HPCA

Chr 1

hippocalcin

Also known as: BDR2, DYT2

NCBI Gene: 3208 ENSG00000121905 UniProt: P84074

The protein is a neuron-specific calcium-binding protein that inhibits rhodopsin kinase in a calcium-dependent manner and regulates photosignal transduction. Mutations cause autosomal recessive torsion dystonia 2 through a predicted gain-of-function mechanism. The protein localizes to the cytoplasm and cytosol and is thought to play an important role in central nervous system neurons.

ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

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]

ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

UniProtDystonia 2, torsion, autosomal recessive

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · complex movement disorder with or without neurodevelopmental features · AR · ClinGen 2025

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.59

LOEUF

Multiple*

Mechanism· predicted

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

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?

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?

LoF OE?0.13 (0.04–0.59)

0≤0.351.4

Missense OE?0.45 (0.36–0.56)

0≤0.61.4

Synonymous OE?0.81

0≤1.21.6

LoF obs/exp: 1 / 8.0Missense obs/exp: 57 / 126.8Syn Z: 1.10

Background carrier burden — how many people carry a rare variant somewhere in HPCA?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 630

173 rare PASS variants

Rare truncating (LoF)

1 in 22,000

12 rare PASS variants

Rare synonymous (reference)

1 in 810

99 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for HPCA. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 810	1 in 15,000
South Asian	~43k	1 in 620	≈ 1 in 40,000
Remaining (unassigned)	~30k	1 in 810	≈ 1 in 30,000
European (Finnish)	~27k	≈ 1 in 6,700	none seen
Admixed American	~22k	1 in 1,600	≈ 1 in 19,000
African / African American	~21k	1 in 1,200	none seen
East Asian	~20k	1 in 450	≈ 1 in 18,000
Ashkenazi Jewish	~13k	1 in 1,000	none seen
Middle Eastern	~2,884	≈ 1 in 1,400	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 3 coding exons well covered in gnomAD exomes and genomes.? see exons ↓