GNE
protein-codingglucosamine (UDP-N-acetyl)-2-epimerase/N-acetylmannosamine kinase
Gene summary
The protein encoded by this gene is a bifunctional enzyme that initiates and regulates the biosynthesis of N-acetylneuraminic acid (NeuAc), a precursor of sialic acids. It is a rate-limiting enzyme in the sialic acid biosynthetic pathway. Sialic acid modification of cell surface molecules is crucial for their function in many biologic processes, including cell adhesion and signal transduction. Differential sialylation of cell surface molecules is also implicated in the tumorigenicity and metastatic behavior of malignant cells. Mutations in this gene are associated with sialuria, autosomal recessive inclusion body myopathy, and Nonaka myopathy. Alternative splicing of this gene results in transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]
- IBM2
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~62.6 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0958325
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0958325
Submitter: ClinGen
*GNE* was first reported in relation to autosomal recessive macrothrombocytopenia in 2018 (Revel-Vilk et al, PMID: 30171045; Futterer et al, PMID: 29941673). The GNE gene encodes a bifunctional enzyme that is critical for the biosynthesis of sialic acid; the enzyme converts UDP-GlcNAc to ManNAc and adds a phosphate group to ManNAc, leading to the formation of sialic acid. *GNE* related isolated macrothrombocytopenia is an autosomal recessive disorder characterized by reduced number of platelets of large size, bleeding, and a platelet sialyation defect. *GNE* is also associated with myopathy (Nonaka myopathy) and sialuria, which were not included in this curation. Evidence supporting this gene-disease curation includes case level data, segregation data, and experimental data. Summary of Case Level and Segregation Data (12 points): At least 20 unique variants (missense, nonsense, frameshift, splicing) have been reported in humans. Variants in this gene have been reported in at least 16 probands in 13 publications. Variants in this gene segregated with disease in 8 additional family members (Revel-Vilk et al, PMID: 30171045; Noordermeer et al., 2022, PMID: 35255501). Summary of Experimental Data (2.5): The gene-disease relationship is supported by biochemical function (Revel-Vilk et al, PMID: 301710450), western blot protein expression (Bottega et al., 2022, PMID: 34788986), functional alteration in patient and non-patient cells (Noordermeer et al., 2022, PMID: 35255501; Huang et al., 2024, PMID: 38237079), and a mouse model (Huang et al., 2024, PMID: 38237079). In summary there is definitive evidence to support *GNE* in relation to autosomal recessive macrothrombocytopenia. Note: All the individuals in this curation were not noted to have signs of myopathy. However, *GNE*-associated myopathy typically presents in individuals 20-40 years old. The individuals in this curation are all under the age of 30, and therefore, myopathy cannot be ruled out as a future finding. To this point, several papers were excluded from this curation in which individuals had both myopathy and macrothrombocytopenia (Izumi et al., 2014, PMID: 25257349; Paul et al., 2020, PMID: 32505938; Xu et al., 2022 PMID: 35414913). This gene-disease pair was originally evaluated by the ClinGen Hemostasis and Thrombosis (H/T) Gene Curation Expert Panel on 10/27/2020. It was reevaluated on 06/22/2022 and additional evidence was added, upgrading evidence from limited to moderate. On 06/02/2025 the gene-disease classification was re-evaluated again (Gene Clinical Validity Standard Operating Procedures (SOP), Version 11), and additional evidence upgraded the curation from moderate to definitive.
Inheritance Pattern: AR
Disease ID:MONDO:0011603
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0011603
Submitter: Natera
Inheritance Pattern: AD
Disease ID:MONDO:0010028
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0010028
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0010028
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0011603
Submitter: Myriad Women's Health
Inheritance Pattern: AD
Disease ID:MONDO:0011603
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0014518
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0010028
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0011603
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0010028
Submitter: Natera
Inheritance Pattern: AR
Disease ID:MONDO:0011603
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0010028
Submitter: Genomics England PanelApp
Clinical Genomic Database (CGD)
Manifestation: Biochemical; Gastrointestinal; Hematologic; Musculoskeletal; Neurologic
Intervention: Hematologic
Rationale: The condition can involve thrombocytopenia and risk of bleeding episodes, and awareness may enable preventive measures (eg, related to surgery) and early management of bleeding episodes
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to GNE variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_005476.7. 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 | 11 | 239 | 1 | 252 | |
| missense | 14 | 90 | 377 | 5 | 486 | |
| nonsense | 25 | 22 | 47 | |||
| start loss | 1 | 1 | ||||
| frameshift | 40 | 38 | 78 | |||
| splice donor/acceptor (+/-2bp) | 6 | 23 | 1 | 30 | ||
| Total | 86 | 173 | 390 | 244 | 1 | 894 |
Highest pathogenic variant AF is 0.00074525713
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_005467.1 | 11 | MANE Select | |
| Ensembl | ENSP00000494141.2 | 11 | MANE Select | |
| RefSeq | NP_001121699.1 | 12 | MANE Plus Clinical | |
| RefSeq | NP_001177312.1 | 10 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| gne | Danio rerio | Structure: fast muscle cell Quality: disorganized abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Amino sugar and nucleotide sugar metabolism - Homo sapiens (human)
- Sialuria or French Type Sialuria
- Sialuria or French Type Sialuria
- Amino Sugar Metabolism
- G(M2)-Gangliosidosis: Variant B, Tay-sachs disease
Biological Process
- N-acetylglucosamine biosynthetic process
- UDP-N-acetylglucosamine metabolic process
- N-acetylneuraminate metabolic process
- cell adhesion
- carbohydrate phosphorylation
Molecular Function
- hydrolase activity, hydrolyzing O-glycosyl compounds
- protein binding
- ATP binding
- UDP-N-acetylglucosamine 2-epimerase activity
- N-acylmannosamine kinase activity
Cellular Component
- cytoplasm
- cytosol
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000396594
- Coding exons
- 12
- Length
- 62616
- Individuals with no LoFs
- 125691
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 57
- Defined
- 125748
- p
- 0.000227
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 2.59 | 271 | 420 | 0.645 | 0.0000233 | 4958 |
| Missense (PolyPhen) | 90 | 168.57 | 0.53389 | 1949 | ||
| Synonymous | 1.59 | 128 | 153 | 0.837 | 0.00000846 | 1505 |
| Loss of Function | 0.828 | 27 | 32.1 | 0.842 | 0.00000194 | 367 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00025 | 0.00025 | rare |
| Latino/Admixed American | 0.00014 | 0.00014 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00016 | 0.00016 | rare |
| Finnish | 0.000046 | 0.000046 | rare |
| European (Non-Finnish) | 0.00036 | 0.00035 | rare |
| South Asian | 0.00013 | 0.00013 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Regulates and initiates biosynthesis of N- acetylneuraminic acid (NeuAc), a precursor of sialic acids. Plays an essential role in early development (By similarity). Required for normal sialylation in hematopoietic cells. Sialylation is implicated in cell adhesion, signal transduction, tumorigenicity and metastatic behavior of malignant cells. {ECO:0000250, ECO:0000269|PubMed:10334995}.;
- Disease
- DISEASE: Sialuria (SIALURIA) [MIM:269921]: In sialuria, free sialic acid accumulates in the cytoplasm and gram quantities of neuraminic acid are secreted in the urine. The metabolic defect involves lack of feedback inhibition of UDP-GlcNAc 2-epimerase by CMP-Neu5Ac, resulting in constitutive overproduction of free Neu5Ac. Clinical features include variable degrees of developmental delay, coarse facial features and hepatomegaly. Sialuria inheritance is autosomal dominant. {ECO:0000269|PubMed:10330343, ECO:0000269|PubMed:10356312, ECO:0000269|PubMed:11326336, ECO:0000269|PubMed:2808337}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Nonaka myopathy (NM) [MIM:605820]: Autosomal recessive muscular disorder, allelic to inclusion body myopathy 2. It is characterized by weakness of the anterior compartment of the lower limbs with onset in early adulthood, and sparing of the quadriceps muscles. As the inclusion body myopathy, NM is histologically characterized by the presence of numerous rimmed vacuoles without inflammatory changes in muscle specimens. {ECO:0000269|PubMed:11528398, ECO:0000269|PubMed:11916006, ECO:0000269|PubMed:12177386, ECO:0000269|PubMed:12325084, ECO:0000269|PubMed:12409274, ECO:0000269|PubMed:12473753, ECO:0000269|PubMed:12473769, ECO:0000269|PubMed:12473780, ECO:0000269|PubMed:12497639, ECO:0000269|PubMed:12811782, ECO:0000269|PubMed:12913203, ECO:0000269|PubMed:15146476}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.257
Intolerance Scores
- LoFtool
- 0.0436
- RVIS EVS
- -0.03
- RVIS percentile EVS
- 51.92
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.971
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |