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AMPD2
adenosine monophosphate deaminase 2
AMPD2 is located on the short (p) arm of chromosome 1, at band 1p13.3. Arm ratio per GRCh38 - banding schematic.
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Overview
AMPD2 encodes adenosine monophosphate deaminase 2, a member of the AMP deaminase enzyme family that regulates purine nucleotide metabolism. The enzyme catalyses the deamination of adenosine monophosphate (AMP) to inosine monophosphate (IMP), a critical step in controlling the balance of adenine nucleotides within cells. While three AMPD genes exist in humans, AMPD2 shows particularly high expression in non-muscle tissues including the brain, liver, and kidneys.
Pathogenic variants in AMPD2 have been identified in individuals with neurodevelopmental disorders, including intellectual disability, cerebellar abnormalities, and epilepsy. The gene's inclusion on multiple NHS clinical panels reflects its recognised role in rare neurological conditions, particularly those affecting early brain development and cerebellar function.
What the gene does
The AMPD2 protein functions as an enzyme within the purine nucleotide cycle, catalysing the irreversible deamination of adenosine monophosphate to produce inosine monophosphate and ammonia. This enzymatic activity serves to regulate the intracellular pool of adenine nucleotides, which are essential for energy metabolism, signal transduction, and nucleic acid synthesis.
The enzyme operates as part of a broader metabolic network that maintains appropriate ratios of ATP, ADP, and AMP within cells. By converting excess AMP to IMP, AMPD2 influences cellular energy charge and helps prevent the accumulation of adenosine, which can function as a signalling molecule affecting neurotransmission. In neural tissues, this regulatory function appears particularly important during development, when rapid cell division and differentiation require precise control of nucleotide metabolism.
AMPD2 exhibits distinct tissue distribution compared to other family members, with AMPD1 predominantly expressed in skeletal muscle and AMPD3 showing broader distribution. The specific expression pattern of AMPD2 in the central nervous system suggests specialised roles in neuronal function and brain development.
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Chromosome location
AMPD2 is located on chromosome 1 at position p13.3, within the short arm of the chromosome. This chromosomal region contains multiple genes involved in metabolic processes and developmental regulation. The precise genomic structure, including exon count and transcript variants, contributes to the protein's functional diversity across different tissue types.
Protein structure
The AMPD2 protein comprises 825 amino acids and shares structural similarity with other members of the AMP deaminase family. The enzyme contains catalytic domains essential for its deaminase activity, though detailed experimental characterisation of all functional regions remains ongoing. An N-terminal disordered region spanning amino acids 1 to 49 precedes the structured catalytic core. Disordered regions in enzymes often serve regulatory functions, potentially influencing protein-protein interactions or providing flexibility for conformational changes during catalysis.
Key variants
Pathogenic variants in AMPD2 have been identified in individuals with neurodevelopmental phenotypes, though the variant spectrum remains incompletely characterised compared to more extensively studied genes. Reported variants include missense changes affecting catalytic function and loss-of-function variants predicted to eliminate enzyme activity. The inheritance pattern can vary, with both autosomal recessive and dominant mechanisms reported depending on the specific variant and associated phenotype.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.102_103del | p.Gly35fs | Pathogenic/Likely pathogenic | ★★☆☆ | Hereditary spastic paraplegia 63 |
c.1859G>A | p.Arg620His | Pathogenic/Likely pathogenic | ★★☆☆ | Pontocerebellar hypoplasia type 9 |
c.520G>T | p.Glu174Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Pontocerebellar hypoplasia type 9 |
c.646del | p.Leu216fs | Pathogenic/Likely pathogenic | ★★☆☆ | Hereditary spastic paraplegia 63 |
c.2007C>A | p.Tyr669Ter | Pathogenic | ★☆☆☆ | Pontocerebellar hypoplasia type 9 |
c.265_277del | p.Ala89fs | Pathogenic | ★☆☆☆ | Hereditary spastic paraplegia 63 |
c.319C>T | p.Gln107Ter | Pathogenic | ★☆☆☆ | Hereditary spastic paraplegia 63 |
c.-42dup | A10fs | Pathogenic | ★☆☆☆ | Pontocerebellar hypoplasia type 9 |
c.886_887del | p.Tyr295_Pro296insTer | Pathogenic | ★☆☆☆ | Hereditary spastic paraplegia 63 |
c.-90_-69dup | M1fs | Pathogenic | ★☆☆☆ | Pontocerebellar hypoplasia type 9 |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Variants in AMPD2 are associated with a range of neurodevelopmental conditions characterised by intellectual disability, cerebellar abnormalities, and epilepsy. Affected individuals may present with developmental delay, ataxia, and seizures of varying severity. The phenotypic spectrum includes cerebellar hypoplasia, a structural brain abnormality involving underdevelopment of the cerebellum, which coordinates movement and balance. Some cases present as part of syndromic epilepsy, where seizures occur alongside other neurological and developmental features. The rarity of identified cases means the full clinical spectrum is still being defined through ongoing research and clinical reporting.
No disease links recorded for this gene in our reference set.
UK clinical status
AMPD2 appears on multiple NHS Genomic Medicine Service gene panels, reflecting its clinical relevance for rare neurological conditions. The gene holds green classification status on panels including Ataxia and cerebellar anomalies, Cerebellar hypoplasia, and Hereditary ataxia, indicating sufficient evidence for its inclusion in diagnostic testing pathways. It is also listed on the Early onset or syndromic epilepsy panel, the Intellectual disability panel, and the Fetal anomalies panel, demonstrating its relevance across paediatric neurodevelopmental conditions. Green status on the DDG2P panel confirms its recognition as a developmental disorder gene with established evidence.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What does the AMPD2 gene do?
AMPD2 provides instructions for making an enzyme that converts adenosine monophosphate (AMP) into inosine monophosphate (IMP), helping to regulate the balance of nucleotides that cells use for energy and signalling. This function is particularly important in the brain and nervous system.
How are AMPD2 variants inherited?
AMPD2 variants can follow different inheritance patterns depending on the specific change and associated condition. Some pathogenic variants are inherited in an autosomal recessive pattern, requiring variants in both gene copies, while others may act in a dominant manner.
Is AMPD2 testing available on the NHS?
Yes, AMPD2 is included on multiple NHS Genomic Medicine Service panels for conditions including cerebellar abnormalities, ataxia, intellectual disability, and early-onset epilepsy. Testing eligibility depends on clinical presentation and referral criteria set by the NHS.