NEURL1

Summary

NEURL1 (neuralized E3 ubiquitin protein ligase 1, HGNC:7761) is a protein-coding gene on chromosome 10q24.33, encoding E3 ubiquitin-protein ligase NEURL1 (O76050). Plays a role in hippocampal-dependent synaptic plasticity, learning and memory.

Predicted to enable translation regulator activity and ubiquitin protein ligase activity. Involved in negative regulation of Notch signaling pathway; negative regulation of cell population proliferation; and positive regulation of apoptotic process. Located in plasma membrane.

Source: NCBI Gene 9148 — automated summary from GO annotations (Alliance of Genome Resources).

At a glance

• GWAS associations: 20
• Clinical variants (ClinVar): 93 total
• GTEx eGene: eQTL in 19 tissues, sQTL in 2 (q < 0.05)
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 1.04 (unconstrained)
• MANE Select transcript: NM_004210
• Notable: 93 clinical variants but no curated precision-oncology (CIViC) evidence yet

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7761
Approved symbol	NEURL1
Name	neuralized E3 ubiquitin protein ligase 1
Location	10q24.33
Locus type	gene with protein product
Status	Approved
Aliases	h-neu, RNF67, neu-1
Ensembl gene	ENSG00000107954
Ensembl biotype	protein_coding
OMIM	603804
Entrez	9148

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 7 protein_coding, 1 protein_coding_CDS_not_defined

MANE Select: ENST00000369780

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

ENST00000369780, ENST00000437579, ENST00000455386, ENST00000465048, ENST00000945279, ENST00001028967, ENST00001093521, ENST00001135947

RefSeq mRNA: 1 — MANE Select: NM_004210 NM_004210

CCDS: CCDS7551

Canonical transcript exons

ENST00000369780 — 6 exons

Exon	Start	End
ENSE00000723390	103584536	103585225
ENSE00000723391	103589514	103589660
ENSE00001161351	103590134	103592546
ENSE00001450873	103493705	103494472
ENSE00003501364	103570872	103571113
ENSE00003789384	103571501	103571822

Expression profiles

Bgee: expression breadth ubiquitous, 193 present calls, max score 96.28.

FANTOM5 (CAGE): breadth broad, TPM avg 7.7948 / max 213.5105, expressed in 853 samples.

Highest expression (Bgee): hindlimb stylopod muscle, hemisphere of cerebellum, gastrocnemius, cerebellar hemisphere, cerebellar cortex.

Genetic regulation across tissues (GTEx eQTL / sQTL)

NEURL1 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 19 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 21 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Cells Cultured fibroblasts	eqtl	4.4e-16	-0.55	10:103582915:A:G
Artery Tibial	eqtl	2.8e-10	+0.33	10:103585444:C:A
Pancreas	eqtl	1.8e-07	+0.44	10:103549237:T:A
Testis	sqtl	1.3e-05	-0.60	10:103630919:C:T
Nerve Tibial	eqtl	2.6e-04	-0.20	10:103579065:G:A
Skin Not Sun Exposed Suprapubic	eqtl	4.3e-04	+0.20	10:103584999:T:C
Skin Sun Exposed Lower leg	eqtl	6.6e-04	+0.19	10:103584999:T:C
Artery Aorta	eqtl	1.5e-03	+0.37	10:102828147:T:A
Adipose Subcutaneous	eqtl	1.6e-03	+0.20	10:103574095:T:C
Esophagus Muscularis	eqtl	1.9e-03	-0.17	10:103907352:T:C
Brain Caudate basal ganglia	eqtl	3.1e-03	-0.10	10:103593233:G:T
Lung	eqtl	4.7e-03	-0.55	10:103307517:C:T
Spleen	eqtl	7.9e-03	+1.05	10:102536932:T:G
Pancreas	sqtl	8.9e-03	+0.55	10:103549237:T:A
Brain Nucleus accumbens basal ganglia	eqtl	1.0e-02	+0.36	10:104272492:C:T
Brain Cerebellum	eqtl	2.5e-02	+0.21	10:103538219:T:C
Esophagus Mucosa	eqtl	2.7e-02	+0.22	10:103517410:C:G
Brain Anterior cingulate cortex BA24	eqtl	3.1e-02	-0.12	10:103553473:C:T
Thyroid	eqtl	3.3e-02	+0.20	10:103484808:G:A
Heart Atrial Appendage	eqtl	4.3e-02	-0.32	10:103775573:T:C

FANTOM5 promoters

showing 10 of 17 alternative TSS:

Promoter ID	TPM avg	Samples expressed
106822	1.6420	215
106835	1.4858	245
106828	1.0996	343
106816	0.6952	204
106832	0.5405	254
106823	0.5116	150
106815	0.4539	131
106817	0.3407	153
106827	0.2241	100
106818	0.1945	86

Top tissues by expression

showing 100 of 281 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
hindlimb stylopod muscle	UBERON:0004252	96.28	gold quality
right hemisphere of cerebellum	UBERON:0014890	95.00	gold quality
gastrocnemius	UBERON:0001388	94.80	gold quality
cerebellar hemisphere	UBERON:0002245	94.07	gold quality
cerebellar cortex	UBERON:0002129	93.94	gold quality
right frontal lobe	UBERON:0002810	93.79	gold quality
muscle of leg	UBERON:0001383	93.44	gold quality
cerebellum	UBERON:0002037	92.52	gold quality
cingulate cortex	UBERON:0003027	92.15	gold quality
anterior cingulate cortex	UBERON:0009835	92.15	gold quality
prefrontal cortex	UBERON:0000451	91.09	gold quality
nucleus accumbens	UBERON:0001882	90.75	gold quality
muscle organ	UBERON:0001630	90.16	gold quality
Brodmann (1909) area 9	UBERON:0013540	89.99	gold quality
amygdala	UBERON:0001876	89.85	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	89.85	gold quality
Brodmann (1909) area 10	UBERON:0013541	89.82	gold quality
frontal cortex	UBERON:0001870	89.37	gold quality
neocortex	UBERON:0001950	89.17	gold quality
mucosa of transverse colon	UBERON:0004991	88.11	gold quality
putamen	UBERON:0001874	87.50	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	87.47	gold quality
cerebral cortex	UBERON:0000956	87.31	gold quality
caudate nucleus	UBERON:0001873	87.23	gold quality
telencephalon	UBERON:0001893	86.91	gold quality
forebrain	UBERON:0001890	85.96	gold quality
brain	UBERON:0000955	85.94	gold quality
body of uterus	UBERON:0009853	85.77	gold quality
cortical plate	UBERON:0005343	85.58	gold quality
central nervous system	UBERON:0001017	85.47	gold quality
granulocyte	CL:0000094	85.44	gold quality
temporal lobe	UBERON:0001871	84.45	gold quality
frontal pole	UBERON:0002795	84.44	gold quality
skeletal muscle tissue	UBERON:0001134	84.26	gold quality
monocyte	CL:0000576	84.15	gold quality
islet of Langerhans	UBERON:0000006	84.06	gold quality
paraflocculus	UBERON:0005351	84.03	gold quality
Ammon’s horn	UBERON:0001954	84.02	gold quality
mononuclear cell	CL:0000842	83.62	gold quality
leukocyte	CL:0000738	83.34	gold quality
hypothalamus	UBERON:0001898	82.74	gold quality
Brodmann (1909) area 46	UBERON:0006483	82.74	gold quality
body of pancreas	UBERON:0001150	82.14	gold quality
transverse colon	UBERON:0001157	81.95	gold quality
pancreas	UBERON:0001264	81.83	gold quality
superior frontal gyrus	UBERON:0002661	81.78	gold quality
endocervix	UBERON:0000458	81.48	gold quality
gluteal muscle	UBERON:0002000	81.34	silver quality
pituitary gland	UBERON:0000007	80.29	gold quality
middle frontal gyrus	UBERON:0002702	80.19	silver quality
muscle tissue	UBERON:0002385	80.15	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	80.10	gold quality
postcentral gyrus	UBERON:0002581	79.96	gold quality
primary visual cortex	UBERON:0002436	79.85	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	79.84	gold quality
parietal lobe	UBERON:0001872	79.36	gold quality
small intestine Peyer’s patch	UBERON:0003454	79.29	gold quality
cerebellar vermis	UBERON:0004720	79.08	gold quality
left testis	UBERON:0004533	78.85	gold quality
adenohypophysis	UBERON:0002196	78.56	gold quality
occipital lobe	UBERON:0002021	78.52	gold quality
right testis	UBERON:0004534	78.40	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	78.12	silver quality
small intestine	UBERON:0002108	77.74	gold quality
orbitofrontal cortex	UBERON:0004167	77.59	silver quality
rectum	UBERON:0001052	77.42	gold quality
entorhinal cortex	UBERON:0002728	77.27	gold quality
ectocervix	UBERON:0012249	77.09	gold quality
testis	UBERON:0000473	77.03	gold quality
substantia nigra	UBERON:0002038	76.98	gold quality
myometrium	UBERON:0001296	76.90	gold quality
biceps brachii	UBERON:0001507	76.50	silver quality
midbrain	UBERON:0001891	76.29	gold quality
endothelial cell	CL:0000115	76.09	gold quality
tendon of biceps brachii	UBERON:0008188	75.61	gold quality
pancreatic ductal cell	CL:0002079	73.59	silver quality
duodenum	UBERON:0002114	73.43	gold quality
buccal mucosa cell	CL:0002336	73.32	silver quality
CA1 field of hippocampus	UBERON:0003881	73.27	silver quality
sural nerve	UBERON:0015488	73.21	gold quality
intestine	UBERON:0000160	72.79	gold quality
deltoid	UBERON:0001476	72.72	silver quality
blood	UBERON:0000178	72.66	gold quality
urinary bladder	UBERON:0001255	72.66	gold quality
diaphragm	UBERON:0001103	72.58	gold quality
pons	UBERON:0000988	72.03	gold quality
colon	UBERON:0001155	71.65	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	71.63	gold quality
uterine cervix	UBERON:0000002	71.51	gold quality
large intestine	UBERON:0000059	71.44	gold quality
colonic epithelium	UBERON:0000397	71.26	gold quality
spinal cord	UBERON:0002240	71.11	gold quality
fundus of stomach	UBERON:0001160	70.66	gold quality
ventral tegmental area	UBERON:0002691	70.34	silver quality
pharyngeal mucosa	UBERON:0000355	69.96	gold quality
vena cava	UBERON:0004087	69.58	gold quality
nipple	UBERON:0002030	69.50	gold quality
cardia of stomach	UBERON:0001162	69.48	gold quality
substantia nigra pars compacta	UBERON:0001965	69.40	silver quality
body of stomach	UBERON:0001161	69.37	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-GEOD-125970	yes	21.19
E-CURD-119	yes	18.16
E-CURD-114	yes	11.42
E-ANND-3	yes	7.16
E-ENAD-27	no	3.31

HPA expression

RNA tissue specificity: Tissue enhanced

showing 60 of 76 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Skeletal muscle	tissue	136.2	not detected
Frontal cortex	tissue	133.6
Postcentral gyrus	tissue	122.4
Caudate putamen	tissue	118.8
Hippocampus	tissue	109.5	medium
Nucleus accumbens	tissue	94.4
Hippocampal formation	tissue	73.8
Cerebral cortex	tissue	66.5	medium
Temporal cortex	tissue	66.5
Insular cortex	tissue	63.7
Amygdala	tissue	63.5
Prefrontal cortex	tissue	60.8
Entorhinal cortex	tissue	59.3
Locus coeruleus	tissue	57.5
Tongue	tissue	55.8
Motor cortex	tissue	54.6
Retrosplenial and cingulate cortex	tissue	50.6
Retrosplenial cortex	tissue	49.3
Basal ganglia	tissue	42.1	low
Somatosensory cortex	tissue	41.9
Cerebellum	tissue	38.0	high
Ventral forebrain	tissue	37.7
Septum	tissue	37.1
Occipital cortex	tissue	36.9
Retina	tissue	35.3
Hypothalamus	tissue	33.4
Putamen	tissue	32.0
Pons	tissue	22.7
Periaqueductal gray	tissue	21.1
Substantia nigra	tissue	20.7
Olfactory bulb	tissue	20.4
Pancreas	tissue	17.4	medium
Thalamus	tissue	16.7
Midbrain	tissue	16.6
Superior colliculi	tissue	16.6
Small intestine	tissue	16.0	not detected
Pituitary gland	tissue	14.1
Epididymis	tissue	13.8	not detected
Medulla oblongata	tissue	12.2
Colon	tissue	11.5	low
Choroid plexus	tissue	11.4
Duodenum	tissue	10.1	not detected
Spinal cord	tissue	9.8
Rectum	tissue	9.4	low
Parathyroid gland	tissue	7.6	not detected
Corpus callosum	tissue	7.4
Endometrium 1	tissue	6.5	not detected
Testis	tissue	5.8	not detected
Cervix	tissue	4.8	not detected
Stomach 1	tissue	4.8	not detected
Smooth muscle	tissue	4.7	not detected
Placenta	tissue	4.3	not detected
Adrenal gland	tissue	4.2	not detected
Esophagus	tissue	3.9	not detected
Appendix	tissue	3.5	not detected
Urinary bladder	tissue	3.2	not detected
Vagina	tissue	2.3	not detected
Fallopian tube	tissue	1.9	not detected
Spleen	tissue	1.7	not detected
Gallbladder	tissue	1.7	not detected

Brain sub-regions (HPA Brain Atlas): detected in 189; highest nTPM — Posterior cingulate cortex (142.8), Precentral gyrus (134.5), Temporal pole (132.8), Hippocampus, CA3 (132.7), Temporo-occipital transitional zone (130.9).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): HEY1

miRNA regulators (miRDB)

Targeting NEURL1 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 87 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
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-5193	100.00	67.26	1744
HSA-MIR-1184	99.99	68.19	1458
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-2110	99.96	66.68	1930
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-4697-3P	99.89	67.09	1123
HSA-MIR-4271	99.88	68.32	2244
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-6124	99.87	69.78	3551
HSA-MIR-221-5P	99.86	65.45	1052
HSA-MIR-8073	99.86	65.21	1118
HSA-MIR-6739-5P	99.80	67.87	2806
HSA-MIR-6764-5P	99.75	67.89	2304
HSA-MIR-6733-5P	99.74	67.94	2759
HSA-MIR-6752-3P	99.72	66.71	1587
HSA-MIR-4306	99.72	70.50	3630
HSA-MIR-3660	99.68	67.33	1149
HSA-MIR-4526	99.68	67.07	1136
HSA-MIR-6887-3P	99.66	67.83	1778
HSA-MIR-4310	99.59	68.84	2527
HSA-MIR-1915-3P	99.58	66.79	1988

Functional genomics

gnomAD constraint: pLI 2.31e-07, LOEUF 1.04, missense Z -0.45 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD)

ENST00000369780 splits into 5 regions with different missense tolerance; 0 are missense-constrained. Missense variants in a constrained region (low observed/expected) are more likely to be pathogenic. gnomAD

Region (GRCh38)	Missense obs / exp	o/e	Constrained
10:103,494,388–103,570,993	94 / 96.6	0.97	no
10:103,570,994–103,571,677	65 / 131.6	0.49	no
10:103,571,678–103,584,653	114 / 144.8	0.79	no
10:103,584,654–103,590,185	443 / 408.1	1.09	no
10:103,590,186–103,590,369	45 / 89.9	0.50	no

Literature-anchored findings (GeneRIF, showing 8)

• NEURL1 expression was downregulated in medulloblastoma compared to normal cerebellar tissue with lowest expression levels in hedgehog-activated tumors; conclude NEURL1 is candidate tumor suppressor in MB at least in part through effects on Notch pathway (PMID:20847082)
• This is a novel gene implicated in atrial fibrillation (PMID:25124494)
• Fe65 negatively regulates Jagged1 signaling by decreasing Jagged1 protein stability through the E3 ligase Neuralized-like 1. (PMID:26276215)
• NEURL rs12415501 and CAND2 rs4642101 are significantly associated with postoperative atrial fibrillation susceptibility after coronary artery bypass grafting among Chinese population (PMID:27203392)
• Significant allelic and genotypic associations were identified between NEURL variant rs6584555 and GJA1 variant rs13216675 and Atrial fibrillation (AF). Significant genotypic association was found between CUX2 SNP rs6490029 and AF (PMID:29459676)
• Study found no association between NEURL1 rs6584555 and increased risk of atrial fibrillation. (PMID:31039368)
• Neuralized family member NEURL1 is a ubiquitin ligase for the cGMP-specific phosphodiesterase 9A. (PMID:31068605)
• Neuritin affects the activity of neuralized-like 1 by promoting degradation and weakening its affinity for substrate. (PMID:37249336)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	neurl1aa	ENSDARG00000069438
mus_musculus	Neurl1a	ENSMUSG00000006435
rattus_norvegicus	Neurl1	ENSRNOG00000020339

Paralogs (3): NEURL3 (ENSG00000163121), NEURL1B (ENSG00000214357), NEURL4 (ENSG00000215041)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:1334263) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 17 distinct phenotype terms.

Mouse phenotype (MP)	Records
abnormal nursing	1
abnormal olfactory discrimination memory	1
male infertility	1
asthenozoospermia	1
abnormal locomotor coordination	1
abnormal milk composition	1
teratozoospermia	1
abnormal mammary gland growth during pregnancy	1
abnormal mammary gland growth during lactation	1
abnormal spermatid morphology	1
absent sperm head	1
absent gastric milk in neonates	1
abnormal sperm connecting piece morphology	1
abnormal sperm axoneme morphology	1
hypolactation	1
abnormal sperm fibrous sheath morphology	1
biflagellated sperm	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
Xenopus laevis	Q6INH1	73.9%	Diamond
Arabidopsis thaliana	Q8L7N4	57.0%	Diamond
Dictyostelium discoideum	Q557E7	52.1%	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
STN1	protein-coding	79991
SH3PXD2A	protein-coding	9644
CALHM3	protein-coding	119395
CALHM1	protein-coding	255022
SH3PXD2A-AS1	ncRNA	100505839
NEURL1-AS1	ncRNA	102724341
CALHM2	protein-coding	51063
PDCD11	protein-coding	22984

Protein

Protein identifiers

E3 ubiquitin-protein ligase NEURL1 — O76050 (reviewed: O76050)

Alternative names: Neuralized-like protein 1A, RING finger protein 67, RING-type E3 ubiquitin transferase NEURL1

All UniProt accessions (3): O76050, X6RBV8, X6RLA8

UniProt curated annotations — full annotation on UniProt →

Function. Plays a role in hippocampal-dependent synaptic plasticity, learning and memory. Involved in the formation of spines and functional synaptic contacts by modulating the translational activity of the cytoplasmic polyadenylation element-binding protein CPEB3. Promotes ubiquitination of CPEB3, and hence induces CPEB3-dependent mRNA translation activation of glutamate receptor GRIA1 and GRIA2. Can function as an E3 ubiquitin-protein ligase to activate monoubiquitination of JAG1 (in vitro), thereby regulating the Notch pathway. Acts as a tumor suppressor; inhibits malignant cell transformation of medulloblastoma (MB) cells by inhibiting the Notch signaling pathway.

Subunit / interactions. Interacts with CPEB3 (via N-terminal domain); the interaction increases CPEB3 ubiquitination. Interacts with DLL1.

Subcellular location. Cytoplasm. Perinuclear region. Cell membrane. Perikaryon. Cell projection. Dendrite. Postsynaptic density.

Tissue specificity. Expressed in brain, testis, pituitary gland, pancreas and bone marrow. Also poorly expressed in malignant astrocytomas and several neuroectodermal tumor cell lines. Weakly expressed in medulloblastoma (MB) compared with normal cerebellar tissues.

Post-translational modifications. Myristoylation is a determinant of membrane targeting.

Induction. Down-regulated in medulloblastoma (MB).

Pathway. Protein modification; protein ubiquitination.

Isoforms (2)

UniProt ID	Names	Canonical?
O76050-1	1	yes
O76050-2	2

RefSeq proteins (1): NP_004201* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001841	Znf_RING	Domain
IPR006573	NHR_dom	Domain
IPR013083	Znf_RING/FYVE/PHD	Homologous_superfamily
IPR037962	Neuralized	Family
IPR043136	B30.2/SPRY_sf	Homologous_superfamily

Pfam: PF07177, PF13920

UniProt features (13 total): sequence conflict 4, domain 2, region of interest 2, initiator methionine 1, chain 1, zinc finger region 1, lipid moiety-binding region 1, splice variant 1

Structure

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O76050-F1	71.33	0.29

Human Protein Atlas

Protein class: Enzymes, ENZYME proteins, Transferases, Metabolic proteins, Predicted intracellular proteins, UniProt - Evidence at transcript level

Protein evidence: Evidence at protein level

Antibody reliability (HPA): IH enhanced

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 (1)

Type	Positions
N-myristoyl glycine	2

Function

Pathways and Gene Ontology

Reactome pathways

3 curated (TAS) of 17; 9 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

17 pathways:

ID	Pathway	Evidence
R-HSA-2691232	Constitutive Signaling by NOTCH1 HD Domain Mutants ⚕	curated
R-HSA-2894862	Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants ⚕	curated
R-HSA-2644606	Constitutive Signaling by NOTCH1 PEST Domain Mutants ⚕	curated
R-HSA-1643685	Disease ⚕	—
R-HSA-5663202	Diseases of signal transduction by growth factor receptors and second messengers ⚕	—
R-HSA-2691230	Signaling by NOTCH1 HD Domain Mutants in Cancer ⚕	—
R-HSA-2894858	Signaling by NOTCH1 HD+PEST Domain Mutants in Cancer ⚕	—
R-HSA-2644602	Signaling by NOTCH1 PEST Domain Mutants in Cancer ⚕	—
R-HSA-2644603	Signaling by NOTCH1 in Cancer ⚕	—
R-HSA-2122948	Activated NOTCH1 Transmits Signal to the Nucleus	electronic
R-HSA-2979096	NOTCH2 Activation and Transmission of Signal to the Nucleus	electronic
R-HSA-9013507	NOTCH3 Activation and Transmission of Signal to the Nucleus	electronic
R-HSA-162582	Signal Transduction	—
R-HSA-157118	Signaling by NOTCH	—
R-HSA-1980143	Signaling by NOTCH1	—
R-HSA-1980145	Signaling by NOTCH2	—
R-HSA-9012852	Signaling by NOTCH3	—

MSigDB gene sets: 217 (showing top): GSE45365_NK_CELL_VS_CD8_TCELL_DN, GSE18804_SPLEEN_MACROPHAGE_VS_COLON_TUMORAL_MACROPHAGE_DN, MORF_RAGE, GOBP_DENDRITE_DEVELOPMENT, RNGTGGGC_UNKNOWN, REACTOME_SIGNALING_BY_NOTCH, MORF_FLT1, GOBP_MUSCLE_TISSUE_DEVELOPMENT, BENPORATH_ES_WITH_H3K27ME3, TGCGCANK_UNKNOWN, GOBP_RESPONSE_TO_ACID_CHEMICAL, GOBP_REGULATION_OF_NEURONAL_SYNAPTIC_PLASTICITY, LFA1_Q6, GCANCTGNY_MYOD_Q6, MODULE_45

GO Biological Process (17): protein monoubiquitination (GO:0006513), Notch signaling pathway (GO:0007219), nervous system development (GO:0007399), skeletal muscle tissue development (GO:0007519), negative regulation of cell population proliferation (GO:0008285), regulation of Notch signaling pathway (GO:0008593), positive regulation of apoptotic process (GO:0043065), negative regulation of Notch signaling pathway (GO:0045746), positive regulation of long-term neuronal synaptic plasticity (GO:0048170), positive regulation of filopodium assembly (GO:0051491), positive regulation of dendritic spine development (GO:0060999), cellular response to amino acid stimulus (GO:0071230), positive regulation of synapse maturation (GO:0090129), regulation of translation (GO:0006417), regulation of cell communication (GO:0010646), protein ubiquitination (GO:0016567), regulation of signaling (GO:0023051)

GO Molecular Function (7): ubiquitin-protein transferase activity (GO:0004842), zinc ion binding (GO:0008270), translation regulator activity (GO:0045182), ubiquitin protein ligase activity (GO:0061630), protein binding (GO:0005515), transferase activity (GO:0016740), metal ion binding (GO:0046872)

GO Cellular Component (7): plasma membrane (GO:0005886), postsynaptic density (GO:0014069), dendritic spine (GO:0043197), perikaryon (GO:0043204), perinuclear region of cytoplasm (GO:0048471), apical dendrite (GO:0097440), dendrite (GO:0030425)

Reactome top-level categories

11 top-level categories:

Category	Pathways
Signaling by NOTCH	3
Signaling by NOTCH1 in Cancer	3
Signaling by NOTCH1	1
Signaling by NOTCH1 PEST Domain Mutants in Cancer	1
Signaling by NOTCH1 HD Domain Mutants in Cancer	1
Signaling by NOTCH1 HD+PEST Domain Mutants in Cancer	1
Signaling by NOTCH2	1
Signaling by NOTCH3	1
Signal Transduction	1
Diseases of signal transduction by growth factor receptors and second messengers	1
Disease	1

GO top-level categories

58 GO namespaces:

Category	Terms
Notch signaling pathway	2
positive regulation of developmental process	2
dendrite	2
cellular anatomical structure	2
protein ubiquitination	1
cell surface receptor signaling pathway	1
system development	1
animal gross anatomical part developmental process	1
striated muscle tissue development	1
skeletal muscle organ development	1
cell population proliferation	1
regulation of cell population proliferation	1
negative regulation of cellular process	1
regulation of signal transduction	1
apoptotic process	1
regulation of apoptotic process	1
positive regulation of programmed cell death	1
regulation of Notch signaling pathway	1
negative regulation of signal transduction	1
regulation of long-term neuronal synaptic plasticity	1
positive regulation of neurogenesis	1
filopodium assembly	1
regulation of filopodium assembly	1
positive regulation of plasma membrane bounded cell projection assembly	1
dendritic spine development	1
regulation of dendritic spine development	1
response to amino acid	1
cellular response to acid chemical	1
positive regulation of cellular component organization	1
synapse maturation	1
regulation of synapse maturation	1
translation	1
post-transcriptional regulation of gene expression	1
regulation of protein metabolic process	1
cell communication	1
regulation of cellular process	1
protein modification by small protein conjugation	1
signaling	1
regulation of biological process	1
ubiquitin-like protein transferase activity	1
transition metal ion binding	1
molecular_function	1
regulation of translation	1
ubiquitin-protein transferase activity	1
ubiquitin-like protein ligase activity	1
binding	1
catalytic activity	1
cation binding	1
membrane	1
cell periphery	1
asymmetric synapse	1
postsynaptic specialization	1
neuron spine	1
postsynapse	1
neuronal cell body	1
cytoplasm	1
neuron projection	1
dendritic tree	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 4 of 31 annotations. The rest are phylogenetic / computational / electronic (IEA).

4 experimentally-supported GO terms:

GO term	NS	Evidence
negative regulation of Notch signaling pathway	BP	direct assay
negative regulation of cell population proliferation	BP	direct assay
positive regulation of apoptotic process	BP	direct assay
plasma membrane	CC	direct assay

Protein interactions and networks

STRING

showing 15 of 797 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NEURL1	CISH	Q9NSE2	632
NEURL1	CAND2	O75155	622
NEURL1	NEURL2	Q9BR09	527
NEURL1	STPG3	Q8N7X2	452
NEURL1	NCAN	O14594	441
NEURL1	TSGA10	Q9BZW7	434
NEURL1	PAK6	Q9NQU5	427
NEURL1	SH3PXD2A	Q5TCZ1	423
NEURL1	ZFHX3	Q15911	422
NEURL1	IQSEC3	Q9UPP2	419
NEURL1	SYNPO2L	Q9H987	418
NEURL1	CUX2	O14529	414
NEURL1	PITX2	Q99697	400
NEURL1	MIB2	Q96AX9	394
NEURL1	C21orf91	Q9NYK6	383

IntAct

Human interaction partners of NEURL1 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

5 partners by confidence:

Partner	Interaction type	MIscore	Records
YWHAE	physical association	0.400	2
CKAP4	physical association	0.400	1
SFN	physical association	0.400	1
UBE2H	physical association	0.370	1
UBE2N	physical association	0.370	1

BioGRID (32 interactions; top human partners by supporting records): PDE9A (Affinity Capture-Western; 4 records), JAG1 (Affinity Capture-Western; 3 records), CTNNB1 (Affinity Capture-Western; 2 records), APBB1 (Affinity Capture-Western), ARFIP2 (Co-fractionation), BRWD3 (Affinity Capture-MS), DDX58 (Affinity Capture-RNA), ELAVL1 (Affinity Capture-RNA), MKRN2 (Affinity Capture-RNA), PARP16 (Proximity Label-MS), PARP2 (Proximity Label-MS), SETD3 (Affinity Capture-MS), TP53 (Synthetic Lethality), UBE2D1 (Reconstituted Complex), UBE2H (Two-hybrid)

SIGNOR signaling

4 signaling interactions:

A	Effect	B	Mechanism
Ub:E2	“up-regulates activity”	NEURL1	ubiquitination
NEURL1	“down-regulates quantity by destabilization”	PDE9A	polyubiquitination
NEURL1	“up-regulates activity”	CPEB3	ubiquitination
NEURL1	“down-regulates quantity by destabilization”	JAG1	ubiquitination

Disease & clinical

Genetic variants

Variant evidence for NEURL1: 93 ClinVar records (0 pathogenic / likely pathogenic); 20 GWAS associations.

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	90
Likely benign	3
Benign	0

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 36 predictions of 726):

Position(s)	Effect	Δscore	Sites
10:103494473–103494474	donor_loss	0.9900	5
10:103515413	donor_gain	0.9900
10:103570870–103570871	acceptor_loss	0.9900	6
10:103571099	donor_gain	0.9900
10:103571823–103571824	donor_loss	0.9900	5
10:103585226–103585227	donor_loss	0.9900	5
10:103590132–103590133	acceptor_loss	0.9900	6
10:103585227	donor_loss	0.9800
10:103585230	donor_loss	0.9700
10:103555414–103555415	donor_loss	0.9500	5

AlphaMissense

1,326 missense substitutions predicted likely pathogenic (of 3,716 scored), across 301 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
M539	9	0.842	0.986
D205	8	0.998	0.999
H538	8	0.998	0.999
D566	8	0.996	0.999
F95	8	0.995	1.000
F65	8	0.993	1.000
F89	8	0.990	1.000
F125	8	0.987	1.000
H66	8	0.983	0.998
D145	8	0.974	0.992
D425	8	0.973	0.987
D173	8	0.967	0.998
S88	8	0.966	0.999
F170	8	0.955	0.999
F327	8	0.948	0.994
F191	8	0.935	0.980
D129	8	0.929	0.996
D530	8	0.929	0.997
F190	8	0.924	0.986
F296	8	0.918	0.996

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

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

2 prognostic cancer types:

Cancer	Prognostic	p-value
Colon Adenocarcinoma (TCGA)	favorable	0.000104
Rectum Adenocarcinoma (validation)	unfavorable	0.000236

Disease associations

OMIM: gene MIM:603804 | disease phenotypes:

GWAS associations

20 associations:

Study	Trait	p-value
GCST006414_53	Atrial fibrillation	9e-66
GCST006061_41	Atrial fibrillation	5e-58
GCST006061_42	Atrial fibrillation	1e-47
GCST006414_6	Atrial fibrillation	8e-41
GCST004373_14	Atrial fibrillation	3e-24
GCST004295_7	Atrial fibrillation	2e-22
GCST004297_17	Atrial fibrillation	3e-21
GCST004301_8	Prevalent atrial fibrillation	4e-16
GCST005306_9	Atrial fibrillation	2e-14
GCST003013_2	White matter hyperintensity burden	3e-9
GCST006414_44	Atrial fibrillation	4e-9
GCST005580_195	Intraocular pressure	5e-9
GCST003013_16	White matter hyperintensity burden	6e-9
GCST004300_4	Incident atrial fibrillation	2e-8
GCST000693_8	Platelet aggregation	2e-7
GCST004352_5	Early onset atrial fibrillation	3e-7
GCST002875_1	Diisocyanate-induced asthma	1e-6
GCST002875_53	Diisocyanate-induced asthma	1e-6
GCST004296_7	Atrial fibrillation	2e-6
GCST007059_12	Response to antidepressants (symptom improvement)	4e-6

EFO canonical traits (from GWAS)

3 canonical traits:

EFO ID	Trait name
EFO:0006995	response to diisocyanate
EFO:0005665	white matter hyperintensity measurement
EFO:0004695	intraocular pressure measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (CPIC guideline: no)

CTD chemical–gene interactions

29 total (human), top 29 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects methylation, decreases expression, increases expression	3
Particulate Matter	increases abundance, increases expression	2
testosterone enanthate	affects expression	1
arsenite	affects binding, decreases reaction	1
butyraldehyde	increases expression	1
zinc chromate	decreases expression, increases abundance	1
tobacco tar	decreases reaction, increases expression	1
diallyl disulfide	decreases reaction, increases expression	1
allyl sulfide	decreases reaction, increases expression	1
chromium hexavalent ion	decreases expression, increases abundance	1
CGP 52608	affects binding, increases reaction	1
abrine	increases expression	1
Grape Seed Proanthocyanidins	increases expression, affects cotreatment	1
(+)-JQ1 compound	decreases expression	1
Sunitinib	increases expression	1
Air Pollutants	increases abundance, increases expression	1
Catechin	affects cotreatment, increases expression	1
Estradiol	decreases expression	1
Naled	affects expression	1
Smoke	increases expression	1
Tobacco Smoke Pollution	decreases expression	1
Tretinoin	decreases expression	1
Valproic Acid	increases methylation	1
Mifepristone	increases expression	1
Sodium Selenite	increases expression	1
Antirheumatic Agents	decreases expression	1
Cadmium Chloride	increases expression	1
Okadaic Acid	decreases expression	1
Acrylamide	decreases expression	1

Clinical trials (associated diseases)

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