NADK2
protein-codingNAD kinase 2, mitochondrial
Gene summary
This gene encodes a mitochondrial kinase that catalyzes the phosphorylation of NAD to yield NADP. Mutations in this gene result in 2,4-dienoyl-CoA reductase deficiency. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2014]
- C5orf33
- NADKD1
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~49.7 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0014464
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0014464
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0014464
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0014464
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0014464
Submitter: ClinGen
NADK2 was first reported in relation to autosomal recessive 2,4-dienoyl-CoA reductase (DECR) deficiency in 2014 (Houten et al., PMID 24847004). At least 3 variants (missense, intronic) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least 3 probands in 3 publications (PMIDs 24847004, 27940755, 29388319). This gene-disease association is supported by animal models and expression studies (PMIDs 23212377, 28923496, 35796562). In summary, there is moderate evidence to support this gene-disease relationship. 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 Fatty Acid Oxidation Disorders GCEP on May 8, 2018. It was reevaluated on May 29, 2025. As a result of this reevaluation, the classification did not change.
Clinical Genomic Database (CGD)
Manifestation: Biochemical; 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 NADK2 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001085411.3. 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 | 2 | 62 | 3 | 67 | ||
| missense | 121 | 3 | 4 | 128 | ||
| nonsense | 2 | 4 | 6 | |||
| start loss | 1 | 1 | ||||
| frameshift | 1 | 4 | 5 | |||
| splice donor/acceptor (+/-2bp) | 1 | 1 | ||||
| Total | 0 | 4 | 132 | 65 | 7 | 208 |
Highest pathogenic variant AF is 0.0000107166925
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001078880.1 | 12 | MANE Select | |
| Ensembl | ENSP00000371362.4 | 12 | MANE Select | |
| RefSeq | NP_001274269.1 | 9 | Standard | |
| RefSeq | NP_001274270.1 | 10 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Nicotinate and nicotinamide metabolism - Homo sapiens (human)
- Metabolism
- Nicotinate metabolism
- Metabolism of water-soluble vitamins and cofactors
- Metabolism of vitamins and cofactors
Biological Process
- NADP biosynthetic process
- phosphorylation
- NAD metabolic process
Molecular Function
- NAD+ kinase activity
- ATP binding
- protein homodimerization activity
Cellular Component
- mitochondrion
- mitochondrial matrix
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000381937
- Coding exons
- 12
- Length
- 49688
- Individuals with no LoFs
- 125732
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 8
- Defined
- 125740
- p
- 0.0000318
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 2.05 | 124 | 207 | 0.600 | 0.0000107 | 2807 |
| Missense (PolyPhen) | 33 | 80.949 | 0.40767 | 1007 | ||
| Synonymous | 0.402 | 67 | 71.3 | 0.939 | 0.00000342 | 877 |
| Loss of Function | 3.37 | 7 | 25.3 | 0.277 | 0.00000137 | 306 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.000062 | 0.000062 | rare |
| Latino/Admixed American | 0.000029 | 0.000029 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000037 | 0.000035 | rare |
| South Asian | 0.000068 | 0.000065 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Mitochondrial NAD(+) kinase that phosphorylates NAD(+) to yield NADP(+). Can use both ATP or inorganic polyphosphate as the phosphoryl donor. Also has weak NADH kinase activity in vitro; however NADH kinase activity is much weaker than the NAD(+) kinase activity and may not be relevant in vivo. {ECO:0000269|PubMed:23212377}.;
Intolerance Scores
- RVIS EVS
- 0.53
- RVIS percentile EVS
- 80.73
Essentials
- Essential (CRISPR)
- N
- Essential (gene trap)
- N
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |