PCLO

Summary

PCLO (piccolo presynaptic cytomatrix protein, HGNC:13406) is a protein-coding gene on chromosome 7q21.11, encoding Protein piccolo (Q9Y6V0). Scaffold protein of the presynaptic cytomatrix at the active zone (CAZ) which is the place in the synapse where neurotransmitter is released.

The protein encoded by this gene is part of the presynaptic cytoskeletal matrix, which is involved in establishing active synaptic zones and in synaptic vesicle trafficking. Variations in this gene have been associated with bipolar disorder and major depressive disorder. Two transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 27445 — RefSeq curated summary.

At a glance

• Gene–disease (curated): pontocerebellar hypoplasia type 3 (Strong, GenCC)
• GWAS associations: 13
• Clinical variants (ClinVar): 3,318 total — 67 pathogenic, 8 likely-pathogenic
• Phenotypes (HPO): 36
• MANE Select transcript: NM_033026

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:13406
Approved symbol	PCLO
Name	piccolo presynaptic cytomatrix protein
Location	7q21.11
Locus type	gene with protein product
Status	Approved
Aliases	KIAA0559, DKFZp779G1236, ACZ
Ensembl gene	ENSG00000186472
Ensembl biotype	protein_coding
OMIM	604918
Entrez	27445

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 3 protein_coding, 3 protein_coding_CDS_not_defined, 2 nonsense_mediated_decay

ENST00000333891, ENST00000413807, ENST00000423517, ENST00000426442, ENST00000432078, ENST00000437081, ENST00000456006, ENST00000461143

RefSeq mRNA: 2 — MANE Select: NM_033026 NM_014510, NM_033026

CCDS: CCDS47630, CCDS47631

Canonical transcript exons

ENST00000333891 — 25 exons

Exon	Start	End
ENSE00001622512	83154748	83156392
ENSE00001646940	82965771	82966487
ENSE00001715762	82951856	82956935
ENSE00001774996	83134250	83135656
ENSE00002431590	82760639	82760784
ENSE00002432640	82914686	82916873
ENSE00002457830	82801518	82801591
ENSE00002459797	82835667	82835693
ENSE00002462574	82761359	82761493
ENSE00002490267	82902651	82902741
ENSE00002527473	82822495	82822689
ENSE00002529510	82908877	82909013
ENSE00002709222	82949476	82951490
ENSE00003501634	82827873	82827966
ENSE00003503371	82879337	82879462
ENSE00003509997	82805688	82805829
ENSE00003532351	82841459	82841509
ENSE00003573676	82846567	82846634
ENSE00003581347	82847139	82847247
ENSE00003621206	82838218	82838342
ENSE00003644760	82826589	82826660
ENSE00003647047	82824236	82824416
ENSE00003668844	82845271	82845485
ENSE00003702933	82754012	82758715
ENSE00003847485	83162345	83162884

Expression profiles

Bgee: expression breadth ubiquitous, 235 present calls, max score 97.73.

FANTOM5 (CAGE): breadth broad, TPM avg 5.4201 / max 433.8534, expressed in 686 samples.

FANTOM5 promoters (11 alternative TSS)

Promoter ID	TPM avg	Samples expressed
84630	3.0831	483
84628	0.7575	275
84631	0.5449	140
84604	0.3164	88
84605	0.2409	87
84619	0.2088	60
84626	0.0882	45
84606	0.0710	32
84629	0.0469	23
84603	0.0380	17

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
Brodmann (1909) area 23	UBERON:0013554	97.73	gold quality
middle temporal gyrus	UBERON:0002771	97.64	gold quality
cerebellar vermis	UBERON:0004720	95.85	gold quality
orbitofrontal cortex	UBERON:0004167	95.75	gold quality
CA1 field of hippocampus	UBERON:0003881	95.53	gold quality
endothelial cell	CL:0000115	95.42	gold quality
frontal pole	UBERON:0002795	94.85	gold quality
entorhinal cortex	UBERON:0002728	94.56	gold quality
Brodmann (1909) area 46	UBERON:0006483	94.27	gold quality
superior frontal gyrus	UBERON:0002661	93.76	gold quality
cortical plate	UBERON:0005343	93.62	gold quality
Brodmann (1909) area 10	UBERON:0013541	93.44	gold quality
paraflocculus	UBERON:0005351	93.01	gold quality
postcentral gyrus	UBERON:0002581	92.47	gold quality
parietal lobe	UBERON:0001872	92.05	gold quality
cerebellum	UBERON:0002037	92.01	gold quality
primary visual cortex	UBERON:0002436	91.98	gold quality
cerebellar cortex	UBERON:0002129	91.64	gold quality
cerebellar hemisphere	UBERON:0002245	91.47	gold quality
right hemisphere of cerebellum	UBERON:0014890	91.39	gold quality
lateral nuclear group of thalamus	UBERON:0002736	90.62	gold quality
middle frontal gyrus	UBERON:0002702	90.57	gold quality
prefrontal cortex	UBERON:0000451	90.53	gold quality
occipital lobe	UBERON:0002021	90.13	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	89.45	gold quality
frontal cortex	UBERON:0001870	88.22	gold quality
neocortex	UBERON:0001950	86.76	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	86.31	gold quality
cerebral cortex	UBERON:0000956	86.24	gold quality
pons	UBERON:0000988	86.13	gold quality

Single-cell (SCXA)

Detected in 11 experiment(s), a significant marker in 7.

Experiment	Marker?	Max mean expression
E-HCAD-35	yes	75.87
E-HCAD-25	yes	35.50
E-MTAB-5061	yes	16.42
E-GEOD-93593	yes	14.61
E-GEOD-137537	yes	7.29
E-GEOD-81547	yes	5.76
E-GEOD-75367	no	163.95
E-MTAB-8060	no	48.75
E-HCAD-31	no	5.46
E-ENAD-27	no	3.81
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

90 targeting PCLO, 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-432-3P	100.00	67.86	705
HSA-MIR-6748-5P	100.00	65.81	1057
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-1193	100.00	65.93	529
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-507	99.97	70.11	1915
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-557	99.96	70.01	1640
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-218-5P	99.93	72.22	2103
HSA-MIR-6835-3P	99.93	70.49	2904
HSA-MIR-22-3P	99.93	68.13	917
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-205-3P	99.92	69.92	3165
HSA-MIR-10527-5P	99.91	72.28	3754
HSA-MIR-129-5P	99.88	70.26	3273
HSA-MIR-30A-3P	99.87	69.74	2928
HSA-MIR-30D-3P	99.87	69.92	2917
HSA-MIR-30E-3P	99.87	69.68	2942
HSA-MIR-3919	99.87	69.45	2489
HSA-MIR-548AR-3P	99.85	71.26	3889
HSA-MIR-383-3P	99.85	65.84	1359
HSA-MIR-544A	99.84	68.66	1965
HSA-MIR-4799-5P	99.82	70.60	2663
HSA-MIR-4495	99.82	72.08	3080
HSA-MIR-3681-5P	99.82	66.88	387
HSA-MIR-548AZ-3P	99.82	70.56	3549
HSA-MIR-548BC	99.82	70.61	3524

Literature-anchored findings (GeneRIF, showing 25)

• Variation within PCLO may have a modest effect on early-onset type 2 diabetes, possibly as a result of reduced insulin action, but has minimal, if any, impact on population-based risk for type 2 diabetes. (PMID:18647954)
• From this GWAS results for the PCLO region were intriguing, this highly plausible hypothesis did not find support in a large-scale replication attempt. (PMID:19065144)
• The PCLO/Piccolo of SNPs(rs2522833)is a potentially causal variant in a biologically plausible candidate gene, with major depressive disorder. (PMID:19546850)
• PCLO is associated with depressive disorders in a population-based study. (PMID:19942622)
• Piccolo transgenic mice exhibit depression-like behavior in forced swim and tail suspension tests, which may suggest that a single nucleotide polymorphism in the piccolo C2A domain may be a causal risk factor for major depression. (PMID:20980930)
• one SNP (rs13438494), in an intron of the piccolo gene, was significantly associated with bipolar disorder (PMID:21185011)
• In major depressive disorder genome-wide association study, best femalee-specific SNP was rs2715148 within PCLO gene (PMID:21621269)
• In this study, the genotype distributions and allele frequencies of PCLO rs2522833 polymorphisms were examined in 267 Japanese healthy subjects (PMID:22293360)
• Single-nucleotide polymorphism rs2522833 within the PCLO gene might increase vulnerability to major depression both by physiological and behavioral pathways. (PMID:22832399)
• The PCLO risk allele was found to be specifically associated with altered emotion processing, but not with executive dysfunction. Moreover, the PCLO risk allele appears to modulate amygdala function during fearful facial processing. (PMID:22832909)
• The role of the PCLO risk allele on functional magnetic resonance imaging (MRI) correlates of emotional memory in a sample of 89 major depressive disorder patients, was investigated. (PMID:23620758)
• The results demonstrate that rs13438494 intron 24 of PCLO gene alters the splicing efficiency by creating or disrupting a splicing motif that functions by binding of the splicing regulatory protein and may ultimately influence bipolar disorder. (PMID:24167553)
• For neither PCLO nor GRM7 we found a more associated variant. For SLC6A4, we found a new SNP that showed a lower P-value than in the GAIN-MDD GWAS (PMID:24278217)
• PCLO and CACNA1C depression risk alleles jointly affect memory-related subgenual cingulate activity. (PMID:24643163)
• PCLO risk allele carrying remitted depressed patients did not show more negatively biased memory than non-risk allele carriers, not even patients with stressful childhood events. (PMID:25379724)
• The subsequent validation study on 68 LCBs identified recurrent mutations in TERT promoter, chromatin regulators (BAP1, PBRM1 and ARID2), a synapse organization gene (PCLO), IDH genes and KRAS. (PMID:25636086)
• PCLO intron rs13438494 is associated with drug abuse and contributes to the pathogenesis of psychiatric disorders via modulation of neurotransmitter turnover. (PMID:25817861)
• A homozygous, nonsense PCLO mutation underlies the autosomal recessive neurodegenerative disorder pontocerebellar hypoplasia type III. (PMID:25832664)
• Study created and characterized a knock-in mouse model carrying the PCLO Ser to Ala missense variant rs2522833, which has shown suggestive association with major depressive disorder in human population studies (PMID:26045179)
• Results provide some support for the involvement of BICC1 and PCLO in late-life depressive disorders and preliminary evidence that these genetic variants may also influence brain structural volumes (PMID:26391493)
• The results showed that Piccolo, a protein that is essential in the maintenance of active zone structure, constitutes a potential serological correlate of recovery from GBS. (PMID:27776345)
• we report an additional patient with the 7q21.11 deletion syndrome and provide evidence that haploinsufficiency for a single gene may not be the disease mechanism. In vitro studies of the interaction between PCLO and CACNA2D1 will be required to examine the hypothesis that combined haploinsufficiency for these two synaptic proteins results in neuronal dysfunction (PMID:28240412)
• Piccolo contributes to tumor aggressiveness in esophageal squamous cell carcinoma, likely by stabilizing EGFR and promoting EGFR-dependent signaling. (PMID:28263981)
• In an analysis comparing 1,942 cases with lifetime diagnosis of MDD and 4,565 controls, PCLO showed a genome-wide significant association with major depressive disorder at SNP (rs2715157, p = 2.91 x 10-8) and gene-based (p = 1.48 x 10-7) level. (PMID:28540843)
• No symphony without bassoon and piccolo: changes in synaptic active zone proteins in Huntington’s disease. (PMID:32493491)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
mus_musculus	Pclo	ENSMUSG00000061601
rattus_norvegicus	Pclo	ENSRNOG00000005726
caenorhabditis_elegans		WBGENE00018468

Paralogs (1): BSN (ENSG00000164061)

Protein

Protein identifiers

Protein piccolo — Q9Y6V0 (reviewed: Q9Y6V0)

Alternative names: Aczonin

All UniProt accessions (4): E9PE96, Q9Y6V0, H7C114, H7C261

UniProt curated annotations — full annotation on UniProt →

Function. Scaffold protein of the presynaptic cytomatrix at the active zone (CAZ) which is the place in the synapse where neurotransmitter is released. After synthesis, participates in the formation of Golgi-derived membranous organelles termed Piccolo-Bassoon transport vesicles (PTVs) that are transported along axons to sites of nascent synaptic contacts. At the presynaptic active zone, regulates the spatial organization of synaptic vesicle cluster, the protein complexes that execute membrane fusion and compensatory endocytosis. Organizes as well the readily releasable pool of synaptic vesicles and safeguards a fraction of them to be not immediately available for action potential-induced release. Also functions in processes other than assembly such as the regulation of specific presynaptic protein ubiquitination by interacting with SIAH1 or the regulation of presynaptic autophagy. Also mediates synapse to nucleus communication leading to reconfiguration of gene expression by associating with the transcriptional corepressor CTBP1 and by subsequently reducing the size of its pool available for nuclear import.

Subunit / interactions. Interacts with BSN, ERC2/CAST1, RIMS1 and UNC13A. Interacts (via C-terminus) with TRIO (via N-terminus). Interacts with CTBP1. Interacts with SIAH1; this interaction negatively regulates SIAH1 E3 ligase activity. Directly interacts with GIT1 and GIT2.

Subcellular location. Presynaptic active zone.

Tissue specificity. Moderately expressed in the developing cerebral cortex.

Disease relevance. Pontocerebellar hypoplasia 3 (PCH3) [MIM:608027] A form of pontocerebellar hypoplasia, a disorder characterized by structural defects of the pons and cerebellum. Brain MRI shows an abnormally small cerebellum and brainstem, decreased cerebral white matter, and a thin corpus callosum. PCH3 features include seizures, short stature, optic atrophy, progressive microcephaly, severe developmental delay. The disease is caused by variants affecting the gene represented in this entry.

Cofactor. Binds 3 Ca(2+) ions per C2 domain.

Domain organisation. C2 domain 1 is involved in binding calcium and phospholipids. Calcium binds with low affinity but with high specificity and induces a large conformational change.

Isoforms (3)

UniProt ID	Names	Canonical?
Q9Y6V0-5	5	yes
Q9Y6V0-3	3
Q9Y6V0-6	6

RefSeq proteins (2): NP_055325, NP_149015* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000008	C2_dom	Domain
IPR001478	PDZ	Domain
IPR008899	Znf_piccolo	Domain
IPR011011	Znf_FYVE_PHD	Homologous_superfamily
IPR013083	Znf_RING/FYVE/PHD	Homologous_superfamily
IPR035892	C2_domain_sf	Homologous_superfamily
IPR036034	PDZ_sf	Homologous_superfamily
IPR042720	PCLO_FYVE1	Domain
IPR052098	Presynaptic_Scaffold_Bsn/Pclo	Family

Pfam: PF00168, PF00595, PF05715

UniProt features (183 total): modified residue 61, compositionally biased region 58, region of interest 22, binding site 11, sequence conflict 9, strand 7, splice variant 5, domain 3, sequence variant 2, helix 2, zinc finger region 2, chain 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
1UJD	SOLUTION NMR

Predicted structure (AlphaFold)

No AlphaFold model available for Q9Y6V0 — AlphaFold DB does not currently provide models for proteins above ~3000 aa.

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 (11): 4723; 4723; 4729; 4793; 4793; 4795; 4795; 4795; 4798; 4801; 4801

Post-translational modifications (61): 1356, 1366, 1367, 1396, 1398, 1401, 1402, 1405, 1516, 1517, 1519, 1522, 1546, 1549, 1570, 1572, 1617, 1618, 1628, 1640 …

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-9662360	Sensory processing of sound by inner hair cells of the cochlea

MSigDB gene sets: 365 (showing top): GOBP_SYNAPTIC_VESICLE_LOCALIZATION, GOBP_VESICLE_LOCALIZATION, GOBP_SYNAPSE_ASSEMBLY, GOBP_INSULIN_SECRETION, GOBP_REGULATION_OF_EXOCYTOSIS, GOBP_REGULATION_OF_HORMONE_LEVELS, GOBP_CELLULAR_COMPONENT_MAINTENANCE, GOBP_NEUROTRANSMITTER_TRANSPORT, GOBP_HORMONE_TRANSPORT, GOBP_VESICLE_MEDIATED_TRANSPORT, RODWELL_AGING_KIDNEY_NO_BLOOD_DN, GOBP_CELL_CELL_SIGNALING, GOBP_REGULATION_OF_VESICLE_MEDIATED_TRANSPORT, SENESE_HDAC1_AND_HDAC2_TARGETS_DN, GOBP_EXOCYTOSIS

GO Biological Process (12): cytoskeleton organization (GO:0007010), synaptic vesicle exocytosis (GO:0016079), regulation of exocytosis (GO:0017157), insulin secretion (GO:0030073), protein localization to synapse (GO:0035418), synaptic vesicle clustering (GO:0097091), presynaptic actin cytoskeleton organization (GO:0099140), presynaptic active zone assembly (GO:1904071), maintenance of presynaptic active zone structure (GO:0048790), regulation of transport (GO:0051049), regulation of biological quality (GO:0065008), presynapse organization (GO:0099172)

GO Molecular Function (7): calcium ion binding (GO:0005509), profilin binding (GO:0005522), calcium-dependent phospholipid binding (GO:0005544), zinc ion binding (GO:0008270), structural constituent of presynaptic active zone (GO:0098882), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (12): cytoskeleton (GO:0005856), postsynaptic density (GO:0014069), axon (GO:0030424), synapse (GO:0045202), cytoskeleton of presynaptic active zone (GO:0048788), extracellular exosome (GO:0070062), glutamatergic synapse (GO:0098978), GABA-ergic synapse (GO:0098982), membrane (GO:0016020), cell projection (GO:0042995), organelle (GO:0043226), presynaptic active zone (GO:0048786)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Sensory processing of sound	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
presynapse	2
synaptic vesicle cycle	2
presynaptic active zone organization	2
synapse	2
organelle organization	1
neurotransmitter secretion	1
regulated exocytosis	1
establishment of localization in cell	1
vesicle-mediated transport in synapse	1
signal release from synapse	1
exocytosis	1
regulation of vesicle-mediated transport	1
regulation of secretion by cell	1
protein secretion	1
peptide hormone secretion	1
protein localization to cell junction	1
synaptic vesicle localization	1
actin cytoskeleton organization	1
presynaptic cytoskeleton organization	1
cellular component assembly	1
presynapse assembly	1
maintenance of synapse structure	1
transport	1
regulation of localization	1
biological regulation	1
cellular component organization	1
synapse organization	1
metal ion binding	1
protein binding	1
phospholipid binding	1
transition metal ion binding	1
presynaptic active zone	1
maintenance of presynaptic active zone structure	1
structural constituent of synapse	1
binding	1
cation binding	1
intracellular membraneless organelle	1
asymmetric synapse	1
postsynaptic specialization	1

Protein interactions and networks

STRING

1874 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PCLO	RAPGEF4	Q8WZA2	880
PCLO	RABAC1	Q9UI14	870
PCLO	MUC16	Q8WXI7	667
PCLO	CSMD3	Q7Z407	663
PCLO	LRP1B	Q9NZR2	654
PCLO	UNC13B	O14795	645
PCLO	UNC13A	Q9UPW8	624
PCLO	TTN	Q8WZ42	612
PCLO	ERC1	Q8IUD2	603
PCLO	SYNE1	Q8NF91	596
PCLO	DNAH5	Q8TE73	570
PCLO	RBBP8	Q99708	551
PCLO	OBSCN	Q5VST9	545
PCLO	ZFHX4	Q86UP3	528
PCLO	FAT4	Q6V0I7	525

IntAct

443 interactions, top by confidence:

A	B	Type	Score
E6	PCLO	psi-mi:“MI:0407”(direct interaction)	0.440
Tax	PCLO	psi-mi:“MI:0407”(direct interaction)	0.440
PCLO	E	psi-mi:“MI:0407”(direct interaction)	0.440
NET1	PCLO	psi-mi:“MI:0407”(direct interaction)	0.440
PTEN	PCLO	psi-mi:“MI:0407”(direct interaction)	0.440
RPS6KA1	PCLO	psi-mi:“MI:0407”(direct interaction)	0.440
E	PCLO	psi-mi:“MI:0407”(direct interaction)	0.440
GP1	PCLO	psi-mi:“MI:0407”(direct interaction)	0.440
ABCA1	PCLO	psi-mi:“MI:0407”(direct interaction)	0.440
ACE2	PCLO	psi-mi:“MI:0407”(direct interaction)	0.440
ACVR2A	PCLO	psi-mi:“MI:0407”(direct interaction)	0.440
ADRB2	PCLO	psi-mi:“MI:0407”(direct interaction)	0.440
AGMAT	PCLO	psi-mi:“MI:0407”(direct interaction)	0.440
APC	PCLO	psi-mi:“MI:0407”(direct interaction)	0.440
ARHGAP17	PCLO	psi-mi:“MI:0407”(direct interaction)	0.440
ARHGAP6	PCLO	psi-mi:“MI:0407”(direct interaction)	0.440
ARHGEF26	PCLO	psi-mi:“MI:0407”(direct interaction)	0.440
ARHGEF7	PCLO	psi-mi:“MI:0407”(direct interaction)	0.440
ARVCF	PCLO	psi-mi:“MI:0407”(direct interaction)	0.440
ATP2B1	PCLO	psi-mi:“MI:0407”(direct interaction)	0.440
PCLO	CACYBP	psi-mi:“MI:0407”(direct interaction)	0.440
CREBBP	PCLO	psi-mi:“MI:0407”(direct interaction)	0.440
CFTR	PCLO	psi-mi:“MI:0407”(direct interaction)	0.440
CGN	PCLO	psi-mi:“MI:0407”(direct interaction)	0.440
CIT	PCLO	psi-mi:“MI:0407”(direct interaction)	0.440
CNKSR2	PCLO	psi-mi:“MI:0407”(direct interaction)	0.440
CNTNAP4	PCLO	psi-mi:“MI:0407”(direct interaction)	0.440
PCLO	CTNNB1	psi-mi:“MI:0407”(direct interaction)	0.440

BioGRID (72): PCLO (Affinity Capture-MS), PCLO (Affinity Capture-MS), PCLO (Affinity Capture-MS), PCLO (Affinity Capture-Western), PCLO (Affinity Capture-MS), PCLO (Proximity Label-MS), PCLO (Affinity Capture-RNA), PCLO (Affinity Capture-MS), PCLO (Affinity Capture-MS), PCLO (Affinity Capture-MS), PCLO (Affinity Capture-MS), PCLO (Affinity Capture-MS), PCLO (Two-hybrid), PCLO (Two-hybrid), GIT1 (Two-hybrid)

ESM2 similar proteins: A0JME2, A5H447, A6NF01, A8CG34, E9Q3G8, F4ID16, G0SDP9, G5E8Z2, O08587, O15504, O88797, O95081, P20676, P49790, P49791, P52591, P52594, P98082, Q03173, Q0VA45, Q2TA45, Q4KLH5, Q5FVW4, Q5PRE5, Q5RB98, Q5SV85, Q5XGN1, Q5ZI22, Q5ZIE8, Q5ZM88, Q64028, Q640Z6, Q6P0U9, Q80WC7, Q86XN7, Q8CIC2, Q8K2K6, Q8K3Z9, Q8L7F7, Q8R080

Diamond homologs: A0A075F932, A0FGR8, A4IJ05, K8FE10, O00445, O00750, O08625, O08835, O35681, O43581, P04409, P05128, P05129, P05130, P05696, P10102, P10829, P13677, P17252, P20444, P21521, P21579, P21707, P24505, P24506, P24507, P29101, P34693, P40748, P40749, P41823, P41885, P46096, P46097, P47191, P47708, P47709, P47861, P48018, P50232

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 197 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Synaptic adhesion-like molecules	5	19.6×	4e-04
Neurexins and neuroligins	9	12.8×	2e-05
Assembly and cell surface presentation of NMDA receptors	6	10.9×	1e-03
RHOQ GTPase cycle	6	7.8×	6e-03
RHO GTPase cycle	14	6.0×	2e-05
RHOA GTPase cycle	11	5.9×	3e-04
CDC42 GTPase cycle	11	5.7×	4e-04
Signaling by Rho GTPases	18	4.4×	2e-05

GO biological processes:

GO term	Partners	Fold	FDR
regulation of cardiac conduction	5	23.3×	4e-04
positive regulation of excitatory postsynaptic potential	7	20.4×	4e-05
positive regulation of synaptic transmission, glutamatergic	5	17.2×	1e-03
monoatomic cation transmembrane transport	5	17.2×	1e-03
synapse organization	6	9.3×	4e-03
transport across blood-brain barrier	9	8.9×	3e-04
learning or memory	6	8.0×	8e-03
transmembrane transport	7	6.5×	8e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

3318 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	67
Likely pathogenic	8
Uncertain significance	1879
Likely benign	1176
Benign	84

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1361359	NM_033026.6(PCLO):c.4786G>T (p.Glu1596Ter)	Pathogenic
1363503	NM_033026.6(PCLO):c.3023T>A (p.Leu1008Ter)	Pathogenic
1370269	NM_033026.6(PCLO):c.2089del (p.Ala697fs)	Pathogenic
1389315	NM_033026.6(PCLO):c.488T>A (p.Leu163Ter)	Pathogenic
1402479	NM_033026.6(PCLO):c.10303C>T (p.Arg3435Ter)	Pathogenic
1403391	NM_033026.6(PCLO):c.9148C>T (p.Arg3050Ter)	Pathogenic
1415028	NM_033026.6(PCLO):c.2728_2912delinsA (p.Gly910fs)	Pathogenic
1417146	NM_033026.6(PCLO):c.11927C>G (p.Ser3976Ter)	Pathogenic
1423592	NM_033026.6(PCLO):c.4376_4393del (p.Leu1459_Glu1465delinsTer)	Pathogenic
1453355	NM_033026.6(PCLO):c.14164C>T (p.Arg4722Ter)	Pathogenic
1456245	NM_033026.6(PCLO):c.4046C>G (p.Ser1349Ter)	Pathogenic
1456431	NM_033026.6(PCLO):c.7739dup (p.Tyr2580Ter)	Pathogenic
1456597	NM_033026.6(PCLO):c.8227_8228insGGCCGGGCGCGGTGGCTCACGCCTGTAATCCCAGCACTTTGGGAGGCCGAGGCGGGCGGATCACGAGGTCAGGAGATCGAGACCATCCCGGCTAAAACGGTGAAACCCCGTCTNNNNNNNNNNAAAAAAAAAAAAAAAAAAAACAACTGATA (p.Lys2743delinsArgProGlyAlaValAlaHisAlaCysAsnProSerThrLeuGlyGlyArgGlyGlyArgIleThrArgSerGlyAspArgAspHisProGlyTer)	Pathogenic
1456869	NM_033026.6(PCLO):c.4358dup (p.Ser1454fs)	Pathogenic
1458079	NM_033026.6(PCLO):c.1324C>T (p.Gln442Ter)	Pathogenic
1459373	NM_033026.6(PCLO):c.13381C>T (p.Arg4461Ter)	Pathogenic
193026	NM_033026.6(PCLO):c.10624C>T (p.Arg3542Ter)	Pathogenic
1953577	NM_033026.6(PCLO):c.9628C>T (p.Gln3210Ter)	Pathogenic
2003121	NM_033026.6(PCLO):c.4623T>A (p.Tyr1541Ter)	Pathogenic
2003436	NM_033026.6(PCLO):c.3975C>A (p.Cys1325Ter)	Pathogenic
2004972	NM_033026.6(PCLO):c.1210C>T (p.Gln404Ter)	Pathogenic
2018063	NM_033026.6(PCLO):c.15181del (p.Gln5061fs)	Pathogenic
2026995	NM_033026.6(PCLO):c.13731_13732delinsAT (p.Gln4578Ter)	Pathogenic
2027971	NM_033026.6(PCLO):c.6119del (p.His2040fs)	Pathogenic
2031497	NM_033026.6(PCLO):c.11716C>T (p.Gln3906Ter)	Pathogenic
2035200	NM_033026.6(PCLO):c.2243del (p.Pro748fs)	Pathogenic
2035770	NM_033026.6(PCLO):c.1891G>T (p.Glu631Ter)	Pathogenic
2036904	NM_033026.6(PCLO):c.5092G>T (p.Glu1698Ter)	Pathogenic
2037161	NM_033026.6(PCLO):c.14770del (p.Gln4924fs)	Pathogenic
2067218	NM_033026.6(PCLO):c.6258del (p.Ile2087fs)	Pathogenic

SpliceAI

5965 predictions. Top by Δscore:

Variant	Effect	Δscore
7:82801513:CTTA:C	donor_loss	1.0000
7:82801514:TTA:T	donor_loss	1.0000
7:82801515:TA:T	donor_loss	1.0000
7:82801588:CCCT:C	acceptor_gain	1.0000
7:82801589:CCTC:C	acceptor_gain	1.0000
7:82801590:CT:C	acceptor_gain	1.0000
7:82801596:T:TC	acceptor_gain	1.0000
7:82822493:A:AC	donor_gain	1.0000
7:82822494:C:CC	donor_gain	1.0000
7:82824234:AC:A	donor_gain	1.0000
7:82824235:CC:C	donor_gain	1.0000
7:82824414:TAC:T	acceptor_gain	1.0000
7:82824417:CTGA:C	acceptor_loss	1.0000
7:82826661:C:CC	acceptor_gain	1.0000
7:82826663:A:C	acceptor_gain	1.0000
7:82827967:C:CC	acceptor_gain	1.0000
7:82838212:ACTT:A	donor_loss	1.0000
7:82838213:CTT:C	donor_loss	1.0000
7:82838214:TTA:T	donor_loss	1.0000
7:82838215:T:TG	donor_loss	1.0000
7:82838216:A:AC	donor_gain	1.0000
7:82838216:A:T	donor_loss	1.0000
7:82838216:AC:A	donor_gain	1.0000
7:82838217:C:CG	donor_gain	1.0000
7:82838217:C:G	donor_loss	1.0000
7:82838217:CC:C	donor_gain	1.0000
7:82838217:CCCT:C	donor_gain	1.0000
7:82838338:TGAAG:T	acceptor_gain	1.0000
7:82838339:GAAG:G	acceptor_gain	1.0000
7:82838341:AG:A	acceptor_gain	1.0000

AlphaMissense

33454 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:82826593:C:T	G4804E	1.000
7:82826594:C:A	G4804W	1.000
7:82826632:A:T	V4791D	1.000
7:82826644:A:G	L4787P	1.000
7:82827914:A:G	W4768R	1.000
7:82827914:A:T	W4768R	1.000
7:82838314:A:G	L4709P	1.000
7:82838341:A:G	L4700P	1.000
7:82845446:A:G	L4624S	1.000
7:82916584:A:G	L3801P	1.000
7:82916593:A:G	L3798P	1.000
7:82916600:C:G	A3796P	1.000
7:82916626:A:G	L3787P	1.000
7:82916633:C:G	A3785P	1.000
7:82916644:C:G	R3781P	1.000
7:82916647:A:G	L3780P	1.000
7:82916657:A:G	S3777P	1.000
7:82916677:A:G	L3770P	1.000
7:82916698:A:G	L3763P	1.000
7:82916820:T:A	R3722S	1.000
7:82916820:T:G	R3722S	1.000
7:82950809:A:G	L3260P	1.000
7:82758613:A:G	W5131R	0.999
7:82758613:A:T	W5131R	0.999
7:82758666:C:T	G5113D	0.999
7:82758708:A:G	L5099P	0.999
7:82760643:A:G	L5095P	0.999
7:82760688:A:G	F5080S	0.999
7:82760694:G:T	P5078H	0.999
7:82761402:G:C	C5033W	0.999

dbSNP variants (sampled 300 via entrez): RS1000003776 (7:82968058 T>C), RS1000006166 (7:82958087 C>T), RS1000012390 (7:82787474 T>A), RS1000015507 (7:82898248 T>C), RS1000017813 (7:82761149 T>A), RS1000025082 (7:82807927 T>C), RS1000045357 (7:82867894 G>A), RS1000048249 (7:82882044 T>C), RS1000051319 (7:83015990 A>T), RS1000054261 (7:83086642 T>C), RS1000056277 (7:82860325 A>T), RS1000065629 (7:82853441 T>C,G), RS1000082482 (7:82949377 G>A,C,T), RS1000091538 (7:82944105 C>T), RS1000103048 (7:83016221 A>C,G)

Disease associations

OMIM: gene MIM:604918 | disease phenotypes: MIM:608027

GenCC curated gene-disease

Disease	Classification	Inheritance
pontocerebellar hypoplasia type 3	Strong	Autosomal recessive

Mondo (2): pontocerebellar hypoplasia type 3 (MONDO:0011948), microcephaly (MONDO:0001149)

Orphanet (1): Pontocerebellar hypoplasia type 3 (Orphanet:97249)

HPO phenotypes

36 total (30 of 36 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000218	High palate
HP:0000248	Brachycephaly
HP:0000253	Progressive microcephaly
HP:0000293	Full cheeks
HP:0000343	Long philtrum
HP:0000365	Hearing impairment
HP:0000369	Low-set ears
HP:0000400	Macrotia
HP:0000520	Proptosis
HP:0000543	Optic disc pallor
HP:0000637	Long palpebral fissure
HP:0000648	Optic atrophy
HP:0001250	Seizure
HP:0001257	Spasticity
HP:0001263	Global developmental delay
HP:0001272	Cerebellar atrophy
HP:0001319	Neonatal hypotonia
HP:0001321	Cerebellar hypoplasia
HP:0001347	Hyperreflexia
HP:0002059	Cerebral atrophy
HP:0002079	Hypoplasia of the corpus callosum
HP:0002365	Hypoplasia of the brainstem
HP:0002421	Poor head control
HP:0002705	High, narrow palate
HP:0002714	Downturned corners of mouth
HP:0003577	Congenital onset
HP:0003593	Infantile onset
HP:0003676	Progressive
HP:0004322	Short stature

GWAS associations

13 associations (top):

Study	Trait	p-value
GCST001083_5	Major depressive disorder	1.000000e-06
GCST004486_1	Major depressive disorder	3.000000e-08
GCST004524_5	Energy expenditure (24h)	6.000000e-06
GCST005790_7	Rosacea symptom severity	8.000000e-06
GCST006582_2	Major depressive disorder	5.000000e-06
GCST006631_1	Nicotine dependence and major depression (severity of comorbidity)	4.000000e-06
GCST008531_2	Grapefruit juice consumption	8.000000e-07
GCST009391_1059	Metabolite levels	7.000000e-06
GCST009391_1355	Metabolite levels	8.000000e-06
GCST009600_63	Anorexia nervosa, attention-deficit/hyperactivity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, or Tourette syndrome (pleiotropy)	2.000000e-08
GCST010002_255	Refractive error	1.000000e-23
GCST011743_58	HDL cholesterol levels in HIV infection	4.000000e-06
GCST011769_15	Schizophrenia	2.000000e-08

EFO canonical traits (7, from GWAS)

EFO ID	Trait name
EFO:0009180	rosacea severity measurement
EFO:0007006	depressive symptom measurement
EFO:0009262	nicotine dependence symptom count
EFO:0010094	grapefruit juice consumption measurement
EFO:0010363	lysophosphatidylcholine 20:4 measurement
EFO:0010365	lysophosphatidylcholine 22:6 measurement
EFO:0004612	high density lipoprotein cholesterol measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500
C548072	Pontocerebellar Hypoplasia Type 3 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression	8
Nickel	decreases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Tobacco Smoke Pollution	increases expression, affects expression	2
Aflatoxin B1	decreases methylation, increases methylation	2
aristolochic acid I	decreases expression	1
FR900359	decreases phosphorylation	1
methylmercuric chloride	increases expression	1
bisphenol A	increases methylation	1
trichostatin A	increases expression	1
sodium arsenite	increases expression	1
16 alpha-ethyl-21-hydroxy-19-nor-4-pregnene-3,20-dione	increases expression	1
perfluorooctanoic acid	increases expression	1
benzo(e)pyrene	decreases methylation	1
avobenzone	decreases expression	1
CGP 52608	affects binding, increases reaction	1
corosolic acid	increases expression	1
monomethylarsonous acid	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
quinocetone	increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
(+)-JQ1 compound	increases expression	1
Temozolomide	decreases expression	1
Sunitinib	decreases expression	1
Air Pollutants	increases expression, increases abundance	1
Arsenic	affects methylation	1
Carbamazepine	affects expression	1
Clozapine	decreases expression, affects cotreatment	1
Cuprizone	affects cotreatment, decreases expression	1
Doxorubicin	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05518188	PHASE1/PHASE2	RECRUITING	Melpida: Recombinant Adeno-associated Virus (serotype 9) Encoding a Codon Optimized Human AP4M1 Transgene (hAP4M1opt)
NCT00001639	Not specified	COMPLETED	Evaluation of Patients With Unresolved Chromosome Abnormalities
NCT01151462	Not specified	WITHDRAWN	Postnatal HCMV Infection in Very Preterm Infants. Implications, Morbidity, Growth and Neurodevelopmental Outcomes.
NCT01565005	Not specified	COMPLETED	Microcephaly Genetic Deficiency in Neural Progenitors
NCT02510170	Not specified	COMPLETED	Fetal and Maternal Head Circumference During Pregnancy in Israeli Population
NCT02741882	Not specified	COMPLETED	Zika and Microcephaly: Case-control Study
NCT02943304	Not specified	COMPLETED	Neurodevelopment Outcome of Newborns Exposed to Zika Virus (ZIKV) in Utero
NCT03255369	Not specified	UNKNOWN	Vertical Exposure to Zika Virus and Its Consequences for Child Neurodevelopment (ZIKVIRUSIFF)
NCT03325946	Not specified	RECRUITING	The FBRI VTC Neuromotor Research Clinic
NCT03330600	Not specified	COMPLETED	Efficacy of Aquatic Physiotherapy in Children With Microcephaly by Zika Virus Congenital Syndrome
NCT03548779	Not specified	COMPLETED	North Carolina Genomic Evaluation by Next-generation Exome Sequencing, 2
NCT03651687	Not specified	COMPLETED	Guangzhou Surveillance and Clinical Study in Microcephaly (GSCSM)
NCT03922594	Not specified	TERMINATED	Surveillance of Zika-related Microcephaly in Sub-Saharan Africa and Asia
NCT04816175	Not specified	COMPLETED	Intensive Therapy for Children With Microcephaly, Hyperkinetic Movements, or Global Developmental Delay
NCT05322980	Not specified	COMPLETED	Summary of Infants Weighing 500 Grams or Less
NCT06019182	Not specified	RECRUITING	MEHMO Natural History and Biomarkers
NCT06566066	Not specified	RECRUITING	Register for Patients With Thyroid Hormone Resistance.