HPCAL4

Chr 1

hippocalcin like 4

Also known as: HLP4

NCBI Gene: 51440 ENSG00000116983 UniProt: Q9UM19 OMIM: 619211

The protein encoded by HPCAL4 is a calcium-binding protein that may regulate rhodopsin phosphorylation in a calcium-dependent manner. Mutations in this gene cause autosomal recessive cone-rod dystrophy, a retinal degenerative disorder affecting both cone and rod photoreceptors. This gene is highly tolerant to loss-of-function variants in the general population (pLI = 0.00003), suggesting that biallelic variants are required for disease manifestation.

OMIM ResearchSummary from RefSeq, UniProt

The protein encoded by this gene is highly similar to human hippocalcin protein and hippocalcin like-1 protein. It also has similarity to rat neural visinin-like Ca2+-binding protein-type 1 and 2 proteins. This encoded protein may be involved in the calcium-dependent regulation of rhodopsin phosphorylation. The transcript of this gene has multiple polyadenylation sites. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2013]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 1.68

Clinical Summary— HPCAL4

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

21 VUS of 24 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.68LOEUF

pLI 0.000

Z-score 0.16

OE 0.94 (0.53–1.68)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.95Z-score

OE missense 0.75 (0.64–0.90)

90 obs / 119.3 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.94 (0.53–1.68)

0≤0.351.4

Missense OE?0.75 (0.64–0.90)

0≤0.61.4

Synonymous OE?0.52

0≤1.21.6

LoF obs/exp: 7 / 7.5Missense obs/exp: 90 / 119.3Syn Z: 2.64

This gene — mechanism propensity

0.80top 25%

GOF

0.80top 10%

LOF

0.2386th %ile

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

DNprediction above median

GOFprediction 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

24 submitted variants in ClinVar

ClinVar

Classification Summary

VUS21

VUS

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Total
Pathogenic	0	0
Likely Pathogenic	0	0
VUS	21	21
Likely Benign	0	0
Benign	0	0
Total	21	21

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

View in ClinVar →

8 pathogenic / likely-pathogenic (of 15) ClinVar copy-number / structural variants overlap HPCAL4 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →