HPCAL4

Summary

HPCAL4 (hippocalcin like 4, HGNC:18212) is a protein-coding gene on chromosome 1p34.2, encoding Hippocalcin-like protein 4 (Q9UM19). May be involved in the calcium-dependent regulation of rhodopsin phosphorylation.

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.

Source: NCBI Gene 51440 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 25 total
• MANE Select transcript: NM_016257

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:18212
Approved symbol	HPCAL4
Name	hippocalcin like 4
Location	1p34.2
Locus type	gene with protein product
Status	Approved
Aliases	HLP4, DKFZp761G122
Ensembl gene	ENSG00000116983
Ensembl biotype	protein_coding
OMIM	619211
Entrez	51440

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 6 protein_coding

ENST00000372844, ENST00000612703, ENST00000617690, ENST00000862711, ENST00000862712, ENST00000945844

RefSeq mRNA: 3 — MANE Select: NM_016257 NM_001282396, NM_001282397, NM_016257

CCDS: CCDS441, CCDS72761

Canonical transcript exons

ENST00000372844 — 4 exons

Exon	Start	End
ENSE00001458790	39678648	39682733
ENSE00001458794	39684442	39684611
ENSE00001627527	39683937	39684152
ENSE00001805565	39691306	39691433

Expression profiles

Bgee: expression breadth ubiquitous, 177 present calls, max score 97.10.

FANTOM5 (CAGE): breadth broad, TPM avg 8.1435 / max 431.9964, expressed in 348 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
11877	7.6415	344
11878	0.2684	88
11879	0.1513	69
11880	0.0824	51

Top tissues by expression

277 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
right frontal lobe	UBERON:0002810	97.10	gold quality
prefrontal cortex	UBERON:0000451	97.09	gold quality
cerebellar cortex	UBERON:0002129	97.02	gold quality
cerebellar hemisphere	UBERON:0002245	97.00	gold quality
right hemisphere of cerebellum	UBERON:0014890	96.94	gold quality
cerebellum	UBERON:0002037	96.83	gold quality
anterior cingulate cortex	UBERON:0009835	96.54	gold quality
cingulate cortex	UBERON:0003027	96.49	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	96.46	gold quality
frontal cortex	UBERON:0001870	96.42	gold quality
nucleus accumbens	UBERON:0001882	96.09	gold quality
amygdala	UBERON:0001876	95.78	gold quality
Brodmann (1909) area 9	UBERON:0013540	95.70	gold quality
neocortex	UBERON:0001950	95.51	gold quality
cerebellar vermis	UBERON:0004720	95.37	gold quality
cerebral cortex	UBERON:0000956	94.97	gold quality
temporal lobe	UBERON:0001871	94.94	gold quality
orbitofrontal cortex	UBERON:0004167	94.53	gold quality
entorhinal cortex	UBERON:0002728	94.50	gold quality
Ammon’s horn	UBERON:0001954	94.25	gold quality
superior frontal gyrus	UBERON:0002661	94.23	gold quality
telencephalon	UBERON:0001893	93.93	gold quality
Brodmann (1909) area 46	UBERON:0006483	93.68	gold quality
postcentral gyrus	UBERON:0002581	93.35	gold quality
parietal lobe	UBERON:0001872	92.84	gold quality
hypothalamus	UBERON:0001898	92.15	gold quality
caudate nucleus	UBERON:0001873	92.13	gold quality
brain	UBERON:0000955	90.70	gold quality
forebrain	UBERON:0001890	90.64	gold quality
putamen	UBERON:0001874	90.09	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	2.43

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): NRF1

miRNA regulators (miRDB)

220 targeting HPCAL4, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-6758-5P	100.00	66.21	1470
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-1184	99.99	68.19	1458
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-520G-5P	99.99	66.76	658
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-34C-5P	99.97	70.45	1577
HSA-MIR-449B-5P	99.97	70.26	1580
HSA-MIR-4487	99.96	64.58	1252
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-6809-3P	99.91	71.45	3814
HSA-MIR-329-3P	99.91	66.56	1234
HSA-MIR-362-3P	99.91	66.38	1267
HSA-MIR-4753-3P	99.90	71.03	3786

Cross-species orthologs

18 orthologs

Organism	Symbol	Gene ID
danio_rerio	guca1c	ENSDARG00000030758
danio_rerio	guca1d	ENSDARG00000044629
danio_rerio	guca1g	ENSDARG00000045737
danio_rerio	rcvrna	ENSDARG00000052223
danio_rerio	hpcal4	ENSDARG00000070491
danio_rerio	rcvrnb	ENSDARG00000111827
mus_musculus	Hpcal4	ENSMUSG00000046093
rattus_norvegicus	Hpcal4	ENSRNOG00000050983
drosophila_melanogaster	CG2256	FBGN0029995
drosophila_melanogaster	CG3565	FBGN0035034
drosophila_melanogaster	CG7646	FBGN0036926
drosophila_melanogaster	sowi	FBGN0037460
drosophila_melanogaster	CG15177	FBGN0037461
drosophila_melanogaster	sunz	FBGN0037462
drosophila_melanogaster	d-cup	FBGN0038089
drosophila_melanogaster	CG5890	FBGN0039380
caenorhabditis_elegans	ncs-2	WBGENE00003564
caenorhabditis_elegans		WBGENE00015867

Paralogs (14): CLXN (ENSG00000034239), GUCA1A (ENSG00000048545), NCALD (ENSG00000104490), NCS1 (ENSG00000107130), RCVRN (ENSG00000109047), GUCA1B (ENSG00000112599), KCNIP3 (ENSG00000115041), HPCAL1 (ENSG00000115756), KCNIP2 (ENSG00000120049), HPCA (ENSG00000121905), GUCA1C (ENSG00000138472), VSNL1 (ENSG00000163032), KCNIP1 (ENSG00000182132), KCNIP4 (ENSG00000185774)

Protein

Protein identifiers

Hippocalcin-like protein 4 — Q9UM19 (reviewed: Q9UM19)

All UniProt accessions (2): B4DGW9, Q9UM19

UniProt curated annotations — full annotation on UniProt →

Function. May be involved in the calcium-dependent regulation of rhodopsin phosphorylation.

Miscellaneous. Probably binds two or three calcium ions.

Similarity. Belongs to the recoverin family.

RefSeq proteins (3): NP_001269325, NP_001269326, NP_057341* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002048	EF_hand_dom	Domain
IPR011992	EF-hand-dom_pair	Homologous_superfamily
IPR018247	EF_Hand_1_Ca_BS	Binding_site
IPR028846	Recoverin	Family

Pfam: PF00036, PF13499

UniProt features (23 total): binding site 15, domain 4, initiator methionine 1, chain 1, lipid moiety-binding region 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UM19-F1	86.60	0.62

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (15): 84; 109; 111; 113; 115; 120; 159; 161; 163; 165; 170; 73 …

Post-translational modifications (1): 2

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 123 (showing top): BENPORATH_ES_WITH_H3K27ME3, AREB6_01, TGACCTY_ERR1_Q2, GGGTGGRR_PAX4_03, USF_C, chr1p34, GNF2_TM4SF2, TGANTCA_AP1_C, GOBP_RESPONSE_TO_ABIOTIC_STIMULUS, LASTOWSKA_NEUROBLASTOMA_COPY_NUMBER_DN, LXR_Q3, POU3F2_02, RFX1_02, OCT1_B, TGTYNNNNNRGCARM_UNKNOWN

GO Biological Process (3): central nervous system development (GO:0007417), response to heat (GO:0009408), regulation of signal transduction (GO:0009966)

GO Molecular Function (5): calcium channel regulator activity (GO:0005246), calcium ion binding (GO:0005509), protein domain specific binding (GO:0019904), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (0):

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
nervous system development	1
system development	1
response to stress	1
response to temperature stimulus	1
signal transduction	1
regulation of cell communication	1
regulation of signaling	1
regulation of response to stimulus	1
calcium channel activity	1
ion channel regulator activity	1
metal ion binding	1
protein binding	1
binding	1
cation binding	1

Protein interactions and networks

STRING

3014 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HPCAL4	TRIT1	Q9H3H1	428
HPCAL4	CACNG8	Q8WXS5	398
HPCAL4	ARRB1	P49407	396
HPCAL4	NT5C1A	Q9BXI3	382
HPCAL4	CALY	Q9NYX4	342
HPCAL4	LSAMP	Q13449	342
HPCAL4	ABHD15	Q6UXT9	325
HPCAL4	SLC35F4	A4IF30	310
HPCAL4	MAPT	P10636	297
HPCAL4	NXT2	Q9NPJ8	296
HPCAL4	GNG10	P50151	295
HPCAL4	DDN	O94850	284
HPCAL4	TAGLN3	Q9UI15	279
HPCAL4	DEFB129	Q9H1M3	278
HPCAL4	CABP7	Q86V35	276

IntAct

75 interactions, top by confidence:

A	B	Type	Score
DTX2	HPCAL4	psi-mi:“MI:0915”(physical association)	0.780
HPCAL4	DTX2	psi-mi:“MI:0915”(physical association)	0.780
LITAF	HPCAL4	psi-mi:“MI:0915”(physical association)	0.740
FAM131C	HPCAL4	psi-mi:“MI:0915”(physical association)	0.720
SPRED1	HPCAL4	psi-mi:“MI:0915”(physical association)	0.720
HPCAL4	SPRED1	psi-mi:“MI:0915”(physical association)	0.720
TTC12	HPCAL4	psi-mi:“MI:0915”(physical association)	0.560
TEX13B	HPCAL4	psi-mi:“MI:0915”(physical association)	0.560
SCMH1	HPCAL4	psi-mi:“MI:0915”(physical association)	0.560
AQP4	HPCAL4	psi-mi:“MI:0915”(physical association)	0.560
ANKRD33	HPCAL4	psi-mi:“MI:0915”(physical association)	0.560
CEACAM6	HPCAL4	psi-mi:“MI:0915”(physical association)	0.560
TRPM5	HPCAL4	psi-mi:“MI:0915”(physical association)	0.560
MSRA	HPCAL4	psi-mi:“MI:0915”(physical association)	0.560
F3	HPCAL4	psi-mi:“MI:0915”(physical association)	0.560
	HPCAL4	psi-mi:“MI:0915”(physical association)	0.560
CYP1A1	SNX3	psi-mi:“MI:0914”(association)	0.530
NUFIP1	PDE2A	psi-mi:“MI:0914”(association)	0.530
HPCAL4	tir	psi-mi:“MI:0915”(physical association)	0.510

BioGRID (42): TTC12 (Two-hybrid), DTX2 (Two-hybrid), FAM131C (Two-hybrid), HPCAL4 (Affinity Capture-MS), HPCAL4 (Affinity Capture-MS), HPCAL4 (Affinity Capture-MS), HPCAL4 (Affinity Capture-MS), DTX2 (Two-hybrid), HPCAL4 (Two-hybrid), HPCAL4 (Two-hybrid), HPCAL4 (Affinity Capture-MS), HPCAL4 (Affinity Capture-MS), HPCAL4 (Affinity Capture-MS), HPCAL4 (Affinity Capture-MS), HPCAL4 (Affinity Capture-MS)

ESM2 similar proteins: A9JTH1, B3DLU1, B3VSB7, B5FZ84, P29104, P29105, P35332, P36608, P37235, P37236, P42324, P42325, P61601, P61602, P62166, P62167, P62168, P62748, P62749, P62758, P62759, P62760, P62761, P62762, P62763, P62764, P84074, P84075, P84076, Q06AT0, Q06AT1, Q09711, Q16982, Q28IM6, Q4PL64, Q4R4N4, Q4R5F7, Q5PQN0, Q5R632, Q5R6S5

Diamond homologs: A9JTH1, B3DLU1, B3VSB7, B5FZ84, O73761, O73762, O73763, O95843, P21457, P22728, P25296, P29104, P29105, P31227, P34057, P35243, P35332, P36608, P36609, P37235, P37236, P42322, P42324, P42325, P43080, P43081, P46065, P51177, P61601, P61602, P62166, P62167, P62168, P62748, P62749, P62758, P62759, P62760, P62761, P62762

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

25 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	21
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

658 predictions. Top by Δscore:

Variant	Effect	Δscore
1:39682541:T:TA	donor_gain	1.0000
1:39682594:T:TA	donor_gain	1.0000
1:39682629:AT:A	donor_gain	1.0000
1:39682730:TTGC:T	acceptor_gain	1.0000
1:39682731:TGC:T	acceptor_gain	1.0000
1:39682733:CCTGG:C	acceptor_gain	1.0000
1:39682734:C:CC	acceptor_gain	1.0000
1:39683931:CCGCA:C	donor_loss	1.0000
1:39683932:CGCA:C	donor_loss	1.0000
1:39683933:GCAC:G	donor_loss	1.0000
1:39683934:CA:C	donor_loss	1.0000
1:39683935:A:AT	donor_loss	1.0000
1:39684153:C:CC	acceptor_gain	1.0000
1:39684440:A:T	donor_loss	1.0000
1:39684441:C:T	donor_loss	1.0000
1:39684609:GGC:G	acceptor_gain	1.0000
1:39684611:CCTG:C	acceptor_loss	1.0000
1:39684612:C:CC	acceptor_gain	1.0000
1:39684612:C:CG	acceptor_loss	1.0000
1:39684613:T:A	acceptor_loss	1.0000
1:39682529:CCAG:C	donor_gain	0.9900
1:39682624:T:TA	donor_gain	0.9900
1:39682729:ATTGC:A	acceptor_gain	0.9900
1:39682732:GC:G	acceptor_gain	0.9900
1:39682732:GCCTG:G	acceptor_loss	0.9900
1:39682733:CC:C	acceptor_loss	0.9900
1:39682734:C:A	acceptor_loss	0.9900
1:39682734:C:T	acceptor_gain	0.9900
1:39682735:T:C	acceptor_loss	0.9900
1:39682737:G:C	acceptor_gain	0.9900

AlphaMissense

1301 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:39682588:G:T	A175D	0.999
1:39682599:G:C	F171L	0.999
1:39682599:G:T	F171L	0.999
1:39682600:A:G	F171S	0.999
1:39682601:A:G	F171L	0.999
1:39682663:C:G	R150P	0.999
1:39683956:T:A	E120V	0.999
1:39683989:T:G	D109A	0.999
1:39684000:A:C	F105L	0.999
1:39684000:A:T	F105L	0.999
1:39684002:A:G	F105L	0.999
1:39684013:A:G	L101P	0.999
1:39684060:G:C	F85L	0.999
1:39684060:G:T	F85L	0.999
1:39684062:A:G	F85L	0.999
1:39684069:G:C	F82L	0.999
1:39684069:G:T	F82L	0.999
1:39684071:A:G	F82L	0.999
1:39684106:C:G	R70P	0.999
1:39684108:G:C	F69L	0.999
1:39684108:G:T	F69L	0.999
1:39684110:A:G	F69L	0.999
1:39684112:G:T	A68D	0.999
1:39684123:G:C	F64L	0.999
1:39684123:G:T	F64L	0.999
1:39684125:A:G	F64L	0.999
1:39684147:G:C	F56L	0.999
1:39684147:G:T	F56L	0.999
1:39684149:A:G	F56L	0.999
1:39684502:G:C	F34L	0.999

dbSNP variants (sampled 300 via entrez): RS1000025305 (1:39680422 T>C), RS1000070459 (1:39688016 G>A), RS1000215259 (1:39686613 G>A), RS1000218072 (1:39692663 C>T), RS1000270321 (1:39692982 G>A), RS1000674863 (1:39691420 C>G), RS1001193230 (1:39680255 T>C), RS1001281045 (1:39692605 C>A), RS1001283128 (1:39686843 G>T), RS1001381704 (1:39686082 G>A), RS1001556725 (1:39692290 A>C,T), RS1001586877 (1:39687233 G>A), RS1001836420 (1:39690714 A>G), RS1001931124 (1:39681089 G>A,T), RS1002439164 (1:39691846 A>AC,ACC)

Disease associations

OMIM: gene MIM:619211 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST003654_1	Bone mineral density (Ward’s triangle area)	4.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0007785	femoral neck bone mineral density

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

33 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases expression, affects expression	3
bisphenol A	decreases methylation, increases expression	2
Benzo(a)pyrene	affects methylation, increases methylation	2
Aflatoxin B1	increases methylation	2
sotorasib	affects cotreatment, decreases expression	1
triphenyl phosphate	affects expression	1
propionaldehyde	increases expression	1
testosterone undecanoate	decreases expression	1
ethyl-p-hydroxybenzoate	decreases expression	1
butyraldehyde	increases expression	1
aflatoxin B2	decreases methylation	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression, affects cotreatment, decreases expression	1
beta-methylcholine	affects expression	1
pentanal	increases expression	1
CGP 52608	affects binding, increases reaction	1
entinostat	increases expression	1
abrine	increases expression	1
trametinib	affects cotreatment, decreases expression	1
NVP-BKM120	decreases expression, affects cotreatment	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	decreases expression	1
Zoledronic Acid	decreases expression	1
Acetaminophen	increases expression	1
Aldehydes	increases expression	1
Diethylnitrosamine	increases expression	1
Estradiol	affects cotreatment, increases expression	1
Ivermectin	decreases expression	1
Lead	affects expression	1
Lipopolysaccharides	increases expression, affects cotreatment, decreases expression, affects response to substance	1
Methotrexate	decreases expression	1
Nicotine	increases expression	1

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.