NANS
protein-codingN-acetylneuraminate synthase
Gene summary
This gene encodes an enzyme that functions in the biosynthetic pathways of sialic acids. In vitro, the encoded protein uses N-acetylmannosamine 6-phosphate and mannose 6-phosphate as substrates to generate phosphorylated forms of N-acetylneuraminic acid (Neu5Ac) and 2-keto-3-deoxy-D-glycero-D-galacto-nononic acid (KDN), respectively; however, it exhibits much higher activity toward the Neu5Ac phosphate product. In insect cells, expression of this gene results in Neu5Ac and KDN production. This gene is related to the E. coli sialic acid synthase gene neuB, and it can partially restore sialic acid synthase activity in an E. coli neuB-negative mutant. [provided by RefSeq, Jul 2008]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~26.3 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0012495
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0012495
Submitter: ClinGen
*NANS* was first reported in relation to the autosomal recessive disorder spondyloepimetaphyseal dysplasia, Genevieve type, in 2016 (van Karnebeek et al, PMID: 27213289). *NANS* encodes N-acetylneuraminic acid phosphate synthase, also known as sialic acid synthase, an enzyme that is essential for *de novo* sialic acid synthesis. Sialic acids are a family of 9-carbon sugars; over 50 forms have been identified. The predominant sialic acid in mammals, N-acetylneuraminic acid (NANA, Neu5Ac, NeuNAc) is typically the terminal sugar in cell surface glycans, glycoconjugates, oligosaccharides, lipo-oligosaccharides, and polysaccharides, and has important numerous physiological functions such as cell-cell interactions and immune function. One condition, NANS-related CDG (spondyloepimetaphyseal dysplasia, Genevieve type) has been asserted to be caused by biallelic variants in *NANS*. This condition is characterized by skeletal dysplasia, moderate to severe intellectual disability, and facial dysmorphism, including prominent forehead, depressed nasal bridge, and full lips. This curation includes 23 variants (12 missense, 1 initiator codon, 1 in-frame duplication, 2 nonsense, 4 frameshift, 3 intronic/splice site) that have been reported in 15 probands in 4 publications (van Karnebeek et al, 2016, PMID: 27213289; den Hollander et al, 2021, PMID: 34163424; Masunaga et al, 2022, PMID: 36224347; Yoo and Cheon, 2024, PMID: 38822623). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity appears to be loss of function. This gene-disease relationship is also supported by experimental evidence including the biochemical function of NANS in the synthesis of sialic acids, which is consistent with the finding of elevated precursor, N-acetylmannosamine, in urine from patients with biallelic variants in the gene. In addition, zebrafish treated with morpholinos to knock down the zebrafish orthologue of *NANS*, nansa, have features that recapitulate the human phenotype, including developmental anomalies of the skeleton; these features were ameliorated by sialic acid treatment. Of note, the features of a human infant, who was treated pre- and postnatally with sialic acid appear to be milder than those of two individuals with the same genotype (one treated postnatally, one untreated) (den Hollander et al, 2023, PMID: 37340906). In summary, there is definitive evidence supporting the relationship between *NANS* and the autosomal recessive disorder spondyloepimetaphyseal dysplasia, Genevieve type. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time, This classification was approved by the ClinGen Congenital Disorders of Glycosylation Gene Curation Expert Panel on January 5, 2026 (SOP v11).
Inheritance Pattern: AR
Disease ID:MONDO:0012495
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0012495
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0012495
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0012495
Submitter: G2P
Clinical Genomic Database (CGD)
Manifestation: Musculoskeletal; Neurologic
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 NANS variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_018946.4. 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 | 46 | 1 | 48 | ||
| missense | 1 | 6 | 88 | 7 | 102 | |
| nonsense | 1 | 2 | 3 | |||
| start loss | 1 | 1 | ||||
| frameshift | 3 | 2 | 1 | 6 | ||
| splice donor/acceptor (+/-2bp) | 2 | 2 | 4 | |||
| Total | 5 | 13 | 92 | 53 | 1 | 164 |
Highest pathogenic variant AF is 0.000016873377
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_061819.2 | 6 | MANE Select | |
| Ensembl | ENSP00000210444.5 | 6 | MANE Select | |
| Ensembl | ENSP00000404107.1 | 2 | Standard | |
| Ensembl | ENSP00000404642.1 | 2 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| nansa | Danio rerio | Structure: ceratobranchial cartilage Quality: absent 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
- CMP-N-acetylneuraminate biosynthetic process
- carbohydrate biosynthetic process
Molecular Function
- N-acylneuraminate cytidylyltransferase activity
- N-acylneuraminate-9-phosphate synthase activity
- N-acetylneuraminate synthase activity
Cellular Component
- cytoplasm
- cytosol
- extracellular exosome
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Produces N-acetylneuraminic acid (Neu5Ac) and 2-keto-3- deoxy-D-glycero-D-galacto-nononic acid (KDN). Can also use N- acetylmannosamine 6-phosphate and mannose 6-phosphate as substrates to generate phosphorylated forms of Neu5Ac and KDN, respectively.;
Intolerance Scores
- LoFtool
- 0.718
- RVIS EVS
- 0.42
- RVIS percentile EVS
- 77.06
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.970
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |