NEUROD1
protein-codingneuronal differentiation 1, the group of Basic helix-loop-helix proteins
Gene summary
This gene encodes a member of the NeuroD family of basic helix-loop-helix (bHLH) transcription factors. The protein forms heterodimers with other bHLH proteins and activates transcription of genes that contain a specific DNA sequence known as the E-box. It regulates expression of the insulin gene, and mutations in this gene result in type II diabetes mellitus. [provided by RefSeq, Jul 2008]
- NEUROD
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~12.5 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0011668
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0011668
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0015967
Submitter: ClinGen
*NEUROD1* was first reported in relation to autosomal dominant monogenic diabetes in 1999 (Malecki et al., PMID: 10545951). At the time of the initial curation in 2021 of gene-disease validity for NEUROD1 with autosomal dominant monogenic diabetes, at least 14 variants (missense, nonsense, frameshift) had been reported in humans (PMIDs: 25041077, 28664602, 31216263, 11719843, 17440689, 31595705, 31578821, 10545951, 28095440, 18331410). However, evidence supporting this gene-disease relationship including case-level data and segregation data remained limited (0.9 points). Experimental evidence, suggest *NEUROD1* binds the INS gene promotor to regulate its transcription (PMIDs: 7774807) and, when disrupted in mice, leads to hyperglycemia with ketonuria, suggesting severe diabetes and insulin deficiency, with abnormal pancreatic islet morphology, reduction in insulin producing cells, and lack of mature islets (PMID: 9308961). *NEUROD1 *expression has been confirmed in pancreatic tissue (PMID: 24309898). Evidence supporting this gene-disease relationship included case level data (0.4 points), segregation data (0.5 points), and experimental data (3 points). Summary of genetic and experimental evidence: 3.9 points. This gene-disease relationship was re-evaluated in October 2025. As a result of this re-evaluation, the classification increased from Limited to Moderate, with the addition of new evidence supporting this gene-disease relationship, including case-level (PMIDs:41020216, 40853921, 39264012, 40026692, 32184107; increased to 1.8 points), case-control (PMID: 40779032; increased to 2 points) and experimental data (PMID:40148250; increased to 3.5 points). Updated summary of genetic and experimental evidence: 7.3 points. Of note, this gene has also been implicated in autosomal recessive monogenic diabetes (http://purl.obolibrary.org/obo/MONDO_0015967), which has been assessed separately in a split curation due to differences in phenotypic presentation. This classification was approved by the MDGCEP on February 23, 2026. Gene Clinical Validity Standard Operating Procedures (SOP) - SOP11.
Inheritance Pattern: AR
Disease ID:MONDO:0019200
Submitter: Franklin by Genoox
A proband from the consanguineous autosomal recessive retinitis pigmantosa family underwent DNA examination which revealed a homozygous missense variant, c.724G>A; p.V242I, in NEUROD1 which identified as the most likely cause of disease.
Inheritance Pattern: AD
Disease ID:MONDO:0011668
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0015967
Submitter: ClinGen
*NEUROD1* was first reported in relation to autosomal recessive monogenic diabetes in 2002 (Kanatsuka et al., PMID: 12200761). At least 5 variants (missense and nonsense) have been reported in humans in association with a phenotype consisting of neonatal diabetes, intrauterine growth retardation, cerebellar hypoplasia, sensorineural deafness, visual impairment, and intellectual disability. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Summary of case-level data: 5 points. Variants in this gene have been reported in at least 8 probands in 4 publications (PMIDs: 29521454, 20573748, 12200761, 30259503). Of note, this gene has also been implicated in autosomal dominant monogenic diabetes (http://purl.obolibrary.org/obo/MONDO_0015967), which is being assessed separately. This gene-disease relationship is supported by functional assays, expression studies, and animal models. BETA2 (encoded by *NEUROD1*) was shown to heterodimerize with the ubiquitous helix-loop-helix (HLH) protein E47 and then bind the INS gene promotor to regulate its transcription through yeast two-hybrid assays and transient transfection assays in HIT cells to measure transcriptional activity (PMID: 7774807). Mice homozygous for disruption of BETA2 developed hyperglycemia by 2 days of age with ketonuria, suggesting severe diabetes and insulin deficiency, with abnormal pancreatic islet morphology, reduction in insulin producing cells, and lack of mature islet formation (PMIDs: 9308961, 31519700). *NEUROD1* expression has been confirmed in pancreatic tissue (PMID: 24309898). Summary of experimental data: 3 points. Total: 8 points. In summary, *NEUROD1* is moderately associated with autosomal recessive monogenic diabetes with a neurologic phenotype as described above. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This gene-disease pair was originally evaluated by the Monogenic Diabetes GCEP on October 30, 2020. It was reevaluated on September 12, 2025 by the Monogenic Diabetes GCEP. As a result of this re-evaluation, the classification did not change. This classification was approved by the MDGCEP on February 23, 2026. Gene Clinical Validity Standard Operating Procedures (SOP) - SOP11.
Inheritance Pattern: AD
Disease ID:MONDO:0011668
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0018911
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0011668
Submitter: Genomics England PanelApp
Inheritance Pattern: AR
Disease ID:MONDO:0012192
Submitter: Genomics England PanelApp
Inheritance Pattern: AR
Disease ID:MONDO:0100038
Submitter: Ambry Genetics
Clinical Genomic Database (CGD)
Manifestation: Endocrine
Intervention: General
Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to NEUROD1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_002500.5. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 1 | 1 | 81 | 83 | ||
| missense | 1 | 3 | 196 | 7 | 1 | 208 |
| nonsense | 7 | 7 | ||||
| start loss | 0 | |||||
| frameshift | 1 | 2 | 3 | |||
| splice donor/acceptor (+/-2bp) | 0 | |||||
| Total | 2 | 4 | 206 | 88 | 1 | 301 |
Highest pathogenic variant AF is 0.000016421283
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_002491.3 | 1 | MANE Select | |
| Ensembl | ENSP00000295108.3 | 1 | MANE Select | |
| Ensembl | ENSP00000506907.1 | 1 | Standard | |
| Ensembl | ENSP00000506907.1 | 1 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| neurod1 | Danio rerio | Structure: neuromast hair cell Quality: absent abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Maturity onset diabetes of the young - Homo sapiens (human)
- Anti-diabetic Drug Potassium Channel Inhibitors Pathway, Pharmacodynamics
- Dopaminergic Neurogenesis
- Sudden Infant Death Syndrome (SIDS) Susceptibility Pathways
Biological Process
- pancreatic A cell fate commitment
- pancreatic PP cell fate commitment
- nucleocytoplasmic transport
- nitric oxide mediated signal transduction
- response to glucose
Molecular Function
- DNA-binding transcription factor activity, RNA polymerase II-specific
- RNA polymerase II activating transcription factor binding
- DNA-binding transcription activator activity, RNA polymerase II-specific
- chromatin binding
- DNA-binding transcription factor activity
Cellular Component
- nucleus
- nucleoplasm
- cytoplasm
- RNA polymerase II transcription factor complex
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000295108
- Coding exons
- 1
- Length
- 7789
- Individuals with no LoFs
- 125746
- Homozygous LoFs
- 1
- Heterozygous LoFs
- 1
- Defined
- 125748
- p
- 0.00000795
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.233 | 191 | 200 | 0.954 | 0.0000104 | 2362 |
| Missense (PolyPhen) | 45 | 59.139 | 0.76091 | 706 | ||
| Synonymous | -1.65 | 101 | 82.0 | 1.23 | 0.00000463 | 704 |
| Loss of Function | 2.51 | 1 | 9.23 | 0.108 | 3.97e-7 | 121 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00016 | 0.00011 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0 | 0.0 | absent |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Acts as a transcriptional activator: mediates transcriptional activation by binding to E box-containing promoter consensus core sequences 5'-CANNTG-3'. Associates with the p300/CBP transcription coactivator complex to stimulate transcription of the secretin gene as well as the gene encoding the cyclin-dependent kinase inhibitor CDKN1A. Contributes to the regulation of several cell differentiation pathways, like those that promote the formation of early retinal ganglion cells, inner ear sensory neurons, granule cells forming either the cerebellum or the dentate gyrus cell layer of the hippocampus, endocrine islet cells of the pancreas and enteroendocrine cells of the small intestine. Together with PAX6 or SIX3, is required for the regulation of amacrine cell fate specification. Also required for dendrite morphogenesis and maintenance in the cerebellar cortex. Associates with chromatin to enhancer regulatory elements in genes encoding key transcriptional regulators of neurogenesis (By similarity). {ECO:0000250}.;
- Disease
- DISEASE: Maturity-onset diabetes of the young 6 (MODY6) [MIM:606394]: A form of diabetes that is characterized by an autosomal dominant mode of inheritance, onset in childhood or early adulthood (usually before 25 years of age), a primary defect in insulin secretion and frequent insulin-independence at the beginning of the disease. {ECO:0000269|PubMed:10545951, ECO:0000269|PubMed:11719843, ECO:0000269|PubMed:26773576}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Diabetes mellitus, non-insulin-dependent (NIDDM) [MIM:125853]: A multifactorial disorder of glucose homeostasis caused by a lack of sensitivity to the body's own insulin. Affected individuals usually have an obese body habitus and manifestations of a metabolic syndrome characterized by diabetes, insulin resistance, hypertension and hypertriglyceridemia. The disease results in long-term complications that affect the eyes, kidneys, nerves, and blood vessels. {ECO:0000269|PubMed:10545951}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.737
Intolerance Scores
- LoFtool
- 0.171
- RVIS EVS
- -0.12
- RVIS percentile EVS
- 45.13
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.862
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |