HPCA

Chr 1AR

hippocalcin

Also known as: BDR2, DYT2

NCBI Gene: 3208 ENSG00000121905 UniProt: P84074 OMIM: 142622

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.

GeneReviews OMIM 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]

GeneReviews OMIM ResearchGenerating clinical summary…

MultiplemechanismARLOEUF 0.591 OMIM phenotype

Clinical Summary— HPCA

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Gene-Disease Validity (ClinGen)

complex movement disorder with or without neurodevelopmental features · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Moderately constrained gene (pLI 0.68) — some intolerance to loss-of-function variants.

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ClinVar Variants

3 unique Pathogenic / Likely Pathogenic· 28 VUS of 66 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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GeneReview available — HPCA

Authoritative clinical overview · Recommended first read

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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

This gene — mechanism propensity

0.7326th %ile

GOF

0.75top 25%

LOF

0.3452th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

66 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic3

VUS28

Likely Benign32

Benign3

Pathogenic

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	2	1	0	3
Likely Pathogenic	0	0	0	0
VUS	26	2	0	28
Likely Benign	1	10	21	32
Benign	0	3	0	3
Total	29	16	21	66

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

View in ClinVar →

9 pathogenic / likely-pathogenic (of 13) ClinVar copy-number / structural variants overlap HPCA — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →