ARVCF

Summary

ARVCF (ARVCF delta catenin family member, HGNC:728) is a protein-coding gene on chromosome 22q11.21, encoding Splicing regulator ARVCF (O00192). Contributes to the regulation of alternative splicing of pre-mRNAs.

Armadillo Repeat gene deleted in Velo-Cardio-Facial syndrome (ARVCF) is a member of the catenin family. This family plays an important role in the formation of adherens junction complexes, which are thought to facilitate communication between the inside and outside environments of a cell. The ARVCF gene was isolated in the search for the genetic defect responsible for the autosomal dominant Velo-Cardio-Facial syndrome (VCFS), a relatively common human disorder with phenotypic features including cleft palate, conotruncal heart defects and facial dysmorphology. The ARVCF gene encodes a protein containing two motifs, a coiled coil domain in the N-terminus and a 10 armadillo repeat sequence in the midregion. Since these sequences can facilitate protein-protein interactions ARVCF is thought to function in a protein complex. In addition, ARVCF contains a predicted nuclear-targeting sequence suggesting that it may have a function as a nuclear protein.

Source: NCBI Gene 421 — RefSeq curated summary.

At a glance

• GWAS associations: 29
• Clinical variants (ClinVar): 483 total — 63 pathogenic, 2 likely-pathogenic
• Phenotypes (HPO): 131
• MANE Select transcript: NM_001670

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:728
Approved symbol	ARVCF
Name	ARVCF delta catenin family member
Location	22q11.21
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000099889
Ensembl biotype	protein_coding
OMIM	602269
Entrez	421

Gene structure

Transcript identifiers

Ensembl transcripts: 13 — 6 protein_coding, 5 protein_coding_CDS_not_defined, 2 retained_intron

ENST00000263207, ENST00000401994, ENST00000406259, ENST00000406522, ENST00000462319, ENST00000467828, ENST00000473551, ENST00000480792, ENST00000487793, ENST00000492625, ENST00000495096, ENST00000852538, ENST00000934103

RefSeq mRNA: 2 — MANE Select: NM_001670 NM_001410839, NM_001670

CCDS: CCDS13771, CCDS93120

Canonical transcript exons

ENST00000263207 — 20 exons

Exon	Start	End
ENSE00001305102	20010455	20010508
ENSE00001305650	19971216	19971335
ENSE00001644901	19979743	19980242
ENSE00001728584	19981211	19981737
ENSE00001759472	19978897	19979080
ENSE00001766679	19976706	19976723
ENSE00001881837	19969896	19970743
ENSE00001927738	20016589	20016823
ENSE00002308607	19990585	19990812
ENSE00003459452	19973643	19973793
ENSE00003471476	19977415	19977586
ENSE00003482965	19981933	19982091
ENSE00003487398	19977958	19978075
ENSE00003525882	19972358	19972411
ENSE00003552716	19972925	19973036
ENSE00003578295	19972737	19972827
ENSE00003636865	19973119	19973317
ENSE00003638782	19971886	19971971
ENSE00003678473	19975686	19975757
ENSE00003688873	19974112	19974239

Expression profiles

Bgee: expression breadth ubiquitous, 273 present calls, max score 97.75.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 5.0112 / max 76.8872, expressed in 1255 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
193175	2.9814	1041
193178	0.8147	230
193180	0.7704	292
193179	0.2386	86
193176	0.2062	100

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cerebellar hemisphere	UBERON:0002245	97.75	gold quality
right hemisphere of cerebellum	UBERON:0014890	97.71	gold quality
cerebellar cortex	UBERON:0002129	97.70	gold quality
cerebellum	UBERON:0002037	96.65	gold quality
type B pancreatic cell	CL:0000169	96.44	silver quality
olfactory bulb	UBERON:0002264	95.72	silver quality
right lobe of thyroid gland	UBERON:0001119	95.23	gold quality
ventricular zone	UBERON:0003053	94.71	gold quality
ascending aorta	UBERON:0001496	94.54	gold quality
thoracic aorta	UBERON:0001515	94.43	gold quality
vena cava	UBERON:0004087	94.13	gold quality
apex of heart	UBERON:0002098	94.07	gold quality
sural nerve	UBERON:0015488	93.84	gold quality
nerve	UBERON:0001021	93.82	gold quality
left lobe of thyroid gland	UBERON:0001120	93.82	gold quality
tibial nerve	UBERON:0001323	93.82	gold quality
aorta	UBERON:0000947	93.78	gold quality
ganglionic eminence	UBERON:0004023	93.78	gold quality
popliteal artery	UBERON:0002250	93.36	gold quality
tibial artery	UBERON:0007610	93.35	gold quality
thyroid gland	UBERON:0002046	93.30	gold quality
right coronary artery	UBERON:0001625	93.19	gold quality
descending thoracic aorta	UBERON:0002345	93.10	gold quality
pancreatic ductal cell	CL:0002079	92.06	silver quality
cerebellar vermis	UBERON:0004720	91.90	silver quality
embryo	UBERON:0000922	91.87	gold quality
triceps brachii	UBERON:0001509	91.86	gold quality
diaphragm	UBERON:0001103	91.72	gold quality
metanephros cortex	UBERON:0010533	91.68	gold quality
tongue squamous epithelium	UBERON:0006919	91.38	silver quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	1.86

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): TAL1

miRNA regulators (miRDB)

36 targeting ARVCF, 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-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-4650-5P	99.98	64.69	999
HSA-MIR-767-5P	99.95	70.85	993
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-3065-3P	99.87	70.25	1407
HSA-MIR-6875-3P	99.82	70.26	2983
HSA-MIR-4659A-3P	99.80	72.62	4248
HSA-MIR-4659B-3P	99.80	72.62	4248
HSA-MIR-6752-3P	99.72	66.71	1587
HSA-MIR-545-5P	99.66	70.18	2308
HSA-MIR-4690-5P	99.65	66.24	813
HSA-MIR-6715B-5P	99.64	69.63	1420
HSA-MIR-6132	99.60	65.83	1554
HSA-MIR-762	99.58	66.61	1994
HSA-MIR-4269	99.55	69.89	1373
HSA-MIR-486-3P	99.51	66.82	1901
HSA-MIR-4498	99.47	67.42	2360
HSA-MIR-2392	99.43	67.50	708
HSA-MIR-3182	99.40	68.15	2454
HSA-MIR-155-5P	99.35	70.16	1509
HSA-MIR-328-5P	99.08	64.65	1000
HSA-MIR-5001-5P	99.05	66.76	1972
HSA-MIR-3619-5P	99.00	68.87	2308
HSA-MIR-761	98.71	68.07	2051

Literature-anchored findings (GeneRIF, showing 14)

• Evidence was found for association of illness to rs165849 in ARVCF, and a stronger signal from three-marker haplotypes spanning the 3’ portions of COMT and ARVCF. Val(108/158)Met was in linkage disequilibrium with the markers in ARVCF. (PMID:15340358)
• Interactions with zona occludens-1 and zona occludens-2, in particular, may mediate recruitment of ARVCF to the plasma membrane and the nucleus (PMID:15456900)
• Results implicate a very close association of ARVCF with migrating neurons from the ganglionic eminence. (PMID:15509897)
• Two haplotypes covering the catechol-O-methyltransferase-ARVCF region show significant transmission disequilibrium in anorexia nervosa-restricting Israeli-Jewish families (PMID:16118784)
• Differential expression pattern of protein ARVCF in nephron segments of human kidney. (PMID:18600340)
• Single nucleotide polymorphisms in the ARVGF gene are associated with the risk of schizophrenia. (PMID:19508883)
• Over-expression of TXNRD2, COMT and ARVCF affects incentive learning and working memory in transgenic mice. (PMID:19617637)
• The functional variant rs165815, which affects a critical region of ARVCF, is a considerable source of the genetic variability associated with the risk of developing schizophrenia. (PMID:20333729)
• Five SNPs were validated as being significantly associated with prostate cancer mortality, one each in the LEPR, CRY1, RNASEL, IL4, and ARVCF genes. (PMID:21846818)
• Schizophrenic patients with more copies of the haplotype T-G-A-T-T-G-G-C-T-G-T (ARVCF-Hap1) have lower white matter integrity in caudate nucleus and greater perseverative errors. (PMID:22053977)
• Data indicate that armadillo repeat protein ARVCF interacts with the splicing factors the splicing factor SRSF1 (SF2/ASF), the RNA helicase p68 (DDX5), and the heterogeneous nuclear ribonucleoprotein hnRNP H2. (PMID:24644279)
• Carriage of the minor allele at rs2518824 in the armadillo repeat gene deleted in velocardiofacial syndrome (ARVCF) gene was associated with white matter abnormality. (PMID:24819575)
• observed ARVCF-dependent changes in small GTPase (mainly RhoA) activity in lung cancer cells. We confirmed that ARVCF plays an important role in the malignant phenotype (PMID:25683624)
• p53-induced ARVCF modulates the splicing landscape and supports the tumor suppressive function of p53. (PMID:31827232)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	arvcfb	ENSDARG00000061688
danio_rerio	arvcfa	ENSDARG00000074329
mus_musculus	Arvcf	ENSMUSG00000118669
rattus_norvegicus	Arvcf	ENSRNOG00000001888

Paralogs (6): PKP2 (ENSG00000057294), PKP1 (ENSG00000081277), PKP4 (ENSG00000144283), CTNND2 (ENSG00000169862), PKP3 (ENSG00000184363), CTNND1 (ENSG00000198561)

Protein

Protein identifiers

Splicing regulator ARVCF — O00192 (reviewed: O00192)

Alternative names: Armadillo repeat protein deleted in velo-cardio-facial syndrome

All UniProt accessions (3): O00192, C9JJX6, E9PDC3

UniProt curated annotations — full annotation on UniProt →

Function. Contributes to the regulation of alternative splicing of pre-mRNAs.

Subunit / interactions. Component of a ribonucleoprotein complex containing mRNAs and RNA-binding proteins including DDX5, HNRNPH2 and SRSF1 as well as ARVCF. Interacts (via the extreme C-terminus) with FRMPD2 (via the PDZ 2 domain). Interacts with CCDC85B.

Subcellular location. Cell junction. Adherens junction. Nucleus. Cytoplasm.

Tissue specificity. Found in all the examined tissues including heart, brain, liver and kidney. Found at low level in lung. Expressed in dermal connective tissue, salivary gland duct and in the corneal layer (at protein level). Expressed in arrector pili muscle (at protein level). High levels detected in epithelial cells with lower levels found in fibroblasts and T lymphocytes.

Similarity. Belongs to the beta-catenin family.

Isoforms (2)

UniProt ID	Names	Canonical?
O00192-1	Long	yes
O00192-2	Short

RefSeq proteins (2): NP_001397768, NP_001661* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000225	Armadillo	Repeat
IPR011989	ARM-like	Homologous_superfamily
IPR016024	ARM-type_fold	Homologous_superfamily
IPR028435	Plakophilin/d_Catenin	Family

Pfam: PF00514

UniProt features (46 total): modified residue 14, repeat 10, sequence variant 7, region of interest 6, compositionally biased region 5, chain 1, coiled-coil region 1, short sequence motif 1, splice variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O00192-F1	65.73	0.41

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 (14): 102, 104, 170, 267, 332, 335, 343, 345, 606, 642, 864, 871, 872, 915

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 397 (showing top): GSE45365_CTRL_VS_MCMV_INFECTION_NK_CELL_UP, TGGTGCT_MIR29A_MIR29B_MIR29C, TGCGCANK_UNKNOWN, CCAWYNNGAAR_UNKNOWN, BASSO_B_LYMPHOCYTE_NETWORK, STARK_PREFRONTAL_CORTEX_22Q11_DELETION_DN, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_UP, GOBP_CELL_CELL_ADHESION, KOYAMA_SEMA3B_TARGETS_UP, DOANE_RESPONSE_TO_ANDROGEN_DN, GOBP_RNA_SPLICING, AACTTT_UNKNOWN, MORF_PDPK1, E12_Q6

GO Biological Process (4): mRNA processing (GO:0006397), cell adhesion (GO:0007155), RNA splicing (GO:0008380), cell-cell adhesion (GO:0098609)

GO Molecular Function (2): cadherin binding (GO:0045296), protein binding (GO:0005515)

GO Cellular Component (5): nucleus (GO:0005634), cytoplasm (GO:0005737), plasma membrane (GO:0005886), adherens junction (GO:0005912), anchoring junction (GO:0070161)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
RNA processing	2
mRNA metabolic process	1
cellular process	1
cell adhesion	1
cell adhesion molecule binding	1
binding	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
cellular anatomical structure	1
membrane	1
cell periphery	1
cell-cell junction	1
cell junction	1

Protein interactions and networks

STRING

1158 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ARVCF	COMT	P21964	895
ARVCF	TXNRD2	Q9NNW7	854
ARVCF	FRMPD2	Q68DX3	755
ARVCF	ERBIN	Q96RT1	733
ARVCF	ATP6V1E1	P36543	704
ARVCF	CDH17	Q12864	684
ARVCF	GP1BB	P13224	675
ARVCF	TANGO2	Q6ICL3	665
ARVCF	TJP2	Q9UDY2	658
ARVCF	LRRC7	Q96NW7	609
ARVCF	GNB1L	Q9BYB4	584
ARVCF	TRMT2A	Q8IZ69	533
ARVCF	CDH1	P12830	530
ARVCF	PKP4	Q99569	517
ARVCF	ZDHHC8	Q9ULC8	512

IntAct

163 interactions, top by confidence:

A	B	Type	Score
TAX1BP3	ARVCF	psi-mi:“MI:0914”(association)	0.690
ARVCF	TAX1BP3	psi-mi:“MI:0407”(direct interaction)	0.690
ERBIN	ARVCF	psi-mi:“MI:0915”(physical association)	0.610
ARVCF	ERBIN	psi-mi:“MI:0407”(direct interaction)	0.610
GJB7	PALM3	psi-mi:“MI:0914”(association)	0.530
S1PR2	PALM3	psi-mi:“MI:0914”(association)	0.530
CDH8	ARVCF	psi-mi:“MI:0914”(association)	0.530
SCML1	ARVCF	psi-mi:“MI:0914”(association)	0.530
ARVCF	PDZD2	psi-mi:“MI:0407”(direct interaction)	0.440
ARVCF	HTRA3	psi-mi:“MI:0407”(direct interaction)	0.440
ARVCF	MAGI2	psi-mi:“MI:0407”(direct interaction)	0.440
ARVCF	SCRIB	psi-mi:“MI:0407”(direct interaction)	0.440
ARVCF	SNX27	psi-mi:“MI:0407”(direct interaction)	0.440
ARVCF	SYNJ2BP	psi-mi:“MI:0407”(direct interaction)	0.440
ARVCF	PTPN3	psi-mi:“MI:0407”(direct interaction)	0.440
ARVCF	LRRC7	psi-mi:“MI:0407”(direct interaction)	0.440
ARVCF	DLG4	psi-mi:“MI:0407”(direct interaction)	0.440
ARVCF	TJP2	psi-mi:“MI:0407”(direct interaction)	0.440
ARVCF	DLG1	psi-mi:“MI:0407”(direct interaction)	0.440
ARVCF	TJP3	psi-mi:“MI:0407”(direct interaction)	0.440
ARVCF	SNTG1	psi-mi:“MI:0407”(direct interaction)	0.440
ARVCF	APBA1	psi-mi:“MI:0407”(direct interaction)	0.440
ARVCF	HTRA1	psi-mi:“MI:0407”(direct interaction)	0.440
ARVCF	GORASP2	psi-mi:“MI:0407”(direct interaction)	0.440

BioGRID (71): ARVCF (Affinity Capture-MS), ARVCF (Affinity Capture-MS), ARVCF (Proximity Label-MS), ARVCF (Proximity Label-MS), ARVCF (Affinity Capture-MS), ARVCF (Affinity Capture-MS), ARVCF (Affinity Capture-MS), ARVCF (Affinity Capture-MS), ARVCF (Affinity Capture-MS), ARVCF (Affinity Capture-MS), ARVCF (Affinity Capture-MS), ARVCF (Affinity Capture-MS), ARVCF (Affinity Capture-MS), ARVCF (Affinity Capture-MS), ARVCF (Affinity Capture-MS)

ESM2 similar proteins: A1A4I4, A1A5B6, A4D2P6, B2DCZ9, B4F7F3, O00192, O08773, O08874, O08908, O35465, O43566, O62683, O75808, O95049, P70268, P97492, Q0QWG9, Q12851, Q14164, Q14318, Q16512, Q16513, Q3B7U9, Q3KR56, Q3MII6, Q3UFB7, Q5FVC2, Q60875, Q61161, Q63433, Q63788, Q6P5Z2, Q6PFQ7, Q6V7V2, Q6ZT62, Q7Z5H3, Q865S3, Q8BWW9, Q8IYK8, Q8K045

Diamond homologs: B4F7F3, F1M7L9, O00192, O35116, O35927, O60716, P30999, P97350, P98203, Q08DQ0, Q13835, Q28161, Q68FH0, Q8AXM9, Q99569, Q99959, Q9CQ73, Q9QY23, Q9U308, Q9UQB3, Q9Y446, B0BF33, Q9C9A6, Q86V71, Q8NHA8, Q96N38, A0AUS0, A2ZLU6, C6L7U1, D1FP53, D1FP57, E4NKF8, O22193, O23225, O48700, O80742, O81902, P0C6E7, Q058P4, Q0DR28

SIGNOR signaling

7 interactions.

A	Effect	B	Mechanism
ARVCF	“up-regulates activity”	ERBIN	binding
ARVCF	“up-regulates quantity by stabilization”	CDH3	binding
ARVCF	“up-regulates quantity by stabilization”	CDH2	binding
ARVCF	“up-regulates quantity by stabilization”	CDH5	binding
ARVCF	“up-regulates quantity by stabilization”	CDH1	binding
TJP1	“up-regulates activity”	ARVCF	binding
TJP2	“down-regulates activity”	ARVCF	relocalization

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 118 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
Ras activation upon Ca2+ influx through NMDA receptor	5	35.7×	2e-05
Unblocking of NMDA receptors, glutamate binding and activation	5	34.0×	2e-05
Negative regulation of NMDA receptor-mediated neuronal transmission	5	34.0×	2e-05
Assembly and cell surface presentation of NMDA receptors	10	31.7×	9e-11
Dopamine Neurotransmitter Release Cycle	5	31.0×	3e-05
Long-term potentiation	5	29.7×	3e-05
Neurexins and neuroligins	11	27.1×	7e-11
Protein-protein interactions at synapses	7	23.2×	2e-06

GO biological processes:

GO term	Partners	Fold	FDR
establishment or maintenance of epithelial cell apical/basal polarity	11	58.6×	1e-14
receptor clustering	8	45.8×	1e-09
protein localization to synapse	6	42.2×	7e-07
regulation of postsynaptic membrane neurotransmitter receptor levels	7	31.8×	4e-07
cell-cell junction assembly	6	24.4×	2e-05
adherens junction organization	5	23.4×	1e-04
cell-cell adhesion mediated by cadherin	6	22.6×	2e-05
calcium-dependent cell-cell adhesion	5	22.1×	2e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	63
Likely pathogenic	2
Uncertain significance	228
Likely benign	23
Benign	59

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1330206	GRCh37/hg19 22q11.21(chr22:19036286-21208284)x1	Pathogenic
144516	GRCh38/hg38 22q11.21(chr22:18339130-20343532)x1	Pathogenic
146195	GRCh38/hg38 22q11.21(chr22:18339130-20354644)x3	Pathogenic
146314	GRCh38/hg38 22q11.21(chr22:18178957-20343532)x1	Pathogenic
146436	GRCh38/hg38 22q11.21(chr22:18932429-20324240)x3	Pathogenic
147671	GRCh38/hg38 22q11.21(chr22:18909459-20324240)x1	Pathogenic
148964	GRCh38/hg38 22q11.21(chr22:18907322-20324261)x3	Pathogenic
152384	GRCh38/hg38 22q11.21(chr22:18929315-20325138)x3	Pathogenic
153565	GRCh38/hg38 22q11.21(chr22:18929329-20325138)x1	Pathogenic
153666	GRCh38/hg38 22q11.21(chr22:18339130-20686726)x1	Pathogenic
153702	GRCh38/hg38 22q11.21(chr22:18929329-20324335)x1	Pathogenic
154479	GRCh38/hg38 22q11.21(chr22:18339130-20343532)x1	Pathogenic
155439	GRCh38/hg38 22q11.21(chr22:18929329-20325138)x3	Pathogenic
160932	GRCh38/hg38 22q11.21(chr22:18932429-20324240)x1	Pathogenic
160954	GRCh38/hg38 22q11.21(chr22:18339130-20343532)x3	Pathogenic
161049	GRCh38/hg38 22q11.21(chr22:18339130-20354644)x1	Pathogenic
161087	GRCh38/hg38 22q11.21(chr22:18339130-20343532)x1	Pathogenic
1710917	GRCh37/hg19 22q11.21(chr22:18916842-21465659)x1	Pathogenic
1807729	GRCh37/hg19 22q11.21(chr22:18916843-21033401)x1	Pathogenic
1807875	GRCh37/hg19 22q11.21(chr22:19647905-21153690)x1	Pathogenic
1808077	GRCh37/hg19 22q11.21(chr22:18648867-20311858)x3	Pathogenic
1808239	GRCh37/hg19 22q11.21(chr22:18916843-20311858)x1	Pathogenic
1808737	GRCh37/hg19 22q11.21(chr22:18916843-21075592)x1	Pathogenic
1808875	GRCh37/hg19 22q11.21(chr22:18644791-21041014)x1	Pathogenic
236379	Single allele	Pathogenic
253570	GRCh37/hg19 22q11.21(chr22:18894339-21032422)x3	Pathogenic
253589	GRCh37/hg19 22q11.21(chr22:18661724-21025713)x3	Pathogenic
253657	GRCh37/hg19 22q11.21(chr22:18894339-20255154)x1	Pathogenic
2684927	GRCh37/hg19 22q11.21(chr22:18916843-20716903)x3	Pathogenic
2685672	GRCh37/hg19 22q11.1-11.21(chr22:17832142-20945625)x1	Pathogenic

SpliceAI

4018 predictions. Top by Δscore:

Variant	Effect	Δscore
22:19971882:TTA:T	donor_loss	1.0000
22:19971883:TAC:T	donor_loss	1.0000
22:19971884:A:AC	donor_gain	1.0000
22:19971884:ACTT:A	donor_loss	1.0000
22:19971885:C:CG	donor_gain	1.0000
22:19971885:CTTT:C	donor_gain	1.0000
22:19971967:TCCGT:T	acceptor_gain	1.0000
22:19971968:CCGT:C	acceptor_gain	1.0000
22:19971968:CCGTC:C	acceptor_gain	1.0000
22:19971969:CGT:C	acceptor_gain	1.0000
22:19971969:CGTC:C	acceptor_gain	1.0000
22:19971972:C:CC	acceptor_gain	1.0000
22:19971973:T:G	acceptor_loss	1.0000
22:19972353:CTCA:C	donor_loss	1.0000
22:19972355:CA:C	donor_loss	1.0000
22:19972356:A:AG	donor_loss	1.0000
22:19972357:C:CG	donor_loss	1.0000
22:19972732:CTCA:C	donor_loss	1.0000
22:19972733:TCAC:T	donor_loss	1.0000
22:19972734:CA:C	donor_loss	1.0000
22:19972735:A:AC	donor_gain	1.0000
22:19972736:C:CC	donor_gain	1.0000
22:19972823:GCTGA:G	acceptor_loss	1.0000
22:19972824:CTGA:C	acceptor_gain	1.0000
22:19972824:CTGAC:C	acceptor_loss	1.0000
22:19972825:TGA:T	acceptor_gain	1.0000
22:19972826:GACTG:G	acceptor_loss	1.0000
22:19972827:AC:A	acceptor_loss	1.0000
22:19972828:C:CC	acceptor_gain	1.0000
22:19972828:CTG:C	acceptor_loss	1.0000

AlphaMissense

6150 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
22:19973675:A:G	L736P	1.000
22:19974131:A:G	L690P	1.000
22:19974133:G:C	N689K	1.000
22:19974133:G:T	N689K	1.000
22:19974135:T:C	N689D	1.000
22:19977547:A:C	Y580D	1.000
22:19977552:A:G	L578P	1.000
22:19977554:G:C	N577K	1.000
22:19977554:G:T	N577K	1.000
22:19977555:T:A	N577I	1.000
22:19977556:T:C	N577D	1.000
22:19977575:G:C	N570K	1.000
22:19977575:G:T	N570K	1.000
22:19978037:A:G	L540P	1.000
22:19978066:G:C	S530R	1.000
22:19978066:G:T	S530R	1.000
22:19978068:T:G	S530R	1.000
22:19978072:A:C	N528K	1.000
22:19978072:A:T	N528K	1.000
22:19978074:T:C	N528D	1.000
22:19978075:C:A	R527S	1.000
22:19978075:C:G	R527S	1.000
22:19978897:C:A	R527M	1.000
22:19978897:C:G	R527T	1.000
22:19978900:A:G	L526P	1.000
22:19978906:C:T	G524D	1.000
22:19978907:C:G	G524R	1.000
22:19979043:C:A	K478N	1.000
22:19979043:C:G	K478N	1.000
22:19979065:A:G	L471P	1.000

dbSNP variants (sampled 300 via entrez): RS1000022300 (22:20015424 G>A,T), RS1000080644 (22:19975376 T>C), RS1000082916 (22:20010104 C>A,T), RS1000092855 (22:20016541 G>A,C,T), RS1000111847 (22:19983940 G>A,C), RS1000126313 (22:19984939 C>T), RS1000144429 (22:19983582 C>A), RS1000193986 (22:19971065 C>A,G,T), RS1000242766 (22:19985143 G>C), RS1000292738 (22:19971219 G>A), RS1000373379 (22:19966222 G>A), RS1000385878 (22:19987850 G>A), RS1000426668 (22:19980263 C>T), RS1000469413 (22:19983933 G>T), RS1000548929 (22:20013946 C>T)

Disease associations

OMIM: gene MIM:602269 | disease phenotypes: MIM:181500, MIM:188400, MIM:128600, MIM:209850, MIM:608363

GenCC curated gene-disease

Mondo (14): schizophrenia (MONDO:0005090), DiGeorge syndrome (MONDO:0008564), dilated cardiomyopathy (MONDO:0005021), long QT syndrome (MONDO:0002442), autism spectrum disorder (MONDO:0005258), congenital heart disease (MONDO:0005453), leukopenia (MONDO:0003785), normocytic anemia (MONDO:0004139), flatfoot (MONDO:0005293), ear malformation (MONDO:0007500), attention deficit-hyperactivity disorder (MONDO:0007743), autism (MONDO:0005260), chromosome 22q11.2 microduplication syndrome (MONDO:0012020), microcephaly (MONDO:0001149)

Orphanet (5): 22q11.2 deletion syndrome (Orphanet:567), Dilated cardiomyopathy (Orphanet:217604), 22q11.2 duplication syndrome (Orphanet:1727), NON RARE IN EUROPE: Schizophrenia (Orphanet:3140), NON RARE IN EUROPE: Autism (Orphanet:106)

HPO phenotypes

131 total (30 of 131 shown, HPO-id order):

HPO	Term
HP:0000023	Inguinal hernia
HP:0000028	Cryptorchidism
HP:0000047	Hypospadias
HP:0000076	Vesicoureteral reflux
HP:0000089	Renal hypoplasia
HP:0000113	Polycystic kidney dysplasia
HP:0000130	Abnormality of the uterus
HP:0000160	Narrow mouth
HP:0000164	Abnormality of the dentition
HP:0000175	Cleft palate
HP:0000238	Hydrocephalus
HP:0000252	Microcephaly
HP:0000262	Turricephaly
HP:0000272	Malar flattening
HP:0000276	Long face
HP:0000286	Epicanthus
HP:0000316	Hypertelorism
HP:0000322	Short philtrum
HP:0000343	Long philtrum
HP:0000347	Micrognathia
HP:0000365	Hearing impairment
HP:0000369	Low-set ears
HP:0000385	Small earlobe
HP:0000389	Chronic otitis media
HP:0000396	Overfolded helix
HP:0000405	Conductive hearing impairment
HP:0000414	Bulbous nose
HP:0000426	Prominent nasal bridge
HP:0000431	Wide nasal bridge
HP:0000453	Choanal atresia

GWAS associations

29 associations (top):

Study	Trait	p-value
GCST001337_55	Platelet count	3.000000e-08
GCST004278_17	Pulse pressure	6.000000e-12
GCST004603_148	Platelet count	1.000000e-11
GCST004610_101	White blood cell count	9.000000e-11
GCST004625_194	Monocyte count	1.000000e-09
GCST004627_112	Lymphocyte count	1.000000e-10
GCST004775_13	Pulse pressure	4.000000e-07
GCST004775_46	Pulse pressure	1.000000e-13
GCST005667_44	Central corneal thickness	3.000000e-09
GCST006434_1	Systolic blood pressure x alcohol consumption interaction (2df test)	3.000000e-08
GCST007096_90	Pulse pressure	3.000000e-09
GCST007099_76	Systolic blood pressure	1.000000e-06
GCST007267_163	Systolic blood pressure	8.000000e-09
GCST007269_146	Pulse pressure	4.000000e-14
GCST007703_120	Systolic blood pressure	3.000000e-07
GCST007705_19	Pulse pressure	2.000000e-10
GCST007705_28	Pulse pressure	1.000000e-06
GCST007705_42	Pulse pressure	4.000000e-07
GCST007926_1	Medication use (antihypertensives)	4.000000e-09
GCST007929_104	Medication use (calcium channel blockers)	5.000000e-08
GCST90000025_702	Appendicular lean mass	5.000000e-14
GCST90000654_73	Central corneal thickness	3.000000e-11
GCST90002388_596	Lymphocyte count	2.000000e-21
GCST90002393_583	Monocyte count	8.000000e-18
GCST90002398_74	Neutrophil count	1.000000e-09
GCST90002400_499	Plateletcrit	8.000000e-26
GCST90002401_343	Platelet distribution width	7.000000e-17
GCST90002402_641	Platelet count	1.000000e-21
GCST90002407_191	White blood cell count	6.000000e-22

EFO canonical traits (13, from GWAS)

EFO ID	Trait name
EFO:0004309	platelet count
EFO:0005763	pulse pressure measurement
EFO:0005091	monocyte count
EFO:0004587	lymphocyte count
EFO:0005213	central corneal thickness
EFO:0004329	alcohol drinking
EFO:0006335	systolic blood pressure
EFO:0009927	Antihypertensive use measurement
EFO:0009930	Calcium channel blocker use measurement
EFO:0004980	appendicular lean mass
EFO:0004833	neutrophil count
EFO:0007985	platelet crit
EFO:0007984	platelet component distribution width

MeSH disease descriptors (9)

Descriptor	Name	Tree numbers
D001321	Autistic Disorder	F03.625.164.113.500
D002311	Cardiomyopathy, Dilated	C14.280.195.160; C14.280.238.070; C16.320.488.750
D004062	DiGeorge Syndrome	C05.660.207.103.500; C14.240.400.021.500; C14.280.400.044.500; C15.604.451.249.500; C16.131.077.019.500; C16.131.240.400.021.500; C16.131.260.019.500; C16.131.482.249.500; C16.131.621.207.103.500; C16.320.180.019.500; C19.642.482.500.500
D005413	Flatfoot	C05.330.488.655.250; C05.330.495.681.250; C05.660.585.512.380.813.250; C16.131.621.585.512.500.681.250
D006330	Heart Defects, Congenital	C14.240.400; C14.280.400; C16.131.240.400
D007970	Leukopenia	C15.378.243.750; C15.378.553.546
D008133	Long QT Syndrome	C14.280.067.565; C14.280.123.625; C16.131.240.400.715; C23.550.073.547
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500
C567224	Chromosome 22q11.2 Microduplication Syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB variants

5 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs165599	ARVCF, COMT	3	2.75	2	risperidone;bupropion
rs165728	ARVCF, COMT		0.00	0
rs174699	ARVCF, COMT		0.00	0
rs9332377	ARVCF, COMT	3	2.75	2	cisplatin
rs165815	ARVCF		0.00	0

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
methacrylaldehyde	increases expression, increases oxidation, increases abundance, affects cotreatment	2
Acetaminophen	increases expression	2
Acrolein	affects cotreatment, increases expression, increases oxidation, increases abundance	2
Benzo(a)pyrene	increases expression, increases methylation	2
Estradiol	affects expression, affects cotreatment, decreases expression	2
Ozone	affects cotreatment, increases expression, increases oxidation, increases abundance	2
Rotenone	decreases expression	2
Tobacco Smoke Pollution	decreases expression	2
Aflatoxin B1	increases expression	2
FR900359	affects phosphorylation	1
bufotalin	increases expression	1
methyleugenol	increases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	increases oxidation, increases abundance, affects cotreatment, increases expression	1
propionaldehyde	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
sodium arsenite	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
nutlin 3	increases expression, affects cotreatment	1
abrine	increases expression	1
eprenetapopt	affects expression, affects reaction	1
jinfukang	affects cotreatment, increases expression	1
Sunitinib	decreases expression	1
Fulvestrant	increases methylation	1
Air Pollutants	affects cotreatment, increases abundance, increases expression, increases oxidation	1
Caffeine	affects phosphorylation	1
Camptothecin	increases expression	1
Cisplatin	affects cotreatment, increases expression	1
Dactinomycin	affects cotreatment, increases expression	1
N-Nitrosopyrrolidine	increases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
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
NCT00176436	PHASE4	COMPLETED	Atomoxetine for Treatment of Weight Gain in Olanzapine or Clozapine Patients
NCT00177008	PHASE4	COMPLETED	Aripiprazole for the Treatment of Schizophrenia With Co-Morbid Social Anxiety