NEUROG3

Summary

NEUROG3 (neurogenin 3, HGNC:13806) is a protein-coding gene on chromosome 10q22.1, encoding Neurogenin-3 (Q9Y4Z2). Is a transcriptional regulator involved in the control of enteroendocrine cell differentiation.

The protein encoded by this gene is a basic helix-loop-helix (bHLH) transcription factor involved in neurogenesis. The encoded protein likely acts as a heterodimer with another bHLH protein. Defects in this gene are a cause of congenital malabsorptive diarrhea 4 (DIAR4).

Source: NCBI Gene 50674 — RefSeq curated summary.

At a glance

• Gene–disease (curated): permanent neonatal diabetes mellitus (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 11
• Clinical variants (ClinVar): 179 total — 16 pathogenic, 3 likely-pathogenic
• Phenotypes (HPO): 36
• Transcription factor: yes — 38 downstream targets (CollecTRI)
• MANE Select transcript: NM_020999

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:13806
Approved symbol	NEUROG3
Name	neurogenin 3
Location	10q22.1
Locus type	gene with protein product
Status	Approved
Aliases	Atoh5, Math4B, ngn3, bHLHa7
Ensembl gene	ENSG00000122859
Ensembl biotype	protein_coding
OMIM	604882
Entrez	50674

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 2 protein_coding

ENST00000242462, ENST00000929784

RefSeq mRNA: 1 — MANE Select: NM_020999 NM_020999

CCDS: CCDS31212

Canonical transcript exons

ENST00000242462 — 2 exons

Exon	Start	End
ENSE00003993971	69571698	69573044
ENSE00003993985	69573210	69573422

Expression profiles

Bgee: expression breadth broad, 46 present calls, max score 62.40.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.1869 / max 156.0887, expressed in 48 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
109804	0.1869	48

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
mucosa of transverse colon	UBERON:0004991	62.40	gold quality
duodenum	UBERON:0002114	54.25	gold quality
Ammon’s horn	UBERON:0001954	53.73	gold quality
nasal cavity epithelium	UBERON:0005384	51.67	gold quality
small intestine	UBERON:0002108	51.46	gold quality
small intestine Peyer’s patch	UBERON:0003454	50.95	gold quality
transverse colon	UBERON:0001157	49.53	gold quality
colonic epithelium	UBERON:0000397	49.05	gold quality
heart right ventricle	UBERON:0002080	45.33	gold quality
intestine	UBERON:0000160	45.20	gold quality
right adrenal gland cortex	UBERON:0035827	44.59	gold quality
rectum	UBERON:0001052	43.39	gold quality
colon	UBERON:0001155	43.37	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	43.37	gold quality
large intestine	UBERON:0000059	43.27	gold quality
right adrenal gland	UBERON:0001233	43.17	gold quality
amniotic fluid	UBERON:0000173	42.73	gold quality
smooth muscle tissue	UBERON:0001135	42.62	gold quality
secondary oocyte	CL:0000655	42.57	gold quality
bone marrow cell	CL:0002092	42.36	gold quality
body of tongue	UBERON:0011876	42.15	gold quality
gingiva	UBERON:0001828	41.87	gold quality
vastus lateralis	UBERON:0001379	41.69	gold quality
primary visual cortex	UBERON:0002436	41.67	gold quality
middle temporal gyrus	UBERON:0002771	41.67	gold quality
quadriceps femoris	UBERON:0001377	41.64	gold quality
occipital lobe	UBERON:0002021	41.64	gold quality
colonic mucosa	UBERON:0000317	41.40	gold quality
superficial temporal artery	UBERON:0001614	41.33	gold quality
cartilage tissue	UBERON:0002418	41.27	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	3.36

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

38 targets.

Target	Regulation
ABCC8	Activation
ASH1L	Repression
ATOH8	Unknown
CAPS2
CCND1
CDK4
CEL
CPA1	Activation
DLD
DNER
GAST
GCG
INS	Activation
INSM1	Activation
INSM2
MIB1
MYT1	Activation
NEUROD1	Unknown
NEUROD2	Activation
NEUROD4	Repression
NEUROG1	Activation
NEUROG2	Repression
NEUROG3	Unknown
NHLH1	Activation
NKX2-2
NKX6-1	Activation
OVOL1	Unknown
PAX4	Activation
PAX6	Activation
PCSK6

Upstream regulators (CollecTRI, top): E2F1, FOXA2, FOXO1, GLIS3, HES1, HNF1B, INSM1, MYT1, NEUROG3, ONECUT1, PDX1, RBPJ, SOX9

miRNA regulators (miRDB)

8 targeting NEUROG3, 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-302E	99.96	70.74	2669
HSA-MIR-520F-3P	99.82	71.32	1216
HSA-MIR-298	99.63	67.56	1916
HSA-MIR-6871-3P	99.43	68.85	741
HSA-MIR-4651	99.06	67.57	2002
HSA-MIR-608	98.93	67.83	2013
HSA-MIR-630	97.50	66.38	921
HSA-MIR-6890-5P	92.89	65.83	442

Literature-anchored findings (GeneRIF, showing 40)

• adult human pancreatic duct cells can be converted into insulin-expressing cells after ectopic, adenovirus-mediated expression of the class B basic helix-loop-helix factor neurogenin 3 (PMID:12403815)
• Polymorphism contributes to glucose intolerance in a South Indian population. (PMID:15277395)
• The Notch/Ngn3 signalling network is intact and functional in adult islets. (PMID:17922104)
• A genetic variation in the NGN3 gene may be among the genetic determinants involved in the pathogenesis of diabetes. (PMID:18072012)
• Tumors and MEN1 nontumorous endocrine cells showed a prominent cytoplasmatic NEUROG3 and NEUROD1 expression (PMID:19307926)
• mutations of NEUROG3 gene are not a common cause of neonatal/infancy/childhood-onset diabetes (PMID:19538245)
• Ngn3-Cre-based lineage tracing showed that pdx-1-expressing cells differentiated to all the types of pancreatic cells, while Ngn3 marked endocrine-specific progenitors. (PMID:20668890)
• These results support an important inter-species difference in regulating insulin exocytosis where RAB3B is the most expressed isoform in human islets. (PMID:20807725)
• The important role of Ngn3 as a master regulator of endocrine pancreas development directs attention to finding therapeutic approaches to enhance Ngn3 expression in diabetes as a means to increase beta cell mass and functions. (PMID:21099270)
• Severe deficiency of neurogenin 3 causes a rare novel subtype of permanent neonatal diabetes. This finding confirms the essential role of NEUROG3 in islet development and function in humans (PMID:21378176)
• Gastrin-positive neuroendocrine tumors, whether of duodenal or pancreatic origin, frequently expressed PDX1 (17/18), ISL1 (14/18), and NGN3 (14/18). (PMID:21739268)
• The variants in HNFA and NEUROG3 indicate a strong predisposition of normal-weight/lean subjects to T2D in North Indians. (PMID:21814221)
• CCAR1 is a novel partner of Ngn3 in mediating endocrine differentiation. (PMID:22266316)
• Ngn3-mediated pancreatic duct-to-endocrine cell reprogramming was measured employing genome wide mRNA profiling. (PMID:22606327)
• Data indicate associations of SNPs in eight loci CXCR4, HHEX, FOXA2, NGN3, TCF7L2, FLJ39370 (C4orf32), LOC646279 (RPL21P7) and THADA with body mass index (BMI) and weight. (PMID:23349771)
• Recessively inherited NEUROG-3 mutations were originally identified in three patients with unexplained congenital malabsorptive diarrhea and an absence of EC. (PMID:24134759)
• Prospectively isolated NGN3-expressing progenitors from human embryonic stem cells give rise to pancreatic endocrine cells. (PMID:24493854)
• Activation of the developmental pathway neurogenin-3/microRNA-7a regulates cholangiocyte proliferation in response to injury. (PMID:24925797)
• The expression of transcription factor Ngn3 and pancreatic mesenchymal microenvironment are important and necessary to promote pancreatic progenitors differentiated to islet cells regardless of pancreatic development or islets regeneration. (PMID:24969979)
• NEUROG3 deficiency produces a rare clinical syndrome characterised by severe malabsorptive diarrhoea from early life and mild diabetes with a variable age of onset. (PMID:25120094)
• conclude that NEUROG3 is essential for endocrine pancreas development in humans and that as little as 10% NEUROG3 is sufficient for formation of pancreatic endocrine cells (PMID:25650326)
• NGN3 expression in the adult human exocrine pancreas marks a dedifferentiating cell population. (PMID:26288179)
• ChIP experiments confirmed that Pdx1 activates the expression of the downstream transcription factors, Ngn3 and Pax6, by combined with the promoter regions of insulin (Insulin-P), Ngn3 (Ngn3-P), and Pax6 (Pax6-P). (PMID:26345820)
• inflammatory cytokine insults stimulate epithelial-to-mesenchymal transition (EMT) as well as the endocrine program in human pancreatic ductal cells via STAT3-dependent NGN3 activation. (PMID:27068459)
• This reviews the expression and function of NEUROG3 in both mouse and human pancreatic development. [Review Article] (PMID:27615127)
• Sox9 and Ngn3, key transcription factors associated with pancreatic development. (PMID:27836003)
• Collectively, our results demonstrate that the STAT3(K392R) mutation causes premature endocrine differentiation through direct induction of NEUROG3 expression. (PMID:28402852)
• Phosphorylation of NEUROG3 links endocrine differentiation to the cell cycle in pancreatic progenitors (PMID:28441528)
• Neurogenin3 controls its ability to promote pancreatic endocrine differentiation and to maintain beta cell function in the presence of pro-proliferation cues (PMID:28457793)
• novel homozygous nonsense mutation (p.Q4*) as the genetic cause of neonatal diabetes mellitus and severe malabsorptive diarrhea in 2 cousins (PMID:28940958)
• PDX1, Neurogenin-3, and MAFA are critical transcription regulators for beta cell development and regeneration. (Review) (PMID:29096722)
• NEUROG3 pathogenic mutations affect protein stability, dimerization, and DNA binding. (PMID:31178402)
• PTEN and BMI1 help mediate NEUROGENIN-3-induced cell cycle arrest (PMID:31341016)
• human organoid cells derived from the pancreatic tissue can be reprogrammed into the insulin-producing cells (IPCs) by the combination of in vitro transcribed modified mRNA encoding transcription factor neurogenin 3 and small molecules modulating the epigenetic state and signalling pathways. (PMID:31638558)
• Null mutations of NEUROG3 are associated with delayed-onset diabetes mellitus. (PMID:31805014)
• Reversible expansion of pancreatic islet progenitors derived from human induced pluripotent stem cells. (PMID:32065490)
• Recognition of maturity-onset diabetes of the young in China. (PMID:32741144)
• Effect of NEUROG3 polymorphism rs144643855 on regional spontaneous brain activity in major depressive disorder. (PMID:33878431)
• Extensive NEUROG3 occupancy in the human pancreatic endocrine gene regulatory network. (PMID:34352411)
• Protein Production and Purification of a Codon-Optimized Human NGN3 Transcription Factor from E. coli. (PMID:34550497)

Cross-species orthologs

8 orthologs

Organism	Symbol	Gene ID
danio_rerio	neurog3	ENSDARG00000016951
mus_musculus	Neurog3	ENSMUSG00000044312
rattus_norvegicus	Neurog3	ENSRNOG00000024413
drosophila_melanogaster	amos	FBGN0003270
drosophila_melanogaster	ato	FBGN0010433
drosophila_melanogaster	tap	FBGN0015550
caenorhabditis_elegans		WBGENE00003018
caenorhabditis_elegans		WBGENE00003595

Paralogs (15): NEUROD4 (ENSG00000123307), BHLHE23 (ENSG00000125533), NEUROD1 (ENSG00000162992), NEUROD6 (ENSG00000164600), ATOH8 (ENSG00000168874), NEUROD2 (ENSG00000171532), ATOH1 (ENSG00000172238), OLIG3 (ENSG00000177468), NEUROG2 (ENSG00000178403), ATOH7 (ENSG00000179774), BHLHA15 (ENSG00000180535), BHLHE22 (ENSG00000180828), NEUROG1 (ENSG00000181965), OLIG1 (ENSG00000184221), OLIG2 (ENSG00000205927)

Protein

Protein identifiers

Neurogenin-3 — Q9Y4Z2 (reviewed: Q9Y4Z2)

Alternative names: Class A basic helix-loop-helix protein 7, Protein atonal homolog 5

All UniProt accessions (1): Q9Y4Z2

UniProt curated annotations — full annotation on UniProt →

Function. Is a transcriptional regulator involved in the control of enteroendocrine cell differentiation. Together with NKX2-2, initiates transcriptional activation of NEUROD1. Involved in neurogenesis. Also required for the specification of a common precursor of the 4 pancreatic endocrine cell types.

Subunit / interactions. Efficient DNA binding requires dimerization with another bHLH protein. Interacts with ATOH8.

Subcellular location. Nucleus.

Disease relevance. Diarrhea 4, malabsorptive, congenital, with diabetes mellitus and combined pituitary hormone deficiency (DIAR4) [MIM:610370] An autosomal recessive disease characterized by severe, life-threatening watery diarrhea associated with generalized malabsorption and a paucity of enteroendocrine cells. In addition to malabsorptive diarrhea, most patients develop insulin-dependent diabetes mellitus in the neonatal period or early childhood, and manifest short stature and delayed puberty. Pituitary gland hypoplasia with multiple pituitary hormone deficiencies and proximal renal tubulopathy have also been observed. The disease is caused by variants affecting the gene represented in this entry.

RefSeq proteins (1): NP_066279* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR011598	bHLH_dom	Domain
IPR032656	Ngn3_bHLH	Domain
IPR036638	HLH_DNA-bd_sf	Homologous_superfamily
IPR050359	bHLH_transcription_factors	Family

Pfam: PF00010

UniProt features (20 total): sequence variant 10, compositionally biased region 4, sequence conflict 3, chain 1, domain 1, region of interest 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y4Z2-F1	70.55	0.34

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-210744	Regulation of gene expression in late stage (branching morphogenesis) pancreatic bud precursor cells
R-HSA-210746	Regulation of gene expression in endocrine-committed (NEUROG3+) progenitor cells

MSigDB gene sets: 160 (showing top): GOBP_SPINAL_CORD_DEVELOPMENT, GOBP_DENDRITE_DEVELOPMENT, GOBP_HINDBRAIN_DEVELOPMENT, GOBP_EPITHELIUM_DEVELOPMENT, BENPORATH_ES_WITH_H3K27ME3, CMYB_01, GOBP_POSITIVE_REGULATION_OF_NEURON_DIFFERENTIATION, GOBP_REGULATION_OF_DENDRITE_MORPHOGENESIS, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_UP, GRAESSMANN_RESPONSE_TO_MC_AND_SERUM_DEPRIVATION_UP, MAZ_Q6, AP4_Q6, GOBP_NEUROGENESIS, CAGCTG_AP4_Q5, GOBP_FOREBRAIN_DEVELOPMENT

GO Biological Process (19): negative regulation of transcription by RNA polymerase II (GO:0000122), nervous system development (GO:0007399), central nervous system development (GO:0007417), peripheral nervous system development (GO:0007422), sensory organ development (GO:0007423), spinal cord development (GO:0021510), forebrain development (GO:0030900), hindbrain development (GO:0030902), enteroendocrine cell differentiation (GO:0035883), positive regulation of neuron differentiation (GO:0045666), positive regulation of DNA-templated transcription (GO:0045893), positive regulation of transcription by RNA polymerase II (GO:0045944), regulation of dendrite morphogenesis (GO:0048814), transdifferentiation (GO:0060290), axon development (GO:0061564), regulation of DNA-templated transcription (GO:0006355), cell differentiation (GO:0030154), epithelial cell differentiation (GO:0030855), positive regulation of cell differentiation (GO:0045597)

GO Molecular Function (12): 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), DNA-binding transcription activator activity, RNA polymerase II-specific (GO:0001228), chromatin DNA binding (GO:0031490), protein dimerization activity (GO:0046983), E-box binding (GO:0070888), DNA binding (GO:0003677), double-stranded DNA binding (GO:0003690), DNA-binding transcription factor activity (GO:0003700), protein binding (GO:0005515), sequence-specific double-stranded DNA binding (GO:1990837)

GO Cellular Component (2): chromatin (GO:0000785), nucleus (GO:0005634)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Regulation of beta-cell development	2

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
RNA polymerase II transcription regulatory region sequence-specific DNA binding	4
regulation of transcription by RNA polymerase II	3
system development	3
anatomical structure development	3
cell differentiation	3
transcription by RNA polymerase II	2
nervous system development	2
brain development	2
DNA-templated transcription	2
regulation of DNA-templated transcription	2
DNA-binding transcription factor activity, RNA polymerase II-specific	2
DNA binding	2
negative regulation of DNA-templated transcription	1
animal organ development	1
central nervous system development	1
epithelial cell differentiation	1
neuron differentiation	1
positive regulation of cell differentiation	1
regulation of neuron differentiation	1
positive regulation of RNA biosynthetic process	1
positive regulation of DNA-templated transcription	1
regulation of anatomical structure morphogenesis	1
dendrite morphogenesis	1
regulation of dendrite development	1
neuron projection development	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
cellular developmental process	1
epithelium development	1
regulation of cell differentiation	1
positive regulation of cellular process	1
positive regulation of developmental 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 repressor activity	1
DNA-binding transcription activator activity	1
positive regulation of transcription by RNA polymerase II	1
chromatin binding	1

Protein interactions and networks

STRING

1606 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NEUROG3	PAX4	O43316	921
NEUROG3	RFX6	Q8HWS3	892
NEUROG3	ISL1	P20663	890
NEUROG3	GCG	P01275	885
NEUROG3	NKX6-1	P78426	882
NEUROG3	NKX6-2	Q9C056	875
NEUROG3	ONECUT1	Q9UBC0	874
NEUROG3	PDX1	P52945	868
NEUROG3	SLC2A2	P11168	852
NEUROG3	INS	P01308	845
NEUROG3	SST	P01166	833
NEUROG3	PPY	P01298	831
NEUROG3	NKX2-2	O95096	807
NEUROG3	FOXA2	Q9Y261	795
NEUROG3	INSM1	Q01101	788

IntAct

24 interactions, top by confidence:

A	B	Type	Score
NEUROG3	TCF12	psi-mi:“MI:0915”(physical association)	0.800
TCF12	NEUROG3	psi-mi:“MI:0915”(physical association)	0.800
NEUROG3	TCF12	psi-mi:“MI:0915”(physical association)	0.780
TCF12	NEUROG3	psi-mi:“MI:0915”(physical association)	0.780
NEUROG3	GXYLT2	psi-mi:“MI:0914”(association)	0.640
TCF4	NEUROG3	psi-mi:“MI:0915”(physical association)	0.600
REL	NEUROG3	psi-mi:“MI:0915”(physical association)	0.560
NEUROG3	REL	psi-mi:“MI:0915”(physical association)	0.560
POU6F2	NEUROG3	psi-mi:“MI:0915”(physical association)	0.560
NEUROG3	MYO9A	psi-mi:“MI:0914”(association)	0.350
NEUROG3	TCF4	psi-mi:“MI:0915”(physical association)	0.000
NEUROG3	TCF12	psi-mi:“MI:0915”(physical association)	0.000
NEUROG3	POU6F2	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (196): NEUROG3 (Two-hybrid), NEUROG3 (Two-hybrid), TCF12 (Two-hybrid), TCF3 (Affinity Capture-MS), TCF4 (Affinity Capture-MS), TCF12 (Affinity Capture-MS), TEP1 (Affinity Capture-MS), DCAF4 (Affinity Capture-MS), ARID3B (Affinity Capture-MS), RMDN2 (Affinity Capture-MS), HES6 (Affinity Capture-MS), ZNF100 (Affinity Capture-MS), YY1AP1 (Affinity Capture-MS), ZNF430 (Affinity Capture-MS), RRP1 (Affinity Capture-MS)

ESM2 similar proteins: A0A1W2PRP0, A6NCS4, A7Y7W2, O14512, O43638, O57601, O70220, O96004, P07812, P09023, P10085, P10284, P17483, P22091, P24899, P50548, P52954, P52955, P55318, P57100, P63156, P63157, P70447, P79772, P97832, Q02346, Q05917, Q0VCE2, Q12952, Q1XID0, Q28555, Q3I5G5, Q3Y598, Q60688, Q61660, Q63244, Q63250, Q64279, Q64305, Q64731

Diamond homologs: A6NI15, O08574, O09105, O42202, P41894, P46581, P48986, P79765, P79766, P79920, P97309, Q08DI0, Q0VG99, Q13562, Q28C89, Q4R5G6, Q60430, Q60867, Q64289, Q90ZL1, Q91616, Q96NK8, Q9BRJ9, Q9DEQ9, Q9HD90, Q9JK54, Q9W690, Q9W6C7, Q9Y4Z2, A8E5T6, B6VQA1, O13125, O13126, O16867, O35437, O42606, O43680, O57598, O60682, O73615

SIGNOR signaling

8 interactions.

A	Effect	B	Mechanism
NEUROG3	“down-regulates quantity by repression”	ASH1L	“transcriptional regulation”
NEUROG3	“up-regulates quantity by expression”	NEUROD1	“transcriptional regulation”
NEUROG3	“down-regulates quantity by repression”	NEUROD4	“transcriptional regulation”
NEUROG3	“up-regulates quantity by expression”	NEUROG1	“transcriptional regulation”
NEUROG3	“down-regulates quantity by repression”	NEUROG2	“transcriptional regulation”
NEUROG3	“up-regulates quantity by expression”	NHLH1	“transcriptional regulation”
NEUROG3	“down-regulates quantity by repression”	VSX2	“transcriptional regulation”
NEUROG3	“up-regulates quantity by expression”	INSM1	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	16
Likely pathogenic	3
Uncertain significance	86
Likely benign	60
Benign	8

Top pathogenic / likely-pathogenic (19)

Variant ID	HGVS	Classification
1327470	NM_020999.4(NEUROG3):c.371C>G (p.Thr124Arg)	Pathogenic
1327471	NM_020999.4(NEUROG3):c.284G>C (p.Arg95Pro)	Pathogenic
1381799	NM_020999.4(NEUROG3):c.212del (p.Pro71fs)	Pathogenic
2120575	NM_020999.4(NEUROG3):c.220G>T (p.Glu74Ter)	Pathogenic
2735407	NM_020999.4(NEUROG3):c.82G>T (p.Glu28Ter)	Pathogenic
2780410	NM_020999.4(NEUROG3):c.320del (p.Arg107fs)	Pathogenic
3767257	NEUROG3, THR138ARG	Pathogenic
3767258	E28*	Pathogenic
3767259	L135P	Pathogenic
3767260	E123*	Pathogenic
3767261	NEUROG3, 1-BP DUP, 510G	Pathogenic
3767262	I132F	Pathogenic
3767263	NEUROG3, THR124ARG (SCV002029230)	Pathogenic
3767264	NEUROG3, ARG95PRO (SCV002029231)	Pathogenic
435975	NM_020999.4(NEUROG3):c.162C>A (p.Cys54Ter)	Pathogenic
4763832	NM_020999.4(NEUROG3):c.163del (p.Arg55fs)	Pathogenic
1162203	NM_020999.4(NEUROG3):c.394A>T (p.Ile132Phe)	Likely pathogenic
3255339	NM_020999.4(NEUROG3):c.410A>G (p.Gln137Arg)	Likely pathogenic
3898962	NM_020999.4(NEUROG3):c.253C>T (p.Arg85Ter)	Likely pathogenic

SpliceAI

132 predictions. Top by Δscore:

Variant	Effect	Δscore
10:69573042:ATCCT:A	acceptor_loss	0.8800
10:69573043:TCCTA:T	acceptor_loss	0.8800
10:69573044:CCTAC:C	acceptor_loss	0.8800
10:69573045:C:CA	acceptor_loss	0.8800
10:69573046:T:G	acceptor_loss	0.8800
10:69573045:C:CC	acceptor_gain	0.8700
10:69573043:TC:T	acceptor_gain	0.8600
10:69573044:CC:C	acceptor_gain	0.8600
10:69573057:C:CT	acceptor_gain	0.8600
10:69573041:CATC:C	acceptor_gain	0.8400
10:69573204:TATTA:T	donor_loss	0.8300
10:69573205:ATTAC:A	donor_loss	0.8300
10:69573206:TTA:T	donor_loss	0.8300
10:69573207:TACCT:T	donor_loss	0.8300
10:69573208:ACCTT:A	donor_loss	0.8300
10:69573047:A:C	acceptor_loss	0.8200
10:69573209:CCTTT:C	donor_gain	0.8100
10:69573210:CTTTC:C	donor_gain	0.8100
10:69573211:TTTCT:T	donor_gain	0.8100
10:69573040:TCATC:T	acceptor_gain	0.7900
10:69573041:CATCC:C	acceptor_gain	0.7900
10:69572606:CAAG:C	donor_gain	0.7800
10:69573203:ATATT:A	donor_loss	0.7700
10:69573049:G:T	acceptor_gain	0.7600
10:69573051:C:CT	acceptor_gain	0.7600
10:69573210:CTTT:C	donor_loss	0.7600
10:69573058:A:T	acceptor_gain	0.7300
10:69573042:ATC:A	acceptor_gain	0.7200
10:69573212:TTCT:T	donor_gain	0.7100
10:69573052:G:T	acceptor_gain	0.6900

AlphaMissense

1348 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
10:69572681:C:A	K121N	1.000
10:69572681:C:G	K121N	1.000
10:69572661:G:T	A128D	0.999
10:69572670:A:G	L125P	0.999
10:69572683:T:C	K121E	0.999
10:69572685:G:A	T120I	0.999
10:69572748:A:G	L99P	0.999
10:69572766:C:G	R93P	0.999
10:69572667:C:G	R126P	0.998
10:69572670:A:T	L125Q	0.998
10:69572683:T:G	K121Q	0.998
10:69572744:G:C	N100K	0.998
10:69572744:G:T	N100K	0.998
10:69572748:A:T	L99H	0.998
10:69572767:G:T	R93S	0.998
10:69572768:C:A	E92D	0.998
10:69572768:C:G	E92D	0.998
10:69572769:T:A	E92V	0.998
10:69572682:T:A	K121M	0.997
10:69572727:A:G	L106P	0.997
10:69572727:A:T	L106Q	0.997
10:69572756:C:A	M96I	0.997
10:69572756:C:G	M96I	0.997
10:69572756:C:T	M96I	0.997
10:69572757:A:C	M96R	0.997
10:69572760:C:G	R95P	0.997
10:69572761:G:C	R95G	0.997
10:69572770:C:T	E92K	0.997
10:69572640:A:G	L135P	0.996
10:69572649:A:G	I132T	0.996

dbSNP variants (sampled 300 via entrez): RS1001348641 (10:69571444 C>G,T), RS1001779961 (10:69574036 T>A,C), RS1003178871 (10:69573398 G>A), RS1003401850 (10:69573147 C>T), RS1003931815 (10:69573554 C>G,T), RS1004864061 (10:69572050 C>G), RS1005603942 (10:69572504 G>A), RS1005949962 (10:69574808 G>A,C), RS1006630242 (10:69572120 G>A), RS1006779356 (10:69571761 T>G), RS1007411589 (10:69573656 T>C), RS1009009195 (10:69575226 G>C), RS1009360210 (10:69574792 T>C), RS1010071351 (10:69574198 G>T), RS1010175873 (10:69574743 C>G,T)

Disease associations

OMIM: gene MIM:604882 | disease phenotypes: MIM:610370

GenCC curated gene-disease

Disease	Classification	Inheritance
permanent neonatal diabetes mellitus	Strong	Autosomal recessive
congenital malabsorptive diarrhea 4	Strong	Autosomal recessive

Mondo (2): congenital malabsorptive diarrhea 4 (MONDO:0012479), permanent neonatal diabetes mellitus (MONDO:0100164)

Orphanet (1): Enteric anendocrinosis (Orphanet:83620)

HPO phenotypes

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

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0001081	Cholelithiasis
HP:0001281	Tetany
HP:0001392	Abnormality of the liver
HP:0001396	Cholestasis
HP:0001403	Macrovesicular hepatic steatosis
HP:0001409	Portal hypertension
HP:0001414	Microvesicular hepatic steatosis
HP:0001508	Failure to thrive
HP:0001944	Dehydration
HP:0001992	Organic aciduria
HP:0002013	Vomiting
HP:0002014	Diarrhea
HP:0002024	Malabsorption
HP:0002041	Intractable diarrhea
HP:0002151	Increased circulating lactate concentration
HP:0002155	Hypertriglyceridemia
HP:0002611	Cholestatic liver disease
HP:0002630	Fat malabsorption
HP:0002748	Rickets
HP:0003074	Hyperglycemia
HP:0003112	Abnormal circulating amino acid concentration
HP:0003124	Hypercholesterolemia
HP:0003542	Increased circulating pyruvate concentration
HP:0003623	Neonatal onset
HP:0003689	Multiple mitochondrial DNA deletions
HP:0004918	Hyperchloremic metabolic acidosis
HP:0012115	Hepatitis
HP:0012236	Elevated sweat chloride
HP:0025130	Decreased small intestinal mucosa lactase level

GWAS associations

11 associations (top):

Study	Trait	p-value
GCST003114_6	Carotid intima media thickness	8.000000e-06
GCST005413_1	Type 2 diabetes	8.000000e-09
GCST006107_16	Upper eyelid morphology	4.000000e-06
GCST008839_343	Height	8.000000e-09
GCST009379_100	Type 2 diabetes	2.000000e-06
GCST009379_101	Type 2 diabetes	5.000000e-07
GCST009379_102	Type 2 diabetes	2.000000e-14
GCST009379_98	Type 2 diabetes	7.000000e-18
GCST009379_99	Type 2 diabetes	7.000000e-06
GCST009391_348	Metabolite levels	2.000000e-06
GCST010118_183	Type 2 diabetes	2.000000e-11

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0010432	triacylglycerol 56:5 measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
C563425	Diabetes Mellitus, Permanent Neonatal (supp.)
C563673	Diarrhea 4, Malabsorptive, Congenital (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

19 total (human), top 19 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects methylation, affects cotreatment, decreases expression	2
Benzo(a)pyrene	decreases expression, increases methylation	2
Aflatoxin B1	decreases expression	2
methyleugenol	decreases expression	1
terbufos	increases methylation	1
sulforaphane	decreases expression	1
monoisoamyl-2,3-dimercaptosuccinate	affects expression, affects cotreatment, decreases expression	1
abrine	increases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Atrazine	increases expression	1
Cadmium	decreases expression, increases abundance	1
Diazinon	increases methylation	1
Fonofos	increases methylation	1
Parathion	increases methylation	1
Plant Extracts	affects cotreatment, decreases expression	1
Polychlorinated Biphenyls	affects expression	1
Sodium Selenite	increases expression	1
Cadmium Chloride	decreases expression, increases abundance	1
Okadaic Acid	decreases expression	1

Cellosaurus cell lines

4 cell lines: 3 embryonic stem cell, 1 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_A1BX	iPSC 72.3-NEUROG3	Induced pluripotent stem cell	Male
CVCL_A4L8	SEES3-1V human NEUROG3, clone1	Embryonic stem cell	Male
CVCL_A4L9	SEES3-1V human NEUROG3, clone2	Embryonic stem cell	Male
CVCL_A4M0	SEES3-1V human NEUROG3, clone3	Embryonic stem cell	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT02624817	PHASE4	COMPLETED	Long-Term Sulfonylurea Response in KCNJ11 Neonatal Diabetes
NCT02624830	PHASE4	UNKNOWN	Long-Term Sulfonylurea Response in ABCC8 Neonatal Diabetes (SuResponsSUR)
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns