HPCA
protein-codinghippocalcin, the group of EF-hand domain containing
Gene summary
The protein encoded by this gene is a member of neuron-specific calcium-binding proteins family found in the retina and brain. This protein is associated with the plasma membrane. It has similarities to proteins located in the photoreceptor cells that regulate photosignal transduction in a calcium-sensitive manner. This protein displays recoverin activity and a calcium-dependent inhibition of rhodopsin kinase. It is identical to the rat and mouse hippocalcin proteins and thought to play an important role in neurons of the central nervous system in a number of species. [provided by RefSeq, Jul 2008]
- DYT2
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~12.4 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0009141
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:1060159
Submitter: ClinGen
*HPCA* was first reported in relation to autosomal recessive complex movement disorder with or without neurodevelopmental features in 2015 (Charlesworth et al., PMID: 25799108). This condition is characterized by dystonia, which can be generalized or localized; dysarthria; motor delay; intellectual disability; and involuntary movements/jerking. Seven variants (missense, nonsense, frameshift) that have been reported in at least eight probands across six publications (PMIDs: 25799108, 30145809, 33511595, 34077496, 36698997, 36704070) are included in this curation. The mechanism of pathogenicity appears to be loss-of-function (PMID: 30145809). This gene-disease relationship is also supported by experimental evidence (mouse models, cell culture model, functional alteration evidence; PMIDs: 1280427, 15878804, 23142228, 33502045). Model evidence shows abnormal behavioral, reduced learning ability, and increased neurodegeneration in mutants. Expression-level data shows hippocampal expression of *HPCA*. In summary, there is definitive evidence supporting the relationship between *HPCA* and autosomal recessive complex movement disorder with or without neurodevelopmental features. 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 Cerebral Palsy GCEP on the meeting date 10/2/2025 (SOP Version 11).
Inheritance Pattern: AR
Disease ID:MONDO:0009141
Submitter: Genomics England PanelApp
Inheritance Pattern: AR
Disease ID:MONDO:0009141
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0009141
Submitter: PanelApp Australia
Clinical Genomic Database (CGD)
Manifestation: 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 HPCA variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_002143.3. 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 | 21 | 21 | ||||
| missense | 1 | 1 | 26 | 1 | 29 | |
| nonsense | 0 | |||||
| start loss | 0 | |||||
| frameshift | 0 | |||||
| splice donor/acceptor (+/-2bp) | 0 | |||||
| Total | 1 | 1 | 26 | 22 | 0 | 50 |
Highest pathogenic variant AF is 0.0000027361802
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_002134.2 | 3 | MANE Select | |
| Ensembl | ENSP00000362566.3 | 3 | MANE Select | |
| Ensembl | ENSP00000524830.1 | 3 | Standard | |
| Ensembl | ENSP00000524830.1 | 3 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Biological Process
- brain development
- calcium-mediated signaling
- negative regulation of guanylate cyclase activity
- activation of phospholipase D activity
- positive regulation of adenylate cyclase activity
Molecular Function
- actin binding
- calcium ion binding
- kinase binding
- identical protein binding
Cellular Component
- cytoplasm
- cytosol
- extrinsic component of membrane
- axon
- dendrite membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000373467
- Coding exons
- 3
- Length
- 12448
- Individuals with no LoFs
- 125713
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 2
- Defined
- 125715
- p
- 0.00000795
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 2.20 | 57 | 127 | 0.450 | 0.00000765 | 1291 |
| Missense (PolyPhen) | 12 | 45.756 | 0.26226 | 472 | ||
| Synonymous | 1.10 | 43 | 53.2 | 0.808 | 0.00000353 | 347 |
| Loss of Function | 2.29 | 1 | 7.99 | 0.125 | 4.23e-7 | 89 |
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 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000018 | 0.000018 | rare |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Calcium-binding protein that may play a role in the regulation of voltage-dependent calcium channels (PubMed:28398555). May also play a role in cyclic-nucleotide- mediated signaling through the regulation of adenylate and guanylate cyclases (By similarity). {ECO:0000250|UniProtKB:P84076, ECO:0000269|PubMed:28398555}.;
- Disease
- DISEASE: Dystonia 2, torsion, autosomal recessive (DYT2) [MIM:224500]: A form of torsion dystonia, a disease defined by the presence of sustained involuntary muscle contractions, often leading to abnormal postures. 'Torsion' refers to the twisting nature of body movements, often affecting the trunk. DYT2 is a slowly progressive form that first affects distal limbs and later involves the neck, orofacial, and craniocervical regions. {ECO:0000269|PubMed:25799108, ECO:0000269|PubMed:28398555}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.163
Intolerance Scores
- LoFtool
- 0.150
- RVIS EVS
- -0.1
- RVIS percentile EVS
- 46.2
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- S
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.993
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Low | Low |
| Primary Immunodeficiency | Medium | Low | Medium |
| Cancer | Medium | Medium | Medium |