PCP4

Summary

PCP4 (Purkinje cell protein 4, HGNC:8742) is a protein-coding gene on chromosome 21q22.2, encoding Calmodulin regulator protein PCP4 (P48539). Functions as a modulator of calcium-binding by calmodulin.

Enables calcium ion binding activity and calmodulin binding activity. Involved in positive regulation of CAMKK-AMPK signaling cascade and positive regulation of neuron differentiation. Located in cytosol and nucleus. Part of protein-containing complex. Biomarker of Huntington’s disease and leiomyoma.

Source: NCBI Gene 5121 — automated summary from GO annotations (Alliance of Genome Resources).

At a glance

• GWAS associations: 5
• Clinical variants (ClinVar): 15 total — 1 pathogenic
• GTEx eGene: eQTL in 19 tissues, sQTL in 3 (q < 0.05)
• Constraint (gnomAD): pLI 0.12 (intermediate), LOEUF 1.50 (unconstrained)
• MANE Select transcript: NM_006198

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:8742
Approved symbol	PCP4
Name	Purkinje cell protein 4
Location	21q22.2
Locus type	gene with protein product
Status	Approved
Aliases	PEP-19
Ensembl gene	ENSG00000183036
Ensembl biotype	protein_coding
OMIM	601629
Entrez	5121

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 4 protein_coding, 2 nonsense_mediated_decay, 2 protein_coding_CDS_not_defined

MANE Select: ENST00000328619

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 1, TSL 2: 2, TSL 5: 1

ENST00000328619, ENST00000462224, ENST00000467565, ENST00000468717, ENST00001029782, ENST00001090519, ENST00001090520, ENST00001131559

RefSeq mRNA: 1 — MANE Select: NM_006198 NM_006198

CCDS: CCDS33563

Canonical transcript exons

ENST00000328619 — 3 exons

Exon	Start	End
ENSE00001938571	39867438	39867510
ENSE00003509580	39928984	39929392
ENSE00003668461	39898476	39898527

Expression profiles

Bgee: expression breadth ubiquitous, 245 present calls, max score 100.00.

FANTOM5 (CAGE): breadth broad, TPM avg 58.2799 / max 8615.7024, expressed in 454 samples.

Highest expression (Bgee): lateral nuclear group of thalamus, lateral globus pallidus, middle frontal gyrus, choroid plexus epithelium, putamen.

Genetic regulation across tissues (GTEx eQTL / sQTL)

PCP4 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 19 tissues and its splicing (sQTL) in 3 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 22 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Artery Tibial	eqtl	8.4e-63	+0.58	21:39800545:A:G
Nerve Tibial	eqtl	4.7e-55	-0.80	21:40011485:T:C
Brain Cortex	eqtl	8.9e-12	-0.51	21:39884132:C:G
Heart Atrial Appendage	sqtl	3.4e-10	-0.95	21:39786934:A:C
Colon Sigmoid	eqtl	9.5e-09	-0.28	21:40010541:T:C
Esophagus Muscularis	eqtl	1.1e-07	-0.46	21:40053265:T:C
Thyroid	eqtl	2.2e-05	+0.20	21:39869621:C:T
Brain Frontal Cortex BA9	eqtl	2.9e-05	-0.30	21:39869621:C:T
Pancreas	eqtl	4.1e-05	+0.38	21:39980466:G:A
Spleen	eqtl	1.1e-04	-0.38	21:39793535:C:A
Adrenal Gland	eqtl	1.3e-04	-0.32	21:39984113:G:A
Heart Left Ventricle	eqtl	7.6e-04	-0.19	21:39853231:C:T
Heart Atrial Appendage	eqtl	1.3e-03	+0.19	21:39828777:T:C
Heart Left Ventricle	sqtl	1.5e-03	-0.71	21:39798326:T:C
Esophagus Gastroesophageal Junction	eqtl	1.9e-03	-0.28	21:40053334:G:A
Colon Transverse	eqtl	3.5e-03	-0.14	21:40007811:T:C
Esophagus Mucosa	eqtl	3.6e-03	-0.61	21:39925146:C:T
Testis	eqtl	4.2e-03	+0.33	21:39760631:C:T
Artery Aorta	eqtl	8.6e-03	+0.29	21:40053334:G:A
Pancreas	sqtl	2.5e-02	-0.73	21:39773796:T:A

FANTOM5 promoters

7 alternative TSS:

Promoter ID	TPM avg	Samples expressed
189188	55.8047	442
189189	1.9968	168
209323	0.1675	82
189191	0.1020	45
209321	0.0889	48
209322	0.0827	49
189190	0.0372	14

Top tissues by expression

showing 100 of 288 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
lateral nuclear group of thalamus	UBERON:0002736	100.00	gold quality
lateral globus pallidus	UBERON:0002476	99.92	gold quality
middle frontal gyrus	UBERON:0002702	99.90	gold quality
choroid plexus epithelium	UBERON:0003911	99.87	gold quality
putamen	UBERON:0001874	99.86	gold quality
caudate nucleus	UBERON:0001873	99.85	gold quality
seminal vesicle	UBERON:0000998	99.80	gold quality
nucleus accumbens	UBERON:0001882	99.80	gold quality
pigmented layer of retina	UBERON:0001782	99.73	gold quality
medial globus pallidus	UBERON:0002477	99.57	gold quality
globus pallidus	UBERON:0001875	99.54	gold quality
right lobe of thyroid gland	UBERON:0001119	99.35	gold quality
left lobe of thyroid gland	UBERON:0001120	99.24	gold quality
cerebellar vermis	UBERON:0004720	99.07	gold quality
thyroid gland	UBERON:0002046	99.05	gold quality
cauda epididymis	UBERON:0004360	98.96	gold quality
endocervix	UBERON:0000458	98.80	gold quality
right hemisphere of cerebellum	UBERON:0014890	98.48	gold quality
prostate gland	UBERON:0002367	98.30	gold quality
inferior vagus X ganglion	UBERON:0005363	98.30	gold quality
urethra	UBERON:0000057	98.14	gold quality
corpus epididymis	UBERON:0004359	98.12	gold quality
hypothalamus	UBERON:0001898	97.88	gold quality
substantia nigra pars reticulata	UBERON:0001966	97.72	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	97.55	gold quality
lower esophagus muscularis layer	UBERON:0035833	97.53	gold quality
lower esophagus	UBERON:0013473	97.51	gold quality
paraflocculus	UBERON:0005351	97.50	gold quality
dorsal root ganglion	UBERON:0000044	97.48	gold quality
primary visual cortex	UBERON:0002436	97.47	gold quality
substantia nigra	UBERON:0002038	97.42	gold quality
cingulate cortex	UBERON:0003027	97.40	gold quality
anterior cingulate cortex	UBERON:0009835	97.36	gold quality
right frontal lobe	UBERON:0002810	97.33	gold quality
substantia nigra pars compacta	UBERON:0001965	97.32	gold quality
occipital lobe	UBERON:0002021	97.24	gold quality
cerebellum	UBERON:0002037	97.24	gold quality
prefrontal cortex	UBERON:0000451	97.23	gold quality
Brodmann (1909) area 10	UBERON:0013541	97.23	gold quality
cerebellar cortex	UBERON:0002129	97.22	gold quality
ventral tegmental area	UBERON:0002691	97.21	gold quality
midbrain	UBERON:0001891	97.15	gold quality
cerebellar hemisphere	UBERON:0002245	97.15	gold quality
superior vestibular nucleus	UBERON:0007227	97.10	gold quality
Brodmann (1909) area 9	UBERON:0013540	97.10	gold quality
orbitofrontal cortex	UBERON:0004167	96.93	gold quality
islet of Langerhans	UBERON:0000006	96.92	gold quality
Brodmann (1909) area 46	UBERON:0006483	96.92	gold quality
telencephalon	UBERON:0001893	96.56	gold quality
type B pancreatic cell	CL:0000169	96.53	gold quality
frontal cortex	UBERON:0001870	96.49	gold quality
lower esophagus mucosa	UBERON:0035834	96.22	gold quality
myometrium	UBERON:0001296	96.16	gold quality
pons	UBERON:0000988	95.97	gold quality
neocortex	UBERON:0001950	95.90	gold quality
muscle layer of sigmoid colon	UBERON:0035805	95.90	gold quality
parietal lobe	UBERON:0001872	95.85	gold quality
body of uterus	UBERON:0009853	95.82	gold quality
cerebral cortex	UBERON:0000956	95.61	gold quality
Brodmann (1909) area 23	UBERON:0013554	95.61	gold quality
superior frontal gyrus	UBERON:0002661	95.58	gold quality
endothelial cell	CL:0000115	95.53	gold quality
postcentral gyrus	UBERON:0002581	95.42	gold quality
brain	UBERON:0000955	95.35	gold quality
central nervous system	UBERON:0001017	95.28	gold quality
forebrain	UBERON:0001890	95.26	gold quality
frontal pole	UBERON:0002795	95.23	gold quality
dorsal plus ventral thalamus	UBERON:0001897	95.18	gold quality
medulla oblongata	UBERON:0001896	95.15	gold quality
CA1 field of hippocampus	UBERON:0003881	95.13	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	94.97	gold quality
amygdala	UBERON:0001876	94.91	gold quality
trigeminal ganglion	UBERON:0001675	94.82	gold quality
caput epididymis	UBERON:0004358	94.75	gold quality
Ammon’s horn	UBERON:0001954	94.55	gold quality
adult organism	UBERON:0007023	93.77	gold quality
temporal lobe	UBERON:0001871	93.49	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	93.38	gold quality
inferior olivary complex	UBERON:0002127	93.32	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	93.27	gold quality
spinal cord	UBERON:0002240	93.01	gold quality
esophagus	UBERON:0001043	92.98	gold quality
urinary bladder	UBERON:0001255	92.69	gold quality
mucosa of stomach	UBERON:0001199	92.63	gold quality
metanephros cortex	UBERON:0010533	92.31	gold quality
cranial nerve II	UBERON:0000941	92.20	gold quality
renal medulla	UBERON:0000362	92.14	gold quality
middle temporal gyrus	UBERON:0002771	91.46	gold quality
entorhinal cortex	UBERON:0002728	91.43	gold quality
adult mammalian kidney	UBERON:0000082	91.22	gold quality
smooth muscle tissue	UBERON:0001135	91.07	gold quality
ectocervix	UBERON:0012249	90.04	gold quality
nipple	UBERON:0002030	89.46	gold quality
subthalamic nucleus	UBERON:0001906	89.22	gold quality
esophagus mucosa	UBERON:0002469	88.90	gold quality
corpus callosum	UBERON:0002336	88.89	gold quality
popliteal artery	UBERON:0002250	88.55	gold quality
vagina	UBERON:0000996	88.54	gold quality
tibial artery	UBERON:0007610	88.52	gold quality
right adrenal gland cortex	UBERON:0035827	88.39	gold quality

Single-cell (SCXA)

Detected in 15 experiment(s), a significant marker in 13.

Experiment	Marker?	Max mean expression
E-MTAB-7316	yes	7591.99
E-GEOD-135922	yes	2004.32
E-HCAD-5	yes	1607.30
E-MTAB-9154	yes	1401.07
E-MTAB-10485	yes	1011.78
E-HCAD-31	yes	839.89
E-GEOD-124472	yes	635.25
E-GEOD-114530	yes	431.97
E-GEOD-83139	yes	189.66
E-GEOD-137537	yes	17.71
E-MTAB-5061	yes	12.99
E-GEOD-81547	yes	8.12
E-GEOD-98556	no	341.99
E-HCAD-30	no	158.54
E-ANND-3	no	0.00

HPA expression

RNA tissue specificity: Tissue enhanced

showing 60 of 69 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Putamen	tissue	3004.1
Thalamus	tissue	2712.6
Superior colliculi	tissue	1828.8
Basal ganglia	tissue	1572.3	high
Pons	tissue	1437.8
Midbrain	tissue	1382.7
Seminal vesicle	tissue	1201.5	not detected
Nucleus accumbens	tissue	1099.3
Choroid plexus	tissue	1052.6
Ventral pallidum	tissue	741.5
Cerebellum	tissue	728.5	high
Olfactory bulb	tissue	417.7
Retina	tissue	356.8
Substantia nigra	tissue	356.7
Epididymis	tissue	344.5	not detected
Cerebral cortex	tissue	309.4	medium
Somatosensory cortex	tissue	309.4
Prostate	tissue	302.7	not detected
Occipital cortex	tissue	300.5
Postcentral gyrus	tissue	277.4
Medulla oblongata	tissue	260.1
Septum	tissue	243.5
Urinary bladder	tissue	240.6	not detected
Esophagus	tissue	214.1	not detected
Thyroid gland	tissue	213.3	low
Motor cortex	tissue	202.3
Cingulate cortex	tissue	172.8
Vagina	tissue	162.5	not detected
Spinal cord	tissue	160.8
Retrosplenial cortex	tissue	148.5
Prefrontal cortex	tissue	142.3
Periaqueductal gray	tissue	138.1
Temporal cortex	tissue	127.6
Hypothalamus	tissue	124.1
Hippocampal formation	tissue	113.9
Entorhinal cortex	tissue	113.9
Corpus callosum	tissue	99.9
Cervix	tissue	96.6	not detected
Insular cortex	tissue	96.5
Locus coeruleus	tissue	59.2
Hippocampus	tissue	58.0	medium
Endometrium 1	tissue	56.8	not detected
Smooth muscle	tissue	50.9	low
Adrenal gland	tissue	49.9	low
Kidney	tissue	48.4	not detected
Amygdala	tissue	44.3
Rectum	tissue	30.4	not detected
Parathyroid gland	tissue	18.5	not detected
Colon	tissue	15.2	not detected
Pituitary gland	tissue	10.6
Fallopian tube	tissue	9.6	not detected
Breast	tissue	7.9	not detected
Thymus	tissue	7.4
Pancreas	tissue	5.8	not detected
Adipose tissue	tissue	4.9	not detected
Duodenum	tissue	4.8	not detected
Gallbladder	tissue	3.9	not detected
Heart muscle	tissue	3.7	not detected
Small intestine	tissue	2.6	not detected
Spleen	tissue	2.5	not detected

Brain sub-regions (HPA Brain Atlas): detected in 189; highest nTPM — Caudate nucleus (1071.4), Ventral posteromedial thalamic nucleus (989.7), Habenula (950.1), Centromedial thalamic nucleus (938.9), Pulvinar (920.3).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): HOXA2, RORA

miRNA regulators (miRDB)

Targeting PCP4 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 44 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-33A-5P	99.99	68.62	1055
HSA-MIR-33B-5P	99.99	68.58	1062
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-MIR-493-5P	99.96	72.47	2382
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-3529-3P	99.90	73.55	3045
HSA-MIR-3686	99.90	70.53	2432
HSA-MIR-4779	99.86	66.50	1583
HSA-MIR-556-3P	99.74	68.75	1203
HSA-MIR-4306	99.72	70.50	3630
HSA-MIR-4677-5P	99.70	70.09	1940
HSA-MIR-494-3P	99.70	71.45	2795
HSA-MIR-586	99.65	70.40	2051
HSA-MIR-578	99.46	68.36	1787
HSA-MIR-3911	99.38	66.95	1087
HSA-MIR-5683	99.36	68.59	2083
HSA-MIR-4644	99.35	69.12	2514
HSA-MIR-185-5P	99.35	68.60	2497
HSA-MIR-6505-3P	99.34	67.39	1071
HSA-MIR-2116-5P	99.32	69.34	1273
HSA-MIR-6739-3P	99.22	68.84	1843
HSA-MIR-10399-5P	99.17	69.87	2610
HSA-MIR-6504-3P	99.17	69.31	2891
HSA-MIR-1286	99.09	66.23	1046
HSA-MIR-155-3P	99.03	67.99	924
HSA-MIR-6830-5P	99.01	68.73	1884

Functional genomics

gnomAD constraint: pLI 0.116, LOEUF 1.5, missense Z 1.03 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000328619 — one region, missense o/e 0.73.

Literature-anchored findings (GeneRIF, showing 14)

• PEP-19 has the potential to alter the Ca2+-binding dynamics of free CaM and CaM that is bound to other target proteins (PMID:14551202)
• The PCP4 promoter is activated by Trichostatin A (TSA) treatment according to promoter reporter assays in HEK 293 cells. (PMID:20494980)
• Data show that Pcp4 overexpression induces precocious neuronal differentiation, and is associated with an increase in CaMKIIdelta activation. (PMID:21491429)
• The calmodulin regulator protein, PEP-19, sensitizes ATP-induced Ca2+ release. (PMID:23204517)
• This study demonstrate that Pcp4 overexpression extended these effects later in development by modulating genes in line with the maturation of neurons in the cerebellum. (PMID:24291518)
• PCP4 is a regulator of aldosterone production in normal, hyperplastic, and neoplastic human adrenocortical cells. (PMID:24403568)
• PCP4 protein is highly expressed in the olfactory bulb and caudate putamen and PCP4 expressing cells in the brain are of neuronal origin. (PMID:24954028)
• Data indicated that PCP4/PEP19 regulates apoptosis but exact mechanism is still unknown. (PMID:25153723)
• PCP4/PEP19 has a role in promoting migration, invasion and adhesion in human breast cancer cells (PMID:27384474)
• PCP4 promoter was one of the most hypomethylated in aldosterone-producing adenoma and PCP4 transcription may be associated with demethylation as well as with CEBPA in APAs. (PMID:29294065)
• Compared to other CaM regulatory proteins, PCP4/PEP-19 transcripts were more abundant in human myometrium. The expression of PCP4/PEP-19 was lowest in myometrium of women with preterm pregnancy and chorioamnionitis. (PMID:30744532)
• PCP4/PEP19 downregulates neurite outgrowth via transcriptional regulation of Ascl1 and NeuroD1 expression in human neuroblastoma M17 cells. (PMID:32641824)
• Circ_0019693 promotes osteogenic differentiation of bone marrow mesenchymal stem cell and enhances osteogenesis-coupled angiogenesis via regulating microRNA-942-5p-targeted purkinje cell protein 4 in the development of osteoporosis. (PMID:35030971)
• PCP4 Promotes Alzheimer’s Disease Pathogenesis by Affecting Amyloid-beta Protein Precursor Processing. (PMID:37302034)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	pcp4a	ENSDARG00000053130
danio_rerio		ENSDARG00000110729
mus_musculus	Pcp4	ENSMUSG00000090223
rattus_norvegicus	Pcp4	ENSRNOG00000001628

Paralogs (1): PCP4L1 (ENSG00000248485)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:97509) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 3 distinct phenotype terms.

Mouse phenotype (MP)	Records
abnormal lateral ventricle morphology	1
abnormal motor learning	1
abnormal synaptic plasticity	1

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Bos taurus	Q148C4	96.8%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
MIR4760	ncRNA	100616148
DSCAM	protein-coding	1826
DSCAM-AS1	ncRNA	100506492
IGSF5	protein-coding	150084
B3GALT5	protein-coding	10317
B3GALT5-AS1	ncRNA	114041
DSCAM-IT1	ncRNA	100874326
LINC00323	ncRNA	284835

Protein

Protein identifiers

Calmodulin regulator protein PCP4 — P48539 (reviewed: P48539)

Alternative names: Brain-specific polypeptide PEP-19, Purkinje cell protein 4

All UniProt accessions (2): F6SSA2, P48539

UniProt curated annotations — full annotation on UniProt →

Function. Functions as a modulator of calcium-binding by calmodulin. Thereby, regulates calmodulin activity and the different processes it controls. For instance, may play a role in neuronal differentiation through activation of calmodulin-dependent kinase signaling pathways.

Subunit / interactions. Binds to both calcium-free and calcium-bound calmodulin. The affinity for the calcium-bound form is 50-fold greater.

Domain organisation. Mostly intrinsically disordered, with residual structure localized to the IQ domain which mediates the interaction with calmodulin.

Similarity. Belongs to the PCP4 family.

RefSeq proteins (1): NP_006189* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR052142	Calmodulin_reg_PCP4	Family

UniProt features (14 total): mutagenesis site 6, region of interest 2, chain 1, domain 1, sequence conflict 1, strand 1, helix 1, compositionally biased region 1

Structure

Experimental structures (PDB)

1 structures by resolution:

PDB	Title	Method	Resolution (Å)
2N77	NMR solution structure of a complex of PEP-19 bound to the C-domain of apo calmodulin	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P48539-F1	77.56	0.44

Human Protein Atlas

Protein class: Predicted intracellular proteins

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): nucleoli fibrillar center; nucleoplasm

Antibody reliability (HPA): IH enhanced · IF approved

Functional residue map

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

Mutagenesis-validated functional residues (6)

Position	Phenotype
40	decreased calmodulin modulator function.
29	no effect on the calmodulin modulator function.
31	decreased calmodulin modulator function.
33	decreased calmodulin modulator function.
35	no effect on the calmodulin modulator function.
37	loss of the calmodulin modulator function.

Function

Pathways and Gene Ontology

Reactome pathways

0 curated (TAS) of 0; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

MSigDB gene sets: 172 (showing top): GOBP_REGULATION_OF_CALCIUM_MEDIATED_SIGNALING, YAGI_AML_WITH_INV_16_TRANSLOCATION, GOBP_POSITIVE_REGULATION_OF_NEURON_DIFFERENTIATION, GOZGIT_ESR1_TARGETS_DN, AREB6_01, GOBP_NEUROGENESIS, TOMLINS_PROSTATE_CANCER_DN, MODULE_66, GOBP_POSITIVE_REGULATION_OF_CALCIUM_MEDIATED_SIGNALING, CREIGHTON_ENDOCRINE_THERAPY_RESISTANCE_1, GOBP_REGULATION_OF_NEURON_DIFFERENTIATION, GOBP_POSITIVE_REGULATION_OF_CELL_DIFFERENTIATION, AIYAR_COBRA1_TARGETS_DN, MODULE_165, GOBP_POSITIVE_REGULATION_OF_INTRACELLULAR_SIGNAL_TRANSDUCTION

GO Biological Process (2): positive regulation of neuron differentiation (GO:0045666), positive regulation of CAMKK-AMPK signaling cascade (GO:1905291)

GO Molecular Function (3): calcium ion binding (GO:0005509), calmodulin binding (GO:0005516), protein binding (GO:0005515)

GO Cellular Component (4): nucleus (GO:0005634), cytoplasm (GO:0005737), cytosol (GO:0005829), protein-containing complex (GO:0032991)

GO top-level categories

14 GO namespaces:

Category	Terms
cellular anatomical structure	2
neuron differentiation	1
positive regulation of cell differentiation	1
regulation of neuron differentiation	1
positive regulation of calcium-mediated signaling	1
CAMKK-AMPK signaling cascade	1
regulation of CAMKK-AMPK signaling cascade	1
metal ion binding	1
protein binding	1
binding	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
cytoplasm	1
cellular_component	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 7 of 9 annotations. The rest are phylogenetic / computational / electronic (IEA).

7 experimentally-supported GO terms:

GO term	NS	Evidence
positive regulation of CAMKK-AMPK signaling cascade	BP	mutant phenotype
positive regulation of neuron differentiation	BP	mutant phenotype
cytosol	CC	high-throughput assay
nucleus	CC	high-throughput assay
protein-containing complex	CC	direct assay
calcium ion binding	MF	direct assay
calmodulin binding	MF	direct assay

Protein interactions and networks

STRING

showing 15 of 1,140 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PCP4	ETS2	P15036	706
PCP4	ABCG1	P45844	679
PCP4	RGS14	O43566	647
PCP4	NECAB2	Q7Z6G3	646
PCP4	AMIGO2	Q86SJ2	622
PCP4	CALML6	Q8TD86	594
PCP4	CALML4	Q96GE6	594
PCP4	CALML5	Q9NZT1	594
PCP4	CALML3	P27482	581
PCP4	CALM1	P02593	568
PCP4	CALB1	P05937	533
PCP4	GARNL3	Q5VVW2	531
PCP4	WFS1	O76024	498
PCP4	HOMER3	Q9NSC5	474
PCP4	PVALB	P20472	441

IntAct

Human interaction partners of PCP4 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

11 partners by confidence:

Partner	Interaction type	MIscore	Records
CALML6	physical association	0.560	3
SH3BGRL3	association	0.530	1
TERF2IP	physical association	0.510	2
DAPK1	direct interaction	0.440	1
RAB27A	physical association	0.400	1
POT1	physical association	0.370	1
TERF1	physical association	0.370	1
A2ML1	association	0.350	1
GOLGA7	association	0.350	1
RAB39B	association	0.350	1
PAX6	physical association	0.000	1

BioGRID (46 interactions; top human partners by supporting records): A2ML1 (Affinity Capture-MS), ACAA2 (Affinity Capture-MS), ACPP (Affinity Capture-MS), ANXA8 (Affinity Capture-MS), APOD (Affinity Capture-MS), ARSF (Affinity Capture-MS), ATP12A (Affinity Capture-MS), BCAS2 (Affinity Capture-MS), CALML3 (Affinity Capture-MS), CALML5 (Affinity Capture-MS), CALML6 (Two-hybrid), CPA4 (Affinity Capture-MS), CREG1 (Affinity Capture-MS), CTBS (Affinity Capture-MS), CTSD (Affinity Capture-MS)

SIGNOR signaling

1 signaling interactions:

A	Effect	B	Mechanism
RORA	“up-regulates quantity by expression”	PCP4	“transcriptional regulation”

Disease & clinical

Genetic variants

Variant evidence for PCP4: 15 ClinVar records (1 pathogenic / likely pathogenic); 5 GWAS associations. Per-variant detail is on Sugi Variant.

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	8
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (1)

Showing all 1 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
204003	GRCh37/hg19 21q22.13-22.2(chr21:37839410..41427526)	Pathogenic	criteria provided, single submitter	1

Per-variant reference — Sugi Variant

Explore PCP4’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 24 predictions of 391):

Position(s)	Effect	Δscore	Sites
21:39888182	donor_gain	1.0000
21:39928982–39928983	acceptor_loss	1.0000	4
21:39898467	acceptor_gain	0.9900
21:39928976	acceptor_gain	0.9900
21:39928981	acceptor_gain	0.9900
21:39928982–39928983	acceptor_loss	0.9900	2
21:39898462	acceptor_loss	0.9800
21:39898474–39898475	acceptor_loss	0.9800	6
21:39898528–39898529	donor_loss	0.9800	6
21:39880976	donor_gain	0.9700

AlphaMissense

171 missense substitutions predicted likely pathogenic (of 410 scored), across 33 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
D31	8	0.921	0.947
D33	8	0.918	0.981
F50	7	0.997	0.999
F53	7	0.984	0.997
I46	7	0.982	1.000
Q47	7	0.980	0.999
I32	7	0.928	0.997
M34	7	0.890	0.959
Q54	7	0.861	0.993
E38	7	0.804	0.921
Q49	7	0.802	0.991
A43	6	0.975	0.998
R51	6	0.967	0.999
T39	6	0.966	0.989
A42	6	0.966	0.997
P37	6	0.923	0.956
K52	6	0.897	0.970
K57	6	0.877	0.954
F30	5	0.963	0.973
K56	5	0.900	0.927

HPA cancer prognostics

RNA cancer specificity: Cancer enhanced (Thyroid Carcinoma)

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

2 prognostic cancer types:

Cancer	Prognostic	p-value
Kidney Renal Papillary Cell Carcinoma (TCGA)	favorable	2.64e-06
Glioblastoma Multiforme (validation)	favorable	0.000203

Disease associations

OMIM: gene MIM:601629 | disease phenotypes:

GWAS associations

5 associations:

Study	Trait	p-value
GCST010043_83	Asthma	4e-8
GCST002307_8	Systolic blood pressure (alcohol consumption interaction)	8e-7
GCST009391_1346	Metabolite levels	2e-6
GCST004270_2	Venlafaxine response in generalised anxiety disorder (responders vs non-responders after 12 weeks)	4e-6
GCST009391_838	Metabolite levels	9e-6

EFO canonical traits (from GWAS)

4 canonical traits:

EFO ID	Trait name
EFO:0004329	alcohol drinking
EFO:0006335	systolic blood pressure
EFO:0010407	triacylglycerol 48:4 measurement
EFO:0010399	triacylglycerol 44:1 measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (CPIC guideline: no)

CTD chemical–gene interactions

22 total (human), top 22 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, increases expression	5
Estradiol	increases expression, affects cotreatment, decreases expression	4
bisphenol A	affects cotreatment, increases methylation, increases expression	2
Nickel	decreases expression	2
beta-lapachone	decreases expression	1
sodium arsenite	affects methylation	1
JP8 aviation fuel	affects expression	1
Resveratrol	affects cotreatment, increases expression	1
Sunitinib	decreases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Coumestrol	affects cotreatment, increases expression	1
Polychlorinated Biphenyls	increases expression	1
Potassium Dichromate	increases expression	1
Rotenone	increases expression	1
Selenium	decreases expression	1
Smoke	increases expression	1
Tetrachlorodibenzodioxin	affects cotreatment, decreases expression	1
Thimerosal	increases expression	1
Triclosan	increases expression	1
Zinc	decreases expression	1
Aflatoxin B1	increases methylation	1
Genistein	increases expression	1

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.