HPCA

Chr 1AR

hippocalcin

Also known as: BDR2, DYT2

NCBI Gene: 3208ENSG00000121905UniProt: P84074

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]

Primary Disease Associations & Inheritance

Dystonia 2, torsion, autosomal recessiveMIM #224500
AR
76
ClinVar variants
12
Pathogenic / LP
0.68
pLI score
1
Active trials
Clinical Summary— HPCA
🧬
Gene-Disease Validity (ClinGen)
complex movement disorder with or without neurodevelopmental features · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Moderately constrained gene (pLI 0.68) — some intolerance to loss-of-function variants.
📋
ClinVar Variants
12 Pathogenic / Likely Pathogenic· 29 VUS of 76 total submissions
💊
Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.59LOEUF
pLI 0.678
Z-score 2.29
OE 0.13 (0.04–0.59)
Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
2.20Z-score
OE missense 0.45 (0.36–0.56)
57 obs / 126.8 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.13 (0.04–0.59)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.45 (0.36–0.56)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.81
0≤1.21.6
LoF obs/exp: 1 / 8.0Missense obs/exp: 57 / 126.8Syn Z: 1.10

ClinVar Variant Classifications

76 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic11
Likely Pathogenic1
VUS29
Likely Benign32
Benign3
11
Pathogenic
1
Likely Pathogenic
29
VUS
32
Likely Benign
3
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
2
9
0
11
Likely Pathogenic
0
0
1
0
1
VUS
0
24
5
0
29
Likely Benign
0
1
10
21
32
Benign
0
0
3
0
3
Total027282176

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

HPCA · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
HIPPOCALCIN; HPCA
MIM #142622 · *

Dystonia 2, torsion, autosomal recessive

MIM #224500

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — HPCA
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Genetics and Pathogenesis of Dystonia.
Thomsen M et al.·Annu Rev Pathol
2024Review
Hereditary Prostate Cancer: Genes Related, Target Therapy and Prevention.
Vietri MT et al.·Int J Mol Sci
2021Review
Selenitetriglycerides-Redox-active agents.
Flis A et al.·Pharmacol Rep
2015
Genotype-Phenotype Relations for Isolated Dystonia Genes: MDSGene Systematic Review.
Lange LM et al.·Mov Disord
2021Review
HPCA confirmed as a genetic cause of DYT2-like dystonia phenotype.
Atasu B et al.·Mov Disord
2018Case report
Case Report of Pediatric HPCA-Associated Dystonia: Analysis of Ca(2+) and K(+) Channel Dynamics and Experience With Pallidal Deep Brain Stimulation.
Nou-Fontanet L et al.·Pediatr Neurol
2025Case report
Expression of HPCA-1 and HLA-DR antigens on growth factor- and stroma-dependent colony forming cells.
Watt SM et al.·Br J Haematol
1987
Mini-review: "Hippocalcin: Molecular mechanisms and therapeutic potential in neuronal function".
Park SY·Neurosci Lett
2025Review
Genetic Dystonias: Update on Classification and New Genetic Discoveries.
Keller Sarmiento IJ et al.·Curr Neurol Neurosci Rep
2021Review
A novel investigation into the negative impact of opioid use on the efficacy of immune checkpoint inhibitors in advanced non-small cell lung cancer patients.
Guo H et al.·Int Immunopharmacol
2024Meta-analysis
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
HER-2 Positive Breast CancerEstrogen Receptor Positive Breast Cancer

Randomized, Open Label, Clinical Study of the Targeted Therapy, Palbociclib, to Treat Metastatic Breast Cancer

ACTIVE NOT RECRUITING
NCT02947685Phase PHASE3Alliance Foundation Trials, LLC.Started 2017-06-21
palbociclibtrastuzumabpertuzumab

External Resources

Links to major genomics databases and tools