PHACTR1

Summary

PHACTR1 (phosphatase and actin regulator 1, HGNC:20990) is a protein-coding gene on chromosome 6p24.1, encoding Phosphatase and actin regulator 1 (Q9C0D0). Binds actin monomers (G actin) and plays a role in multiple processes including the regulation of actin cytoskeleton dynamics, actin stress fibers formation, cell motility and survival, formation of tubules by endothelial cells, and regulation of PPP1CA activity.

The protein encoded by this gene is a member of the phosphatase and actin regulator family of proteins. This family member can bind actin and regulate the reorganization of the actin cytoskeleton. It plays a role in tubule formation and in endothelial cell survival. Polymorphisms in this gene are associated with susceptibility to myocardial infarction, coronary artery disease and cervical artery dissection. Alternative splicing of this gene results in multiple transcript variants.

Source: NCBI Gene 221692 — RefSeq curated summary.

At a glance

• Gene–disease (curated): developmental and epileptic encephalopathy, 70 (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 75
• Clinical variants (ClinVar): 130 total — 2 pathogenic, 4 likely-pathogenic
• Phenotypes (HPO): 28
• MANE Select transcript: NM_030948

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:20990
Approved symbol	PHACTR1
Name	phosphatase and actin regulator 1
Location	6p24.1
Locus type	gene with protein product
Status	Approved
Aliases	KIAA1733, dJ257A7.2
Ensembl gene	ENSG00000112137
Ensembl biotype	protein_coding
OMIM	608723
Entrez	221692

Gene structure

Transcript identifiers

Ensembl transcripts: 27 — 13 protein_coding, 8 protein_coding_CDS_not_defined, 6 retained_intron

ENST00000332995, ENST00000379329, ENST00000379335, ENST00000379348, ENST00000379350, ENST00000406205, ENST00000434977, ENST00000481706, ENST00000482982, ENST00000489548, ENST00000674595, ENST00000674637, ENST00000674953, ENST00000675203, ENST00000676159, ENST00000676234, ENST00000687557, ENST00000687600, ENST00000687849, ENST00000689397, ENST00000689548, ENST00000690071, ENST00000692502, ENST00000692662, ENST00000692995, ENST00000693568, ENST00000693693

RefSeq mRNA: 12 — MANE Select: NM_030948 NM_001242648, NM_001322308, NM_001322309, NM_001322310, NM_001322311, NM_001322312, NM_001322313, NM_001322314, NM_001374581, NM_001374583, NM_001374584, NM_030948

CCDS: CCDS75401, CCDS93857, CCDS93858, CCDS93859, CCDS93860

Canonical transcript exons

ENST00000332995 — 15 exons

Exon	Start	End
ENSE00001296130	12749644	12749790
ENSE00001305419	13230037	13230193
ENSE00001317647	13182519	13182686
ENSE00001327268	13227816	13228063
ENSE00001973534	13286146	13286222
ENSE00002250504	13287063	13287837
ENSE00003315796	13205815	13206136
ENSE00003509245	13053365	13053529
ENSE00003532328	13272860	13272915
ENSE00003568630	13278268	13278329
ENSE00003595353	13160204	13160284
ENSE00003658649	13283422	13283562
ENSE00003900678	12718699	12718847
ENSE00003901024	12717509	12717743
ENSE00003903999	12716767	12716896

Expression profiles

Bgee: expression breadth ubiquitous, 210 present calls, max score 92.94.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 37.8752 / max 3199.4395, expressed in 1276 samples.

FANTOM5 promoters (34 alternative TSS)

Promoter ID	TPM avg	Samples expressed
65926	21.8574	504
65880	2.8658	77
65908	2.5370	452
65889	1.5426	406
65883	1.1618	76
65881	1.0375	74
65903	0.9329	482
65892	0.8920	326
65902	0.6869	301
65891	0.5689	213

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cortical plate	UBERON:0005343	92.94	gold quality
postcentral gyrus	UBERON:0002581	89.28	gold quality
nucleus accumbens	UBERON:0001882	89.25	gold quality
parietal lobe	UBERON:0001872	88.96	gold quality
ganglionic eminence	UBERON:0004023	88.57	gold quality
prefrontal cortex	UBERON:0000451	88.43	gold quality
superior frontal gyrus	UBERON:0002661	87.39	gold quality
frontal cortex	UBERON:0001870	87.08	gold quality
right frontal lobe	UBERON:0002810	86.82	gold quality
caudate nucleus	UBERON:0001873	86.77	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	86.62	gold quality
neocortex	UBERON:0001950	86.54	gold quality
entorhinal cortex	UBERON:0002728	86.07	gold quality
putamen	UBERON:0001874	86.00	gold quality
sural nerve	UBERON:0015488	85.43	gold quality
telencephalon	UBERON:0001893	85.35	gold quality
cerebral cortex	UBERON:0000956	85.04	gold quality
cingulate cortex	UBERON:0003027	84.89	gold quality
anterior cingulate cortex	UBERON:0009835	84.68	gold quality
primary visual cortex	UBERON:0002436	84.44	gold quality
ventricular zone	UBERON:0003053	84.36	gold quality
Brodmann (1909) area 9	UBERON:0013540	84.19	gold quality
occipital lobe	UBERON:0002021	84.05	gold quality
cardiac ventricle	UBERON:0002082	84.04	gold quality
apex of heart	UBERON:0002098	84.04	gold quality
heart left ventricle	UBERON:0002084	84.00	gold quality
descending thoracic aorta	UBERON:0002345	83.81	gold quality
popliteal artery	UBERON:0002250	83.43	gold quality
forebrain	UBERON:0001890	83.41	gold quality
tibial artery	UBERON:0007610	83.38	gold quality

Single-cell (SCXA)

Detected in 21 experiment(s), a significant marker in 19.

Experiment	Marker?	Max mean expression
E-HCAD-35	yes	11197.82
E-MTAB-6678	yes	5065.99
E-HCAD-25	yes	2222.55
E-ENAD-20	yes	2062.25
E-HCAD-4	yes	130.30
E-CURD-119	yes	54.73
E-MTAB-10553	yes	36.77
E-MTAB-9467	yes	25.76
E-CURD-46	yes	24.92
E-MTAB-10287	yes	24.29
E-MTAB-9221	yes	20.54
E-CURD-122	yes	19.99
E-ANND-3	yes	18.57
E-HCAD-1	yes	17.78
E-GEOD-93593	yes	14.90

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): FLT1, NRP1

miRNA regulators (miRDB)

50 targeting PHACTR1, 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-4668-3P	100.00	68.74	2635
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-6748-5P	100.00	65.81	1057
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-2110	99.96	66.68	1930
HSA-MIR-4271	99.88	68.32	2244
HSA-MIR-4779	99.86	66.50	1583
HSA-MIR-383-3P	99.85	65.84	1359
HSA-MIR-4307	99.82	70.45	3374
HSA-MIR-4659A-3P	99.80	72.62	4248
HSA-MIR-4659B-3P	99.80	72.62	4248
HSA-MIR-2052	99.79	69.37	2031
HSA-MIR-34B-5P	99.78	67.56	1175
HSA-MIR-449C-5P	99.78	67.63	1168
HSA-MIR-2682-5P	99.73	67.38	1055
HSA-MIR-3714	99.71	70.74	2671
HSA-MIR-548AU-3P	99.70	68.22	1373
HSA-MIR-182-3P	99.57	67.57	825
HSA-MIR-4688	99.48	64.68	828
HSA-MIR-6743-5P	99.48	63.60	721
HSA-MIR-4480	99.42	66.02	735
HSA-MIR-377-3P	99.37	70.18	1905
HSA-MIR-19A-5P	99.36	66.93	1675
HSA-MIR-19B-1-5P	99.36	67.07	1669
HSA-MIR-19B-2-5P	99.36	67.07	1669

Literature-anchored findings (GeneRIF, showing 34)

• Findings suggest that PHACTR-1 is likely to be a key regulator of endothelial cell function properties. (PMID:21798305)
• Phactr-1 is a key component in the angiogenic process (PMID:21939755)
• Results from this GWAS support a central role of PHACTR1 in CAD susceptibility irrespective of lifestyle and ethnic divergences. (PMID:22745674)
• 3 loci from related cardiovascular genomewide studies were significant: PHACTR1 in large-vessel disease (P=2.63e(-6)), PITX2 in cardioembolic stroke (P=4.78e(-8)), and ZFHX3 in cardioembolic stroke (P=5.50e(-7)). (PMID:23042660)
• a novel signaling route whereby TGF-beta silences the expression of miR-584, resulting in enhanced PHACTR1 expression, and further leading to actin rearrangement and breast cancer cell migration. (PMID:23479725)
• GWAS analysis of 1,393 cervical artery dissection cases and 14,416 controls showed that the rs9349379[G] allele was associated with lower risk. This was confirmed independent follow-up samples. (PMID:25420145)
• The rs12526453 CC homozygotes (previously associated with increased risk of myocardial infarction) showed, in 2 independent samples, better long-term survival. (PMID:26086777)
• our result highlighted the pivotal role of phactr-1 protein in the pathogenesis of atherosclerosis. (PMID:26362351)
• PHACTR1 is a key atherosclerosis candidate gene since it is regulated by atherogenic stimuli in macrophages and endothelial cells (PMID:27187934)
• To evaluate the role of two polymorphisms (rs2026458 and rs9349379) of the PHACTR1 gene in the susceptibility to the risk of developing premature coronary artery disease (CAD) in the Mexican population. Results suggest that the PHACTR1 rs9349379 polymorphism plays an important role in the risk of developing premature CAD in the Mexican population. (PMID:27517945)
• Stimulation of Slack K(+) channels alters mass at the plasma membrane by triggering dissociation of Phactr-1. (PMID:27545877)
• the expression of PHACTR1 by genotypes in primary human fibroblasts showed higher expression in rs9349379-A carriers . Phactr1 knockdown in zebrafish resulted in dilated vessels indicating subtle impaired vascular development (PMID:27792790)
• our study suggests that several PHACTR1 and SLC22A3 gene polymorphisms may exert a protective effect against the CAD in the Chinese Han male population. (PMID:27893421)
• There was no significant association between the presence of risk alleles of rs12526453 and coronary heart disease in an Iranian population. (PMID:28287809)
• CRISPR-edited stem cell-derived endothelial cells demonstrate rs9349379, a common SNP in the 3 intron of the PHACTR1 gene, regulates expression of endothelin 1 (EDN1), a gene located 600 kb upstream of PHACTR1. The known physiologic effects of EDN1 on the vasculature may explain the pattern of risk for the five associated vascular diseases. (PMID:28753427)
• PHACTR1 splicing is associated with atherosclerosis. (PMID:29884117)
• The data of this study showed that the PHACTR1 mutations may cause morphological and functional defects in cortical neurons during brain development, which is likely to be related to the pathophysiology of West syndrome and other neurodevelopmental disorders. (PMID:30256902)
• silencing PHACTR1 alleviates the nuclear accumulation of p65 and NF-kappaB via interaction with MRTF-A, ensuing attenuating oxidative stress and inflammation in human coronary artery endothelial cells (PMID:30293016)
• Confirmation of Causal rs9349379- PHACTR1 Expression Quantitative Trait Locus in Human-Induced Pluripotent Stem Cell Endothelial Cells. (PMID:30354304)
• This study reports that rs9349379 PHACTR1/EDN1 genetic locus is the first genetic risk locus for spontaneous coronary artery dissection. (PMID:30621952)
• Phactr-1 was shown to have a role in the inhibition of endothelial cell proliferation and migration, promoted cell apoptosis, and regulated matrix metalloproteinases and apoptosis-associated proteins. (PMID:30772888)
• Our study indicate that the PHACTR1 rs9349379 polymorphism is associated with the increased risk for CAD in the female Chinese Han population. (PMID:30777881)
• Results suggest that PHACTR1 haplotypes inferred from the variants rs9349379, rs2026458 and rs2876300 affect PHACTR1 mRNA and bear the risk for carotid plaque presence in patients with advanced carotid atherosclerosis. (PMID:31200082)
• Phactr1 rs9349379 polymorphism is associated with an elevated susceptibility to coronary artery disease [meta-analysis] (PMID:31204462)
• Associations between PHACTR1 gene polymorphisms and pulse pressure in Chinese Han population. (PMID:32420588)
• Genetic Study of PHACTR1 and Fibromuscular Dysplasia, Meta-Analysis and Effects on Clinical Features of Patients: The ARCADIA-POL Study. (PMID:32475314)
• Association of PHACTR1 intronic variants with the first myocardial infarction and their effect on PHACTR1 mRNA expression in PBMCs. (PMID:33460763)
• Deficiency of macrophage PHACTR1 impairs efferocytosis and promotes atherosclerotic plaque necrosis. (PMID:33630758)
• The association of polymorphism in PHACTR1 rs9349379 and rs12526453 with coronary artery atherosclerosis or coronary artery calcification. A systematic review. (PMID:33660664)
• PHACTR1 genetic variability is not critical in small vessel ischemic disease patients and PcomA recruitment in C57BL/6J mice. (PMID:33727568)
• A Study of Associations Between rs9349379 (PHACTR1), rs2891168 (CDKN2B-AS), rs11838776 (COL4A2) and rs4880 (SOD2) Polymorphic Variants and Coronary Artery Disease in Iranian Population. (PMID:34109516)
• PHACTR1 modulates vascular compliance but not endothelial function: a translational study. (PMID:35653516)
• PHACTR1, a coronary artery disease risk gene, mediates endothelial dysfunction. (PMID:36091033)
• Genotype and phenotype correlation of PHACTR1-related neurological disorders. (PMID:38272663)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	phactr1	ENSDARG00000023916
danio_rerio		ENSDARG00000110206
mus_musculus	Phactr1	ENSMUSG00000054728
rattus_norvegicus	Phactr1	ENSRNOG00000014264
drosophila_melanogaster	CG32264	FBGN0052264
caenorhabditis_elegans	phac-1	WBGENE00009174

Paralogs (3): PHACTR3 (ENSG00000087495), PHACTR2 (ENSG00000112419), PHACTR4 (ENSG00000204138)

Protein

Protein identifiers

Phosphatase and actin regulator 1 — Q9C0D0 (reviewed: Q9C0D0)

All UniProt accessions (9): Q9C0D0, A0A6Q8PFA8, A0A6Q8PG87, A0A6Q8PGC2, A0A8I5KVE0, A0A8I5QJF9, H0Y3U1, H0Y7G2, Q4VY12

UniProt curated annotations — full annotation on UniProt →

Function. Binds actin monomers (G actin) and plays a role in multiple processes including the regulation of actin cytoskeleton dynamics, actin stress fibers formation, cell motility and survival, formation of tubules by endothelial cells, and regulation of PPP1CA activity. Involved in the regulation of cortical neuron migration and dendrite arborization.

Subunit / interactions. Interacts (via RPEL repeats) with ACTA1 and PPP1CA; ACTA1 and PPP1CA compete for the same binding site.

Subcellular location. Cytoplasm. Synapse. Nucleus.

Tissue specificity. Detected in umbilical vein endothelial cells.

Disease relevance. Developmental and epileptic encephalopathy 70 (DEE70) [MIM:618298] A form of epileptic encephalopathy, a heterogeneous group of severe early-onset epilepsies characterized by refractory seizures, neurodevelopmental impairment, and poor prognosis. Development is normal prior to seizure onset, after which cognitive and motor delays become apparent. DEE70 is an autosomal dominant form with onset in first months of life and variable severity. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. Binds three actin monomers via the three C-terminal RPEL repeats.

Induction. Up-regulated by VEGFA.

Similarity. Belongs to the phosphatase and actin regulator family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9C0D0-1	1	yes
Q9C0D0-2	2

RefSeq proteins (11): NP_001229577, NP_001309237, NP_001309238, NP_001309239, NP_001309240, NP_001309241, NP_001309242, NP_001309243, NP_001361510, NP_001361512, NP_112210* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR004018	RPEL_repeat	Repeat

Pfam: PF02755

UniProt features (27 total): modified residue 5, repeat 4, sequence variant 4, compositionally biased region 3, helix 3, region of interest 3, splice variant 2, chain 1, strand 1, short sequence motif 1

Structure

Experimental structures (PDB)

6 structures.

PDB	Method	Resolution (Å)
6ZEG	X-RAY DIFFRACTION	1.09
6ZEH	X-RAY DIFFRACTION	1.3
6ZEI	X-RAY DIFFRACTION	1.39
6ZEJ	X-RAY DIFFRACTION	1.78
6ZEE	X-RAY DIFFRACTION	1.9
6ZEF	X-RAY DIFFRACTION	1.94

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9C0D0-F1	63.45	0.23

Functional residue map

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

Post-translational modifications (5): 67, 78, 104, 467, 505

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 269 (showing top): GOBP_DENDRITE_DEVELOPMENT, GOBP_ACTIN_FILAMENT_BUNDLE_ORGANIZATION, GOBP_NADPPLUS_METABOLIC_PROCESS, chr6p24, GOBP_NEUROGENESIS, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_FOREBRAIN_DEVELOPMENT, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, GOBP_GLUCOSE_6_PHOSPHATE_METABOLIC_PROCESS, GOBP_NUCLEOBASE_CONTAINING_SMALL_MOLECULE_METABOLIC_PROCESS, GOBP_GENERATION_OF_PRECURSOR_METABOLITES_AND_ENERGY, ONKEN_UVEAL_MELANOMA_UP, GOBP_CEREBRAL_CORTEX_DEVELOPMENT, GOBP_DENDRITE_MORPHOGENESIS, GOBP_ACTIN_FILAMENT_ORGANIZATION

GO Biological Process (7): cerebral cortex development (GO:0021987), actin cytoskeleton organization (GO:0030036), actomyosin structure organization (GO:0031032), stress fiber assembly (GO:0043149), cell motility (GO:0048870), dendrite arborization (GO:0140059), regulation of neuron migration (GO:2001222)

GO Molecular Function (3): actin binding (GO:0003779), protein phosphatase inhibitor activity (GO:0004864), protein binding (GO:0005515)

GO Cellular Component (4): nucleus (GO:0005634), cytosol (GO:0005829), synapse (GO:0045202), cytoplasm (GO:0005737)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
pallium development	1
anatomical structure development	1
cytoskeleton organization	1
actin filament-based process	1
actin cytoskeleton organization	1
contractile actin filament bundle assembly	1
actomyosin structure organization	1
cellular process	1
dendrite morphogenesis	1
neuron projection arborization	1
neuron migration	1
regulation of cell migration	1
cytoskeletal protein binding	1
phosphoprotein phosphatase activity	1
phosphatase inhibitor activity	1
protein phosphatase regulator activity	1
binding	1
intracellular membrane-bounded organelle	1
cytoplasm	1
cell junction	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

962 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PHACTR1	MRTFB	Q9ULH7	944
PHACTR1	MRTFA	Q969V6	898
PHACTR1	MYOCD	Q8IZQ8	802
PHACTR1	PPP1CA	P08129	778
PHACTR1	ADAMTS7	Q9UKP4	702
PHACTR1	SRF	P11831	574
PHACTR1	PSRC1	Q6PGN9	574
PHACTR1	MIA3	Q5JRA6	572
PHACTR1	WDR12	Q9GZL7	571
PHACTR1	MRPS6	P82932	571
PHACTR1	CFL2	Q9Y281	512
PHACTR1	CFL1	P23528	512
PHACTR1	SORT1	Q99523	507
PHACTR1	ZC3HC1	Q86WB0	507
PHACTR1	TRPM8	Q7Z2W7	502

IntAct

10 interactions, top by confidence:

A	B	Type	Score
PHACTR1	CBX8	psi-mi:“MI:0915”(physical association)	0.560
PHACTR1	C14orf119	psi-mi:“MI:0915”(physical association)	0.560
PHACTR1	Dlg4	psi-mi:“MI:0407”(direct interaction)	0.440
PHACTR1	EIF4B	psi-mi:“MI:0915”(physical association)	0.400
PHACTR1	H2BC9	psi-mi:“MI:0915”(physical association)	0.400
CBX8	PHACTR1	psi-mi:“MI:0915”(physical association)	0.000
C14orf119	PHACTR1	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (14): PHACTR1 (Affinity Capture-RNA), ACTA1 (Affinity Capture-Western), PPP1CA (Affinity Capture-Western), PHACTR1 (Two-hybrid), PHACTR1 (Affinity Capture-Western), PHACTR1 (Protein-RNA), CBX8 (Two-hybrid), C14orf119 (Two-hybrid), PHACTR1 (Proximity Label-MS), PHACTR1 (Proximity Label-MS), PHACTR1 (Two-hybrid), PHACTR1 (Affinity Capture-MS), PHACTR1 (Cross-Linking-MS (XL-MS)), PHACTR1 (Affinity Capture-RNA)

ESM2 similar proteins: A0A1L8ER70, A1L253, A2AHC3, A5WUN7, B1AZP2, D4AEC2, O14490, P28290, P62024, P97836, P97839, Q148W8, Q14CH0, Q2KI52, Q2M3X8, Q3ZBW7, Q4KM62, Q4R2Y2, Q4R707, Q52KF3, Q5PQL8, Q5R3Z9, Q5RD34, Q5RJX2, Q5VUB5, Q5VZP5, Q5XII9, Q6GLU8, Q6NSV7, Q6P995, Q6PEI3, Q6RFY2, Q7T3E8, Q8BJ42, Q8BYK5, Q8C1B1, Q922B9, Q95X94, Q96BN6, Q96KR7

Diamond homologs: F1MCY2, F1N8V3, F1QIC4, F7EC58, O75167, P62024, P62025, Q2M3X8, Q501J7, Q5HZA1, Q5RAU1, Q5XHF3, Q6GLU8, Q6PEI3, Q6RFY2, Q801X6, Q8BYK5, Q8IZ21, Q96KR7, Q9C0D0

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
FLT1	“up-regulates quantity by expression”	PHACTR1	“transcriptional regulation”
NRP1	“up-regulates quantity by expression”	PHACTR1	“transcriptional regulation”
PHACTR1	“up-regulates activity”	PPP1CA	binding
PHACTR1	“up-regulates activity”	PP1	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	4
Uncertain significance	79
Likely benign	30
Benign	11

Top pathogenic / likely-pathogenic (6)

Variant ID	HGVS	Classification
1679588	NM_030948.6(PHACTR1):c.1396C>A (p.Leu466Met)	Pathogenic
617492	NM_030948.6(PHACTR1):c.1436A>T (p.Asn479Ile)	Pathogenic
1690642	NM_030948.3:c.251-63908_415+29843dup	Likely pathogenic
1704279	NM_030948.6(PHACTR1):c.1278C>G (p.Ile426Met)	Likely pathogenic
2584340	NM_030948.6(PHACTR1):c.209C>G (p.Pro70Arg)	Likely pathogenic
3068777	NM_030948.6(PHACTR1):c.190C>G (p.Arg64Gly)	Likely pathogenic

SpliceAI

3709 predictions. Top by Δscore:

Variant	Effect	Δscore
6:12716893:GCCG:G	donor_gain	1.0000
6:12716894:CCGGT:C	donor_loss	1.0000
6:12716895:CGGT:C	donor_loss	1.0000
6:12716897:G:GG	donor_gain	1.0000
6:12716897:GT:G	donor_loss	1.0000
6:12718694:TATAG:T	acceptor_gain	1.0000
6:12718695:ATAG:A	acceptor_gain	1.0000
6:12718695:ATAGG:A	acceptor_gain	1.0000
6:12718696:T:G	acceptor_gain	1.0000
6:12718696:TA:T	acceptor_loss	1.0000
6:12718696:TAGG:T	acceptor_gain	1.0000
6:12718697:A:AG	acceptor_gain	1.0000
6:12718697:AG:A	acceptor_gain	1.0000
6:12718697:AGGT:A	acceptor_gain	1.0000
6:12718698:G:GA	acceptor_gain	1.0000
6:12718698:GG:G	acceptor_gain	1.0000
6:12718698:GGT:G	acceptor_gain	1.0000
6:12718698:GGTG:G	acceptor_gain	1.0000
6:12718843:TCAAG:T	donor_loss	1.0000
6:12718844:CAAG:C	donor_loss	1.0000
6:12718845:AAGG:A	donor_loss	1.0000
6:12718848:G:A	donor_loss	1.0000
6:12718849:T:A	donor_loss	1.0000
6:12749789:AGGT:A	donor_loss	1.0000
6:12749791:GT:G	donor_loss	1.0000
6:12749792:T:G	donor_loss	1.0000
6:13053335:T:A	acceptor_gain	1.0000
6:13053342:A:AG	acceptor_gain	1.0000
6:13053343:T:G	acceptor_gain	1.0000
6:13053352:T:TA	acceptor_gain	1.0000

AlphaMissense

3810 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:13053481:T:A	W123R	1.000
6:13053481:T:C	W123R	1.000
6:13053487:T:A	W125R	1.000
6:13053487:T:C	W125R	1.000
6:13053489:G:C	W125C	1.000
6:13053489:G:T	W125C	1.000
6:13160228:G:T	R147M	1.000
6:13160229:G:C	R147S	1.000
6:13160229:G:T	R147S	1.000
6:13160246:T:C	L153P	1.000
6:13206097:T:C	L316P	1.000
6:13230073:T:C	L424S	1.000
6:13230075:G:C	A425P	1.000
6:13230085:T:C	L428P	1.000
6:13230095:G:C	R431S	1.000
6:13230095:G:T	R431S	1.000
6:13230112:T:C	L437P	1.000
6:13230154:G:C	R451P	1.000
6:13230187:T:A	L462H	1.000
6:13230187:T:C	L462P	1.000
6:13272862:G:C	R465P	1.000
6:13272865:T:A	L466Q	1.000
6:13272865:T:C	L466P	1.000
6:13272867:A:C	S467R	1.000
6:13272869:C:A	S467R	1.000
6:13272869:C:G	S467R	1.000
6:13272873:A:G	R469G	1.000
6:13272874:G:C	R469T	1.000
6:13272874:G:T	R469M	1.000
6:13272875:G:C	R469S	1.000

dbSNP variants (sampled 300 via entrez): RS1000004832 (6:12979038 T>G), RS1000008114 (6:13084596 C>T), RS1000026902 (6:13187100 T>C), RS1000036141 (6:13225149 G>A), RS1000048431 (6:12790557 C>G), RS1000052315 (6:12747416 C>T), RS1000055128 (6:12830824 A>G), RS1000058855 (6:12953759 G>A), RS1000061213 (6:12864980 T>C), RS1000063168 (6:13266638 A>G), RS1000064260 (6:13085012 C>A,T), RS1000075970 (6:12816892 G>A), RS1000080730 (6:12996849 A>C,G), RS1000083148 (6:12931274 C>T), RS1000086801 (6:12913606 G>C)

Disease associations

OMIM: gene MIM:608723 | disease phenotypes: MIM:618298, MIM:181500

GenCC curated gene-disease

Disease	Classification	Inheritance
developmental and epileptic encephalopathy, 70	Strong	Autosomal dominant
infantile spasms	Supportive	Autosomal dominant

Mondo (3): developmental and epileptic encephalopathy, 70 (MONDO:0032663), schizophrenia (MONDO:0005090), infantile spasms (MONDO:0018097)

Orphanet (1): NON RARE IN EUROPE: Schizophrenia (Orphanet:3140)

HPO phenotypes

28 total (29 of 28 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000028	Cryptorchidism
HP:0000160	Narrow mouth
HP:0000252	Microcephaly
HP:0000316	Hypertelorism
HP:0000369	Low-set ears
HP:0000707	Abnormality of the nervous system
HP:0000729	Autistic behavior
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001285	Spastic tetraparesis
HP:0001336	Myoclonus
HP:0001371	Flexion contracture
HP:0001561	Polyhydramnios
HP:0002119	Ventriculomegaly
HP:0002120	Cerebral cortical atrophy
HP:0002188	Delayed CNS myelination
HP:0002376	Developmental regression
HP:0002421	Poor head control
HP:0002521	Hypsarrhythmia
HP:0002650	Scoliosis
HP:0011097	Epileptic spasm
HP:0011121	Abnormal skin morphology
HP:0011344	Severe global developmental delay
HP:0012469	Infantile spasms
HP:0032792	Tonic seizure
HP:0200134	Epileptic encephalopathy
HP:0100753	Schizophrenia

GWAS associations

75 associations (top):

Study	Trait	p-value
GCST000101_8	Hip geometry	3.000000e-06
GCST000340_4	Myocardial infarction (early onset)	1.000000e-09
GCST000998_3	Coronary heart disease	1.000000e-09
GCST000999_12	Coronary heart disease	9.000000e-26
GCST000999_9	Coronary heart disease	6.000000e-08
GCST001185_1	Coronary heart disease	9.000000e-26
GCST001347_2	Coronary artery calcification	4.000000e-22
GCST001563_3	Migraine	3.000000e-08
GCST001581_1	Coronary heart disease	8.000000e-10
GCST001581_2	Coronary heart disease	4.000000e-07
GCST001581_3	Coronary heart disease	6.000000e-12
GCST001587_1	Coronary heart disease	2.000000e-09
GCST001598_3	Blood pressure	1.000000e-07
GCST002078_30	Migraine without aura	3.000000e-10
GCST002079_20	Migraine - clinic-based	2.000000e-06
GCST002081_27	Migraine	5.000000e-08
GCST002287_1	Coronary artery disease or ischemic stroke	4.000000e-11
GCST002289_14	Coronary artery disease	3.000000e-11
GCST002290_5	Coronary artery disease or large artery stroke	2.000000e-11
GCST002700_1	Cervical artery dissection	1.000000e-11
GCST002868_4	Response to serotonin reuptake inhibitors in major depressive disorder	1.000000e-06
GCST002976_4	HIV-1 viral setpoint	4.000000e-06
GCST003116_12	Coronary artery disease	2.000000e-42
GCST003117_36	Myocardial infarction	9.000000e-35
GCST003428_2	Chronotype	2.000000e-08
GCST003720_25	Migraine	6.000000e-22
GCST003721_3	Migraine without aura	2.000000e-09
GCST003986_2	Migraine	2.000000e-20
GCST004110_12	Gait speed in old age	1.000000e-06
GCST004278_89	Pulse pressure	3.000000e-06

EFO canonical traits (15, from GWAS)

EFO ID	Trait name
EFO:0004685	hip geometry
EFO:0004723	coronary artery calcification
EFO:0005658	response to selective serotonin reuptake inhibitor
EFO:0006319	HIV viral set point measurement
EFO:0005763	pulse pressure measurement
EFO:0009094	idiopathic dilated cardiomyopathy
EFO:0006941	grip strength measurement
EFO:0006336	diastolic blood pressure
EFO:0006335	systolic blood pressure
EFO:0009392	glucose metabolism decline measurement
EFO:0008328	chronotype measurement
EFO:0009939	Antimigraine preparation use measurement
EFO:0010820	spontaneous coronary artery dissection
EFO:0004327	electrocardiography
EFO:0007992	basophil percentage of leukocytes

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB variants

2 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs4615376	PHACTR1		0.00	0
rs9349379	PHACTR1		0.00	0

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, increases expression, increases mutagenesis	4
bisphenol S	affects cotreatment, increases methylation, decreases expression	2
aristolochic acid I	increases expression	1
triphenyl phosphate	affects expression	1
propionaldehyde	increases methylation	1
bisphenol A	decreases methylation	1
nonanal	increases methylation	1
n-hexanal	increases methylation	1
butyraldehyde	increases methylation	1
benzo(e)pyrene	affects methylation	1
aflatoxin B2	increases methylation	1
caprylic aldehyde	increases methylation	1
pentanal	increases methylation	1
heptanal	increases methylation	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
prothioconazole	decreases expression	1
(+)-JQ1 compound	decreases expression	1
Sunitinib	decreases expression	1
Zoledronic Acid	increases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Acetaminophen	decreases expression	1
Diethylhexyl Phthalate	decreases expression	1
Doxorubicin	decreases expression	1
Estradiol	affects cotreatment, increases expression	1
Methapyrilene	affects methylation	1
Methylcholanthrene	increases reaction, affects binding	1
Silicon Dioxide	decreases expression	1
Tobacco Smoke Pollution	increases expression	1
Valproic Acid	affects expression	1

Cellosaurus cell lines

1 cell lines: 1 induced pluripotent stem cell

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_YC64	VCCRIi001-A	Induced pluripotent stem cell	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01413711	PHASE4	WITHDRAWN	An Open-Label, Single and Multiple Oral Dose Pharmacokinetic Study of Vigabatrin in Infants With Infantile Spasms
NCT02092883	PHASE4	COMPLETED	Evaluation of Neuroinflammation in Children With Infantile Spasms
NCT00000374	PHASE4	COMPLETED	Treatment for First-Episode Schizophrenia
NCT00001656	PHASE4	COMPLETED	Comparison of Clozapine vs Olanzapine in Childhood-Onset Psychotic Disorders
NCT00007774	PHASE4	COMPLETED	To Determine if Olanzapine is More Cost Effective Than Haloperidol for the Treatment of Schizophrenia
NCT00014001	PHASE4	COMPLETED	CATIE- Schizophrenia Trial
NCT00018668	PHASE4	COMPLETED	Antipsychotic Response in Schizophrenia
NCT00034801	PHASE4	COMPLETED	Olanzapine Versus Active Comparator in the Treatment of Depression in Patients With Schizophrenia
NCT00034905	PHASE4	COMPLETED	A Comparison of Seroquel vs. Risperidone in Schizophrenia
NCT00036088	PHASE4	COMPLETED	Olanzapine Versus An Active Comparator in the Treatment of Schizophrenia
NCT00044187	PHASE4	COMPLETED	The Assessment of a Weight-Gain Agent for the Treatment of Olanzapine-Associated Anti-Obesity Agent in Patients With Schizophrenia, Schizophreniform Disorder, Schizoaffective Disorder, and Bipolar I Disorder
NCT00044655	PHASE4	COMPLETED	Switching Medication to Treat Schizophrenia
NCT00048828	PHASE4	COMPLETED	Treating Drug-Resistant Childhood Schizophrenia
NCT00053703	PHASE4	COMPLETED	Treatment of Early Onset Schizophrenia Spectrum Disorders (TEOSS)
NCT00056498	PHASE4	COMPLETED	Risperidone Treatment in Schizophrenia Patients Who Are Currently Taking Clozapine
NCT00061802	PHASE4	COMPLETED	Efficacy and Safety of Two Atypical Antipsychotics vs. Placebo in Patients With an Acute Exacerbation of Either Schizophrenia or Schizoaffective Disorder
NCT00080327	PHASE4	COMPLETED	Study of Three Doses of Aripiprazole in Patients With Acute Schizophrenia
NCT00088049	PHASE4	COMPLETED	Study of Olanzapine vs. Aripiprazole in the Treatment of Schizophrenia
NCT00090012	PHASE4	COMPLETED	Comparison of Continuing Olanzapine to Switching to Quetiapine in Overweight or Obese Patients With Schizophrenia and Schizoaffective Disorder
NCT00100776	PHASE4	COMPLETED	Efficacy of High Dose Olanzapine for the Treatment of Schizophrenia and Schizoaffective Disorder
NCT00103571	PHASE4	COMPLETED	Olanzapine Versus Aripiprazole in the Treatment of Acutely Ill Patients With Schizophrenia
NCT00108368	PHASE4	COMPLETED	The Effects of Risperidone and Olanzapine on Thinking
NCT00114595	PHASE4	COMPLETED	Ethyl-Eicosapentaenoic Acid and Tardive Dyskinesia
NCT00130923	PHASE4	COMPLETED	Risperidone Long-acting Versus Oral Risperidone in Patients With Schizophrenia and Alcohol Use Disorder
NCT00137020	PHASE4	COMPLETED	Clinical Effect Of Cross Titration Of Antipsychotics With Ziprasidone In Schizophrenia Or Schizoaffective Disorder
NCT00140166	PHASE4	COMPLETED	Treatment of Acute Schizophrenia With Vitamin Therapy
NCT00145847	PHASE4	COMPLETED	Naltrexone Treatment of Alcohol Abuse in Schizophrenia
NCT00148564	PHASE4	COMPLETED	Energy Homeostasis Under Treatment With Atypical Antipsychotics
NCT00156715	PHASE4	COMPLETED	Efficacy of Quetiapine in the Treatment of Patients With Schizophrenia and a Comorbid Substance Use Disorder
NCT00158223	PHASE4	COMPLETED	Effectiveness of Pimozide in Augmenting the Effects of Clozapine in the Treatment of Schizophrenia
NCT00159081	PHASE4	COMPLETED	One Year Drug Treatment in First-Episode Schizophrenia
NCT00159120	PHASE4	COMPLETED	Maintenance Treatment vs. Stepwise Drug Discontinuation in First-Episode Schizophrenia
NCT00159133	PHASE4	COMPLETED	Prodrome-Based Early Intervention With Antipsychotics vs. Benzodiazepines in First-Episode Schizophrenia
NCT00159757	PHASE4	TERMINATED	12 Week Open, Non-Comparative Switch Study Of Oral Ziprazidone In Previously Treated Schizophrenic Patients
NCT00167817	PHASE4	COMPLETED	Effect of Switch to Aripiprazole on Health and Smoking Parameters in Patients With Schizophrenia: A Pilot Study
NCT00169026	PHASE4	TERMINATED	Alcoholism and Schizophrenia: Effects of Clozapine
NCT00169039	PHASE4	TERMINATED	Clozapine Versus Chlorpromazine for Treatment-Unresponsive Schizophrenia
NCT00169065	PHASE4	COMPLETED	Effectiveness of Clozapine Versus Olanzapine for Treatment-resistant Schizophrenia
NCT00169091	PHASE4	TERMINATED	Clozapine Versus Haloperidol for Treating the First Episode of Schizophrenia
NCT00176423	PHASE4	COMPLETED	Efficacy Study of Galantamine for Cognitive Impairments in Schizophrenia