29 tissues, sQTL in 2 (q < 0.05)
• Constraint (gnomAD): pLI 0.06 (LoF-tolerant), LOEUF 0.65 (unconstrained)
• MANE Select transcript: NM_003633

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3345
Approved symbol	ENC1
Name	ectodermal-neural cortex 1
Location	5q13.3
Locus type	gene with protein product
Status	Approved
Aliases	PIG10, ENC-1, TP53I10, KLHL37
Ensembl gene	ENSG00000171617
Ensembl biotype	protein_coding
OMIM	605173
Entrez	8507

Gene structure

Transcript identifiers

Ensembl transcripts: 20 — 19 protein_coding, 1 protein_coding_CDS_not_defined

MANE Select: ENST00000302351

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 1, TSL 2: 1, TSL 3: 1, TSL 4: 2, TSL 5: 1

ENST00000302351, ENST00000508331, ENST00000509127, ENST00000509284, ENST00000510316, ENST00000618628, ENST00000651128, ENST00000875692, ENST00000875693, ENST00000875694, ENST00000875695, ENST00000875696, ENST00000875697, ENST00000875698, ENST00000875699, ENST00000875700, ENST00000875701, ENST00000875702, ENST00000928979, ENST00001137084

RefSeq mRNA: 4 — MANE Select: NM_003633 NM_001256574, NM_001256575, NM_001256576, NM_003633

CCDS: CCDS4021, CCDS58958

Canonical transcript exons

ENST00000302351 — 3 exons

Exon	Start	End
ENSE00001128061	74627409	74629992
ENSE00001171615	74634684	74636498
ENSE00003244649	74640307	74640728

Expression profiles

Bgee: expression breadth ubiquitous, 280 present calls, max score 99.88.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 46.1902 / max 1865.4284, expressed in 1690 samples.

Highest expression (Bgee): Brodmann (1909) area 10, frontal pole, middle temporal gyrus, ganglionic eminence, orbitofrontal cortex.

Genetic regulation across tissues (GTEx eQTL / sQTL)

ENC1 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 29 tissues and its splicing (sQTL) in 2 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 31 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Whole Blood	eqtl	2.6e-94	+0.92	5:74631711:TG:T
Cells Cultured fibroblasts	eqtl	9.4e-55	+0.47	5:74638399:A:G
Skin Sun Exposed Lower leg	eqtl	2.3e-27	+0.35	5:74639733:CT:C
Testis	eqtl	4.8e-26	+0.43	5:74636490:T:C
Cells EBV-transformed lymphocytes	eqtl	1.9e-22	+0.58	5:74487158:G:T
Skin Not Sun Exposed Suprapubic	eqtl	6.0e-12	+0.22	5:74639733:CT:C
Esophagus Mucosa	eqtl	6.2e-08	-0.33	5:74651367:A:G
Pancreas	eqtl	8.9e-07	+0.31	5:74639733:CT:C
Nerve Tibial	eqtl	1.4e-06	+0.26	5:74644605:A:T
Spleen	eqtl	3.1e-05	+0.33	5:74639581:T:C
Pituitary	eqtl	6.5e-05	+0.24	5:74634617:C:T
Colon Transverse	eqtl	9.7e-05	+0.14	5:74651538:T:C
Lung	eqtl	3.2e-04	+0.17	5:74639581:T:C
Muscle Skeletal	eqtl	8.4e-04	-0.14	5:74400667:A:T
Prostate	eqtl	8.5e-04	-0.45	5:74063642:A:G
Adipose Subcutaneous	eqtl	2.0e-03	+0.19	5:74638428:G:T
Minor Salivary Gland	eqtl	2.0e-03	+0.38	5:74640835:T:C
Adipose Visceral Omentum	eqtl	2.3e-03	+0.20	5:74651766:A:G
Stomach	eqtl	3.6e-03	+0.13	5:74634617:C:T
Colon Sigmoid	eqtl	3.6e-03	+0.16	5:74639733:CT:C

FANTOM5 promoters

showing 10 of 19 alternative TSS:

Promoter ID	TPM avg	Samples expressed
62078	30.0581	1600
62075	11.2163	1568
62077	1.6111	344
62076	1.0718	289
62079	0.4183	115
62081	0.3049	131
62082	0.2525	86
62087	0.2428	88
62074	0.1770	80
62073	0.1617	66

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
Brodmann (1909) area 10	UBERON:0013541	99.88	gold quality
frontal pole	UBERON:0002795	99.86	gold quality
middle temporal gyrus	UBERON:0002771	99.67	gold quality
ganglionic eminence	UBERON:0004023	99.54	gold quality
orbitofrontal cortex	UBERON:0004167	99.41	gold quality
Brodmann (1909) area 46	UBERON:0006483	99.25	gold quality
superior frontal gyrus	UBERON:0002661	99.21	gold quality
CA1 field of hippocampus	UBERON:0003881	99.20	gold quality
ventricular zone	UBERON:0003053	99.02	gold quality
parietal lobe	UBERON:0001872	98.92	gold quality
postcentral gyrus	UBERON:0002581	98.76	gold quality
cortical plate	UBERON:0005343	98.35	gold quality
Brodmann (1909) area 23	UBERON:0013554	98.32	gold quality
entorhinal cortex	UBERON:0002728	98.20	gold quality
prefrontal cortex	UBERON:0000451	98.16	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	98.13	gold quality
frontal lobe	UBERON:0016525	97.92	gold quality
frontal cortex	UBERON:0001870	97.91	gold quality
neocortex	UBERON:0001950	97.69	gold quality
occipital lobe	UBERON:0002021	97.69	gold quality
cerebral cortex	UBERON:0000956	97.67	gold quality
Brodmann (1909) area 9	UBERON:0013540	97.64	gold quality
middle frontal gyrus	UBERON:0002702	97.56	gold quality
adult organism	UBERON:0007023	97.52	gold quality
primary visual cortex	UBERON:0002436	97.10	gold quality
cingulate cortex	UBERON:0003027	96.76	gold quality
embryo	UBERON:0000922	96.74	gold quality
anterior cingulate cortex	UBERON:0009835	96.74	gold quality
temporal lobe	UBERON:0001871	96.64	gold quality
Ammon’s horn	UBERON:0001954	96.37	gold quality
pylorus	UBERON:0001166	96.24	gold quality
right frontal lobe	UBERON:0002810	96.07	gold quality
pons	UBERON:0000988	95.77	gold quality
amygdala	UBERON:0001876	95.34	gold quality
telencephalon	UBERON:0001893	95.05	gold quality
mucosa of urinary bladder	UBERON:0001259	94.85	gold quality
superior vestibular nucleus	UBERON:0007227	94.40	gold quality
lateral globus pallidus	UBERON:0002476	94.25	gold quality
nasal cavity epithelium	UBERON:0005384	93.30	gold quality
forebrain	UBERON:0001890	92.76	gold quality
cardia of stomach	UBERON:0001162	92.12	gold quality
adrenal tissue	UBERON:0018303	92.04	gold quality
endometrium epithelium	UBERON:0004811	91.20	gold quality
olfactory bulb	UBERON:0002264	90.66	gold quality
endothelial cell	CL:0000115	90.36	gold quality
islet of Langerhans	UBERON:0000006	90.24	gold quality
ventral tegmental area	UBERON:0002691	90.19	gold quality
hair follicle	UBERON:0002073	90.12	gold quality
type B pancreatic cell	CL:0000169	89.52	gold quality
nucleus accumbens	UBERON:0001882	89.52	gold quality
medulla oblongata	UBERON:0001896	89.52	gold quality
corpus callosum	UBERON:0002336	89.37	gold quality
gall bladder	UBERON:0002110	89.28	gold quality
brain	UBERON:0000955	89.26	gold quality
putamen	UBERON:0001874	89.25	gold quality
central nervous system	UBERON:0001017	88.72	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	88.61	gold quality
pancreas	UBERON:0001264	88.17	gold quality
caudate nucleus	UBERON:0001873	87.92	gold quality
rectum	UBERON:0001052	87.76	gold quality
diaphragm	UBERON:0001103	87.71	silver quality
germinal epithelium of ovary	UBERON:0001304	87.37	gold quality
epithelial cell of pancreas	CL:0000083	87.25	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	87.25	gold quality
body of pancreas	UBERON:0001150	87.18	gold quality
seminal vesicle	UBERON:0000998	86.94	gold quality
trachea	UBERON:0003126	86.50	gold quality
superficial temporal artery	UBERON:0001614	86.38	silver quality
mucosa of sigmoid colon	UBERON:0004993	86.25	gold quality
visceral pleura	UBERON:0002401	86.16	gold quality
saphenous vein	UBERON:0007318	86.14	gold quality
urethra	UBERON:0000057	85.88	gold quality
pharyngeal mucosa	UBERON:0000355	85.84	gold quality
caecum	UBERON:0001153	85.74	gold quality
pancreatic ductal cell	CL:0002079	85.66	silver quality
hypothalamus	UBERON:0001898	85.53	gold quality
thymus	UBERON:0002370	85.51	silver quality
colonic mucosa	UBERON:0000317	85.44	gold quality
superior surface of tongue	UBERON:0007371	85.23	gold quality
nasal cavity mucosa	UBERON:0001826	85.22	gold quality
duodenum	UBERON:0002114	84.92	gold quality
mucosa of paranasal sinus	UBERON:0005030	84.80	gold quality
ovary	UBERON:0000992	84.68	gold quality
mammary duct	UBERON:0001765	84.58	gold quality
epithelium of mammary gland	UBERON:0003244	84.56	gold quality
nipple	UBERON:0002030	84.15	gold quality
vermiform appendix	UBERON:0001154	84.09	gold quality
dorsal plus ventral thalamus	UBERON:0001897	84.00	gold quality
substantia nigra pars compacta	UBERON:0001965	83.97	gold quality
upper arm skin	UBERON:0004263	83.59	gold quality
pericardium	UBERON:0002407	83.37	gold quality
pleura	UBERON:0000977	83.12	gold quality
liver	UBERON:0002107	83.09	gold quality
stomach	UBERON:0000945	82.97	gold quality
tongue	UBERON:0001723	82.87	silver quality
left ovary	UBERON:0002119	82.86	gold quality
cerebellar vermis	UBERON:0004720	82.84	gold quality
subthalamic nucleus	UBERON:0001906	82.82	gold quality
left ventricle myocardium	UBERON:0006566	82.72	silver quality
minor salivary gland	UBERON:0001830	82.43	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-HCAD-30	yes	2192.51
E-HCAD-56	yes	1174.27
E-GEOD-109979	yes	1099.45
E-MTAB-8894	yes	1082.84
E-HCAD-25	yes	913.48
E-HCAD-5	yes	807.07
E-MTAB-10018	yes	173.85
E-HCAD-35	yes	58.25
E-CURD-114	yes	10.41
E-ANND-3	yes	7.09
E-ENAD-27	yes	6.68

HPA expression

RNA tissue specificity: Tissue enriched

showing 60 of 76 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM
Cerebral cortex	tissue	688.5
Somatosensory cortex	tissue	688.5
Motor cortex	tissue	686.5
Occipital cortex	tissue	634.6
Prefrontal cortex	tissue	593.3
Retrosplenial and cingulate cortex	tissue	526.6
Temporal cortex	tissue	516.2
Hippocampal formation	tissue	514.5
Entorhinal cortex	tissue	514.5
Retrosplenial cortex	tissue	503.3
Insular cortex	tissue	493.1
Postcentral gyrus	tissue	463.2
Hippocampus	tissue	392.5
Frontal cortex	tissue	318.0
Basal ganglia	tissue	187.3
Caudate putamen	tissue	174.2
Putamen	tissue	160.1
Amygdala	tissue	150.0
Locus coeruleus	tissue	130.5
Ventral forebrain	tissue	106.5
Midbrain	tissue	75.8
Septum	tissue	72.6
Nucleus accumbens	tissue	71.0
Olfactory bulb	tissue	61.9
Superior colliculi	tissue	61.7
Thalamus	tissue	58.8
Ovary	tissue	42.9
Pons	tissue	39.2
Corpus callosum	tissue	36.5
Hypothalamus	tissue	32.0
Pancreas	tissue	30.9
Stomach 1	tissue	25.5
Spinal cord	tissue	25.5
Parathyroid gland	tissue	23.2
Small intestine	tissue	20.3
Rectum	tissue	19.9
Urinary bladder	tissue	18.9
Periaqueductal gray	tissue	18.9
Seminal vesicle	tissue	18.2
Gallbladder	tissue	18.0
Liver	tissue	17.6
Substantia nigra	tissue	17.1
Bone marrow	tissue	16.9
Duodenum	tissue	16.8
Medulla oblongata	tissue	16.6
Colon	tissue	13.8
Appendix	tissue	12.8
Choroid plexus	tissue	12.7
Lung	tissue	12.0
Testis	tissue	11.3
Prostate	tissue	11.0
Placenta	tissue	10.7
Spleen	tissue	10.7
Cervix	tissue	9.3
Cerebellum	tissue	7.9
Heart muscle	tissue	7.7
Smooth muscle	tissue	7.1
Pituitary gland	tissue	6.8
Thymus	tissue	6.6
Endometrium 1	tissue	6.5

Brain sub-regions (HPA Brain Atlas): detected in 189; highest nTPM — Hippocampus, CA1 (601.6), Olfactory area (578.0), Perirhinal gyrus (563.9), Temporal pole (531.1), Transversal temporal gyrus, anterior (494.0).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CTNNB1, NFE2L2, TCF4, TCF7L2

miRNA regulators (miRDB)

Targeting ENC1 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 143 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-6758-5P	100.00	66.21	1470
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-4481	100.00	66.42	1669
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-33A-5P	99.99	68.62	1055
HSA-MIR-33B-5P	99.99	68.58	1062
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
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-607	99.97	73.62	5593
HSA-MIR-5688	99.96	73.23	4504
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-8082	99.95	67.27	1170
HSA-MIR-1236-3P	99.94	68.04	1695
HSA-MIR-539-5P	99.93	70.30	2855
HSA-MIR-338-5P	99.92	72.34	2951
HSA-MIR-6809-3P	99.91	71.45	3814
HSA-MIR-4648	99.91	67.00	710

Functional genomics

gnomAD constraint: pLI 0.0639, LOEUF 0.653, missense Z 3.87 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000302351 — one region, missense o/e 0.65.

Literature-anchored findings (GeneRIF, showing 12)

• results suggest that upregulation of ENC-1 contributes to the development of HCL and provides new information on the possible dysregulation of ENC-1 including expression of a novel antisense gene, ENC-1AS (PMID:15459180)
• NRP/B enhances oxidative stress responses in breast cancer cells via the Nrf2 pathway, identifying a novel role of nuclear matrix protein(s) in oxidative stress responses. (PMID:17875699)
• NRP/B mutations impair Nrf2-dependent NQO1 induction in primary brain tumors. (PMID:18981988)
• ENC1 functions as a negative regulator of Nrf2 through suppressing Nrf2 protein translation. (PMID:19424503)
• ENC1 interacts with the phosphorylated p62 to impair autophagic degradation of mutant huntingtin protein aggregates. (PMID:26637326)
• we identified ENC1 and UNC5C as genes with convergent genetic, epigenetic, and transcriptomic evidence supporting a potential role in the dissociation of cognition and neuropathology in an aging population. (PMID:28441426)
• The low expression of ENC1 was associated with favorable prognosis in ovarian cancer patients. And the knockdown of ENC1 can significantly inhibit ovarian cancer cell proliferation, migration, and invasion. (PMID:30125994)
• Ectodermal-neural cortex 1 as a novel biomarker predicts poor prognosis and induces metastasis in breast cancer by promoting Wnt/beta-catenin pathway. (PMID:32618411)
• Ectodermalneural cortex 1 affects the biological function of lung cancer through the MAPK pathway. (PMID:33693958)
• Aberrant super-enhancer-driven oncogene ENC1 promotes the radio-resistance of breast carcinoma. (PMID:34362881)
• The emerging role of ectodermal neural cortex 1 in cancer. (PMID:38177640)
• Comprehensive pan-cancer analysis reveals ENC1 as a promising prognostic biomarker for tumor microenvironment and therapeutic responses. (PMID:39455818)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	enc1	ENSDARG00000035398
mus_musculus	Enc1	ENSMUSG00000041773
rattus_norvegicus	Enc1	ENSRNOG00000016541
drosophila_melanogaster	gprs	FBGN0024232

Paralogs (2): KLHL25 (ENSG00000183655), BTBD17 (ENSG00000204347)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:109610) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 6 distinct phenotype terms.

Mouse phenotype (MP)	Records
decreased circulating HDL cholesterol level	1
increased circulating alkaline phosphatase level	1
decreased circulating cholesterol level	1
increased circulating bilirubin level	1
decreased circulating glucose level	1
decreased blood urea nitrogen level	1

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Culex quinquefasciatus	B0WWP2	100.0%	Diamond
Drosophila sechellia	B4HIK1	100.0%	Diamond
Drosophila yakuba	B4PD06	100.0%	Diamond
Drosophila simulans	B4QLQ2	100.0%	Diamond
Bos taurus	Q08DK3	100.0%	Diamond
Aedes aegypti	Q16RL8	100.0%	Diamond
Drosophila erecta	B3NDN0	99.8%	Diamond
Pongo abelii	Q5R7B8	99.8%	Diamond
Drosophila mojavensis	B4L0G9	99.2%	Diamond
Xenopus laevis	Q6DFF6	99.0%	Diamond
Drosophila persimilis	B4GRJ2	98.9%	Diamond
Drosophila willistoni	B4MXW3	98.9%	Diamond
Drosophila pseudoobscura pseudoobscura	Q2M0J9	98.9%	Diamond
Gallus gallus	Q5ZKD9	98.7%	Diamond
Drosophila ananassae	B3M9V8	98.6%	Diamond
Drosophila virilis	B4LIG6	98.4%	Diamond
Anopheles gambiae	Q7QGL0	98.4%	Diamond
Drosophila grimshawi	B4J045	97.5%	Diamond
Xenopus tropicalis	Q0D2A9	94.6%	Diamond
Caenorhabditis elegans	P34568	68.6%	Diamond
Anopheles stephensi	Q70JS2	60.5%	Diamond
Arabidopsis thaliana	Q9XHZ8	51.2%	Diamond
Dictyostelium discoideum	Q54D84	45.9%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
LINC01335	ncRNA	102503429
LINC01331	ncRNA	104310351
HEXB	protein-coding	3074
FAM169A	protein-coding	26049
FAM169A-AS1	ncRNA	441086
GFM2	protein-coding	84340
LINC01333	ncRNA	101929082
NSA2	protein-coding	10412

Protein

Protein identifiers

Ectoderm-neural cortex protein 1 — O14682 (reviewed: O14682)

Alternative names: Kelch-like protein 37, Nuclear matrix protein NRP/B, p53-induced gene 10 protein

All UniProt accessions (3): O14682, D6R9D7, Q53XS2

UniProt curated annotations — full annotation on UniProt →

Function. Actin-binding protein involved in the regulation of neuronal process formation and in differentiation of neural crest cells. Down-regulates transcription factor NF2L2/NRF2 by decreasing the rate of protein synthesis and not via a ubiquitin-mediated proteasomal degradation mechanism.

Subunit / interactions. Binds to RB1. Hypophosphorylated RB1 associates with ENC1 during neuronal differentiation, while hyperphosphorylated RB1 associates with ENC1 in undifferentiating cells. Part of a complex that contains CUL3, RBX1 and ENC1. Interacts indirectly with KEAP1.

Subcellular location. Nucleus matrix. Cytoplasm. Cytoskeleton.

Tissue specificity. Detected in fetal brain tissue, moderate expression in fetal heart, lung and kidney. Highly expressed in adult brain, particularly high in the hippocampus and amygdala, and spinal cord. Detectable in adult pancreas. May be down-regulated in neuroblastoma tumors.

Post-translational modifications. Ubiquitinated by E3 ubiquitin ligase complex formed by CUL3 and RBX1 and probably targeted for proteasome-independent degradation. Quinone-induced oxidative stress increases its ubiquitination.

Induction. By p53/TP53.

Isoforms (2)

UniProt ID	Names	Canonical?
O14682-1	1	yes
O14682-2	2

RefSeq proteins (4): NP_001243503, NP_001243504, NP_001243505, NP_003624* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000210	BTB/POZ_dom	Domain
IPR006652	Kelch_1	Repeat
IPR011333	SKP1/BTB/POZ_sf	Homologous_superfamily
IPR011705	BACK	Domain
IPR015915	Kelch-typ_b-propeller	Homologous_superfamily
IPR017096	BTB-kelch_protein	Family
IPR030562	ENC1_BTB_POZ_dom	Domain
IPR047097	ENC1_BACK	Domain

Pfam: PF00651, PF01344, PF07707, PF24681

UniProt features (18 total): sequence conflict 8, repeat 6, chain 1, domain 1, splice variant 1, sequence variant 1

Structure

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O14682-F1	88.22	0.62

Human Protein Atlas

Protein class: Predicted intracellular proteins, Cancer-related genes, Candidate cancer biomarkers

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): plasma membrane

Antibody reliability (HPA): IF uncertain

Function

Pathways and Gene Ontology

Reactome pathways

0 curated (TAS) of 0; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

MSigDB gene sets: 450 (showing top): GSE45365_NK_CELL_VS_CD11B_DC_DN, GSE45365_NK_CELL_VS_BCELL_UP, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_UP, GRAESSMANN_RESPONSE_TO_MC_AND_SERUM_DEPRIVATION_UP, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_NEUROGENESIS, GOBP_NEGATIVE_REGULATION_OF_TRANSLATION, RODRIGUES_NTN1_TARGETS_DN, GOBP_TRANSLATION, GOBP_POST_TRANSCRIPTIONAL_REGULATION_OF_GENE_EXPRESSION

GO Biological Process (8): ubiquitin-dependent protein catabolic process (GO:0006511), nervous system development (GO:0007399), proteasomal ubiquitin-independent protein catabolic process (GO:0010499), positive regulation of neuron projection development (GO:0010976), protein ubiquitination (GO:0016567), negative regulation of translation (GO:0017148), proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161), regulation of primary metabolic process (GO:0080090)

GO Molecular Function (3): actin binding (GO:0003779), ubiquitin-like ligase-substrate adaptor activity (GO:1990756), protein binding (GO:0005515)

GO Cellular Component (8): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytoskeleton (GO:0005856), nuclear matrix (GO:0016363), Cul3-RING ubiquitin ligase complex (GO:0031463), neuronal cell body (GO:0043025)

GO top-level categories

28 GO namespaces:

Category	Terms
cellular anatomical structure	4
proteasomal protein catabolic process	2
nuclear lumen	2
protein ubiquitination	1
modification-dependent protein catabolic process	1
system development	1
animal gross anatomical part developmental process	1
regulation of neuron projection development	1
neuron projection development	1
positive regulation of cell projection organization	1
protein modification by small protein conjugation	1
translation	1
regulation of translation	1
negative regulation of gene expression	1
negative regulation of protein metabolic process	1
ubiquitin-dependent protein catabolic process	1
regulation of metabolic process	1
primary metabolic process	1
cytoskeletal protein binding	1
enzyme-substrate adaptor activity	1
binding	1
chromosome	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
intracellular membraneless organelle	1
cullin-RING ubiquitin ligase complex	1
somatodendritic compartment	1
cell body	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 5 of 19 annotations. The rest are phylogenetic / computational / electronic (IEA).

5 experimentally-supported GO terms:

GO term	NS	Evidence
negative regulation of translation	BP	direct assay
proteasomal ubiquitin-independent protein catabolic process	BP	direct assay
protein ubiquitination	BP	direct assay
Cul3-RING ubiquitin ligase complex	CC	direct assay
cytoplasm	CC	direct assay

Protein interactions and networks

STRING

showing 15 of 736 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ENC1	HEXB	P07686	921
ENC1	OGA	O60502	661
ENC1	SNX33	Q8WV41	612
ENC1	PLAGL2	Q9UPG8	536
ENC1	RAG1	P15918	494
ENC1	GM2A	P17900	493
ENC1	TBR1	Q16650	461
ENC1	ARRDC4	Q8NCT1	445
ENC1	GPR85	P60893	431
ENC1	ZIC1	Q15915	413
ENC1	PTCHD4	Q6ZW05	404
ENC1	FICD	Q9BVA6	400
ENC1	TCHP	Q9BT92	390
ENC1	RPS14	P06366	388
ENC1	SLC17A6	Q9P2U8	379

IntAct

Human interaction partners of ENC1 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

18 partners by confidence:

Partner	Interaction type	MIscore	Records
CUL3	association	0.640	1
KLHL25	association	0.640	1
KLHL9	association	0.640	1
SQSTM1	physical association	0.560	5
HTT	colocalization	0.540	4
PLIN5	association	0.530	2
HSP90AB1	physical association	0.400	1
SPG11	physical association	0.370	1
FBXL17	association	0.350	2
ALDH3B1	association	0.350	1
BACH1	association	0.350	1
BACH2	association	0.350	1
CUL1	association	0.350	1
DNAJA2	association	0.350	1
EPHA1	association	0.350	1
IGKC	association	0.350	1
DISC1	physical association	0.000	1
DSCAM	physical association	0.000	1

BioGRID (49 interactions; top human partners by supporting records): CUL3 (Affinity Capture-MS; 7 records), NFE2L2 (Affinity Capture-Western; 7 records), RB1 (Affinity Capture-Western; 3 records), ACTB (Far Western; 2 records), KLHL25 (Affinity Capture-MS; 2 records), NACC1 (Two-hybrid; 2 records), NUDCD3 (Affinity Capture-MS; 2 records), PLIN5 (Affinity Capture-MS; 2 records), SQSTM1 (Affinity Capture-Western; 2 records), AGO2 (Affinity Capture-RNA), BACH2 (Affinity Capture-MS), DSCAM (Two-hybrid), FBXL17 (Affinity Capture-Western), HNRNPL (Affinity Capture-RNA), HSP90AA1 (Affinity Capture-Luminescence)

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 18 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
Neddylation	5	18.2×	3e-04

GO biological processes:

GO term	Partners	Fold	FDR
protein ubiquitination	5	12.2×	9e-03

Disease & clinical

Genetic variants

Variant evidence for ENC1: 41 ClinVar records (1 pathogenic / likely pathogenic); 5 GWAS associations. Per-variant detail is on Sugi Variant.

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	33
Likely benign	0
Benign	1

Top pathogenic / likely-pathogenic (1)

Showing all 1 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
3883	NC_000005.10:g.(?74640023)(74705321_74713505)del	Pathogenic	no assertion criteria provided	1

Per-variant reference — Sugi Variant

Explore ENC1’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 28 predictions of 340):

Position(s)	Effect	Δscore	Sites
5:74637568	donor_gain	0.9900
5:74629993–74629994	acceptor_loss	0.9800	3
5:74636499–74636500	acceptor_loss	0.9800	6
5:74639891	donor_gain	0.9800
5:74640305–74640306	donor_loss	0.9800	5
5:74629993–74629994	acceptor_loss	0.9700	3
5:74631701	donor_gain	0.9700
5:74634682–74634683	donor_loss	0.9700	6
5:74637482	donor_gain	0.9700
5:74640032	donor_gain	0.9700

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

1 prognostic cancer types:

Cancer	Prognostic	p-value
Breast Invasive Carcinoma (TCGA)	unfavorable	0.000604

Disease associations

OMIM: gene MIM:605173 | disease phenotypes:

GenCC curated gene-disease

Mondo (1): Sandhoff disease, infantile form (MONDO:0017721)

Orphanet (1): Sandhoff disease, infantile form (Orphanet:309155)

GWAS associations

5 associations:

Study	Trait	p-value
GCST003989_32	Chin dimples	5e-12
GCST004025_5	Systemic juvenile idiopathic arthritis	5e-7
GCST006444_20	Bone mineral density (hip)	5e-6
GCST003542_85	Night sleep phenotypes	8e-6
GCST004291_3	Residual cognition	8e-6

EFO canonical traits (from GWAS)

3 canonical traits:

EFO ID	Trait name
EFO:0003925	cognition
EFO:0022597	aging
EFO:0007702	hip bone mineral density

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (CPIC guideline: no)

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Estradiol	affects expression, affects cotreatment, decreases expression, increases expression	5
Valproic Acid	decreases methylation, increases expression, affects expression, decreases expression	5
Cyclosporine	affects cotreatment, decreases expression	5
bisphenol A	affects expression, decreases expression	4
trichostatin A	affects cotreatment, affects expression, affects methylation, increases expression	4
sodium arsenite	affects methylation, decreases expression, increases abundance, increases expression	4
Resveratrol	affects cotreatment, decreases expression, increases expression	4
Tretinoin	decreases expression, increases expression	4
Aflatoxin B1	affects expression, increases expression, increases methylation	4
Benzo(a)pyrene	increases expression, increases methylation	3
Formaldehyde	decreases expression, increases expression	3
methylmercuric chloride	increases expression	2
Vorinostat	decreases expression, increases expression	2
Acetaminophen	decreases expression, increases expression	2
Doxorubicin	increases expression	2
Ethinyl Estradiol	affects expression, decreases expression	2
Hydrogen Peroxide	affects expression, increases expression	2
Lipopolysaccharides	affects expression, affects cotreatment, decreases expression, affects reaction	2
Progesterone	affects cotreatment, decreases expression	2
Silicon Dioxide	increases expression	2
Tamoxifen	affects cotreatment, decreases expression, increases expression, affects expression	2
Tunicamycin	decreases expression	2
Raloxifene Hydrochloride	affects expression, affects cotreatment, decreases expression, increases expression	2
3-((6-(2-methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methane sulfonamide	decreases expression	1
GSK-J4	increases expression	1
3,19-(2-bromobenzylidene)andrographolide	decreases expression, decreases response to substance	1
urushiol	decreases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, decreases expression, increases abundance	1
pirinixic acid	affects binding, decreases expression, increases activity	1

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.