PACS2

Summary

PACS2 (phosphofurin acidic cluster sorting protein 2, HGNC:23794) is a protein-coding gene on chromosome 14q32.33, encoding Phosphofurin acidic cluster sorting protein 2 (Q86VP3). Multifunctional sorting protein that controls the endoplasmic reticulum (ER)-mitochondria communication, including the apposition of mitochondria with the ER and ER homeostasis.

Predicted to enable transmembrane transporter binding activity. Involved in endoplasmic reticulum calcium ion homeostasis; mitochondrion-endoplasmic reticulum membrane tethering; and protein localization to plasma membrane. Acts upstream of or within protein localization to phagophore assembly site. Located in endoplasmic reticulum and mitochondrion. Implicated in developmental and epileptic encephalopathy 66.

Source: NCBI Gene 23241 — RefSeq curated summary.

At a glance

• Gene–disease (curated): genetic developmental and epileptic encephalopathy (Definitive, ClinGen) — +1 more curated relationship
• Clinical variants (ClinVar): 1,229 total — 1 likely-pathogenic
• Phenotypes (HPO): 89
• Dosage sensitivity (ClinGen): haploinsufficiency no evidence, triplosensitivity no evidence
• MANE Select transcript: NM_001100913

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:23794
Approved symbol	PACS2
Name	phosphofurin acidic cluster sorting protein 2
Location	14q32.33
Locus type	gene with protein product
Status	Approved
Aliases	KIAA0602
Ensembl gene	ENSG00000179364
Ensembl biotype	protein_coding
OMIM	610423
Entrez	23241

Gene structure

Transcript identifiers

Ensembl transcripts: 48 — 32 protein_coding, 13 retained_intron, 2 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000325438, ENST00000430725, ENST00000447393, ENST00000546915, ENST00000547217, ENST00000547903, ENST00000548265, ENST00000548796, ENST00000549030, ENST00000550790, ENST00000551692, ENST00000551743, ENST00000551801, ENST00000552138, ENST00000685365, ENST00000686173, ENST00000686461, ENST00000687967, ENST00000689240, ENST00000693530, ENST00000858624, ENST00000858625, ENST00000858626, ENST00000858627, ENST00000858628, ENST00000858629, ENST00000858630, ENST00000858631, ENST00000858632, ENST00000858633, ENST00000858634, ENST00000929375, ENST00000929376, ENST00000929377, ENST00000929378, ENST00000929379, ENST00000929380, ENST00000929381, ENST00000929382, ENST00000967339, ENST00000967340, ENST00000967341, ENST00000967342, ENST00000967343, ENST00000967344, ENST00000967345, ENST00000967346, ENST00000967347

RefSeq mRNA: 3 — MANE Select: NM_001100913 NM_001100913, NM_001243127, NM_015197

CCDS: CCDS32168, CCDS45178, CCDS58339

Canonical transcript exons

ENST00000447393 — 25 exons

Exon	Start	End
ENSE00001287264	105355052	105355177
ENSE00001287267	105352378	105352467
ENSE00001287290	105394554	105398147
ENSE00001287295	105314748	105315037
ENSE00001763640	105381914	105382058
ENSE00001773622	105385685	105385717
ENSE00003475443	105368074	105368147
ENSE00003476305	105382477	105382581
ENSE00003477025	105368459	105368539
ENSE00003478234	105389961	105390003
ENSE00003505083	105392619	105392845
ENSE00003521380	105383359	105383513
ENSE00003522472	105367213	105367375
ENSE00003531766	105348493	105348580
ENSE00003564496	105393222	105393335
ENSE00003564770	105391207	105391249
ENSE00003572615	105382807	105382913
ENSE00003598075	105376768	105376925
ENSE00003630355	105379739	105379829
ENSE00003634396	105391631	105391766
ENSE00003645713	105380080	105380154
ENSE00003675622	105384879	105384987
ENSE00003680528	105380957	105381099
ENSE00003687806	105369841	105369900
ENSE00003693885	105384353	105384463

Expression profiles

Bgee: expression breadth ubiquitous, 281 present calls, max score 99.09.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 19.4828 / max 276.1446, expressed in 1799 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
141885	11.5657	1770
141884	7.3129	1715
141883	0.4371	206
141886	0.1334	52
141891	0.0337	15

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
C1 segment of cervical spinal cord	UBERON:0006469	99.09	gold quality
spinal cord	UBERON:0002240	98.55	gold quality
right hemisphere of cerebellum	UBERON:0014890	98.24	gold quality
sural nerve	UBERON:0015488	98.00	gold quality
cerebellar hemisphere	UBERON:0002245	97.87	gold quality
cerebellar cortex	UBERON:0002129	97.77	gold quality
tibial nerve	UBERON:0001323	97.42	gold quality
inferior vagus X ganglion	UBERON:0005363	97.35	gold quality
subthalamic nucleus	UBERON:0001906	97.10	gold quality
hindlimb stylopod muscle	UBERON:0004252	97.04	gold quality
right frontal lobe	UBERON:0002810	96.97	gold quality
putamen	UBERON:0001874	96.62	gold quality
cerebellum	UBERON:0002037	96.62	gold quality
amygdala	UBERON:0001876	96.49	gold quality
apex of heart	UBERON:0002098	96.43	gold quality
nucleus accumbens	UBERON:0001882	96.41	gold quality
ventral tegmental area	UBERON:0002691	96.31	gold quality
cortical plate	UBERON:0005343	96.31	gold quality
ganglionic eminence	UBERON:0004023	96.27	gold quality
substantia nigra pars reticulata	UBERON:0001966	96.24	gold quality
substantia nigra	UBERON:0002038	96.19	gold quality
midbrain	UBERON:0001891	96.18	gold quality
caudate nucleus	UBERON:0001873	96.15	gold quality
gastrocnemius	UBERON:0001388	95.99	gold quality
lateral globus pallidus	UBERON:0002476	95.93	gold quality
adenohypophysis	UBERON:0002196	95.85	gold quality
hypothalamus	UBERON:0001898	95.83	gold quality
substantia nigra pars compacta	UBERON:0001965	95.73	gold quality
muscle of leg	UBERON:0001383	95.69	gold quality
corpus callosum	UBERON:0002336	95.68	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.95

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

171 targeting PACS2, 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-4283	100.00	66.42	2097
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-1184	99.99	68.19	1458
HSA-MIR-499A-5P	99.98	70.79	1323
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-LET-7G-5P	99.98	72.37	1784
HSA-LET-7I-5P	99.98	72.37	1788
HSA-MIR-98-5P	99.98	72.33	1787
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-485-3P	99.98	70.68	1585
HSA-MIR-539-3P	99.98	70.74	1616
HSA-MIR-4650-5P	99.98	64.69	999
HSA-MIR-6888-3P	99.97	65.95	1170
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-LET-7D-5P	99.96	71.76	1632
HSA-MIR-4458	99.96	71.64	1650
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-4725-3P	99.96	69.53	2520

Functional genomics

ClinGen dosage: haploinsufficiency 0 (no evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 20)

• subcellular localization and function of polycystin-2 are directed by phosphofurin acidic cluster sorting protein (PACS)-1 and PACS-2 (PMID:15692563)
• PACS-2 as a novel sorting protein that links the endoplasmic reticulum (ER)-mitochondria axis to ER homeostasis (PMID:15692567)
• PACS-2 is required for Nef action and sorting of itinerant membrane cargo in the TGN/endosomal system (PMID:18296443)
• the phosphorylation state of the calnexin cytosolic domain and its interaction with PACS-2 sort the chaperone between domains of the ER and the plasma membrane (PMID:18417615)
• Results identify PACS-2 as an essential TRAIL effector, and show that Akt cooperates with 14-3-3 to regulate the homeostatic and apoptotic properties of PACS-2 that mediate TRAIL action. (PMID:19481529)
• The sites on Nef and the PACS proteins required for their interaction, are identified. (PMID:22496420)
• Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) protein-induced lysosomal translocation of proapoptotic effectors is mediated by phosphofurin acidic cluster sorting protein-2. (PMID:22645134)
• cIAPs constitutively downregulate PACS-2 by polyubiquitination and proteasomal degradation, thereby restraining TRAIL-induced killing of liver cancer cells (PMID:24633224)
• Protein adaptation and the expanding roles of the PACS1 and PACS2 proteins in tissue homeostasis and disease has been summarized. (Review) (PMID:28476937)
• Missense Mutation in PACS2 gene is associated with Neurodevelopmental Disorders. (PMID:28867141)
• These findings support the causality of this recurrent de novo PACS2 heterozygous missense in Developmental and epileptic encephalopathies with facial dysmorphim and cerebellar dysgenesis. (PMID:29656858)
• Insulin acutely regulates SIRT1 activity by triggering recruitment of PACS-2 and DBC1 to the SIRT1 N terminal region creating a regulatory hub. (PMID:30415949)
• These findings confirmed our previous research and expanded the mutational spectrum of WEE2, making it a potential genetic diagnostic marker for those suffering from human fertilization failure. (PMID:30684285)
• the role of the multifunctional Mitochondria-associated endoplasmic reticulum membrane protein phosphofurin acidic cluster sorting protein 2 (PACS-2) in regulating Vascular Smooth Muscle Cell survival following a challenge by atherogenic lipids. (PMID:31242668)
• Clinical variations of epileptic syndrome associated with PACS2 variant. (PMID:33243487)
• Coloboma may be a shared feature in a spectrum of disorders caused by mutations in the WDR37-PACS1-PACS2 axis. (PMID:33369122)
• [Early infantile epileptic encephalopathy caused by PACS2 gene variation: three cases report and literature review]. (PMID:34405643)
• Knockdown of circ_0002194 protects against oxidized low-density lipoprotein-induced cell damage via the regulation of the miR-637/PACS2 axis in human vascular endothelial cells. (PMID:35951762)
• MAPK1 Mediates MAM Disruption and Mitochondrial Dysfunction in Diabetic Kidney Disease via the PACS-2-Dependent Mechanism. (PMID:38169625)
• Characteristics of Developmental and Epileptic Encephalopathy Associated with PACS2 p.Glu209Lys Pathogenic Variant-Our Experience and Systematic Review of the Literature. (PMID:38540691)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	pacs2	ENSDARG00000078185
mus_musculus	Pacs2	ENSMUSG00000021143
rattus_norvegicus	Pacs2	ENSRNOG00000014744
drosophila_melanogaster	KrT95D	FBGN0020647
caenorhabditis_elegans		WBGENE00044077

Paralogs (1): PACS1 (ENSG00000175115)

Protein

Protein identifiers

Phosphofurin acidic cluster sorting protein 2 — Q86VP3 (reviewed: Q86VP3)

Alternative names: PACS1-like protein

All UniProt accessions (4): Q86VP3, A0A8I5KQA5, A0A8I5QJV1, F8VW41

UniProt curated annotations — full annotation on UniProt →

Function. Multifunctional sorting protein that controls the endoplasmic reticulum (ER)-mitochondria communication, including the apposition of mitochondria with the ER and ER homeostasis. In addition, in response to apoptotic inducer, translocates BIB to mitochondria, which initiates a sequence of events including the formation of mitochondrial truncated BID, the release of cytochrome c, the activation of caspase-3 thereby causing cell death. May also be involved in ion channel trafficking, directing acidic cluster-containing ion channels to distinct subcellular compartments.

Subunit / interactions. Interacts with BID and PKD2. Interacts with SIRT1. Interacts with HDAC1. Interacts with TRPV1. Interacts with WDR37. (Microbial infection) Interacts with HIV-1 Nef.

Subcellular location. Endoplasmic reticulum. Mitochondrion.

Tissue specificity. Broadly expressed, with greatest levels in skeletal muscle followed by heart, brain, pancreas and testis.

Disease relevance. Developmental and epileptic encephalopathy 66 (DEE66) [MIM:618067] 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. DEE66 is an autosomal dominant form characterized by onset of seizures in first days or weeks of life. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the PACS family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q86VP3-1	1	yes
Q86VP3-2	2
Q86VP3-4	4

RefSeq proteins (3): NP_001094383, NP_001230056, NP_056012 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR019381	PACS1/2_C	Domain
IPR057541	PACS1/2_N	Domain

Pfam: PF10254, PF25332

UniProt features (23 total): modified residue 5, splice variant 4, sequence conflict 4, region of interest 3, sequence variant 3, compositionally biased region 3, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q86VP3-F1	67.10	0.36

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): 691, 694, 390, 416, 453

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 306 (showing top): GCM_MAP4K4, GOBP_VACUOLE_ORGANIZATION, MODULE_418, GOBP_PROTEIN_LOCALIZATION_TO_CELL_PERIPHERY, GOBP_MACROAUTOPHAGY, GOBP_MEMBRANE_DOCKING, GOBP_ORGANELLE_ASSEMBLY, GOBP_ENDOPLASMIC_RETICULUM_CALCIUM_ION_HOMEOSTASIS, GOBP_MONOATOMIC_ION_HOMEOSTASIS, GCM_NF2, LIU_CMYB_TARGETS_UP, DELASERNA_MYOD_TARGETS_UP, GOBP_LOCALIZATION_WITHIN_MEMBRANE, GOBP_ORGANELLE_LOCALIZATION, MODULE_455

GO Biological Process (6): autophagosome assembly (GO:0000045), apoptotic process (GO:0006915), endoplasmic reticulum calcium ion homeostasis (GO:0032469), protein localization to phagophore assembly site (GO:0034497), protein localization to plasma membrane (GO:0072659), obsolete mitochondrion-endoplasmic reticulum membrane tethering (GO:1990456)

GO Molecular Function (2): transmembrane transporter binding (GO:0044325), protein binding (GO:0005515)

GO Cellular Component (2): mitochondrion (GO:0005739), endoplasmic reticulum (GO:0005783)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cytoplasm	2
intracellular membrane-bounded organelle	2
Atg12 activating enzyme activity	1
protein-phosphatidylethanolamide deconjugating activity	1
Atg12 conjugating enzyme activity	1
Atg12 ligase activity	1
organelle assembly	1
Atg1/ULK1 kinase complex assembly	1
autophagosome organization	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
endoplasmic reticulum	1
intracellular calcium ion homeostasis	1
autophagosome assembly	1
intracellular protein localization	1
protein localization to membrane	1
protein localization to cell periphery	1
protein binding	1
binding	1
endomembrane system	1

Protein interactions and networks

STRING

872 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PACS2	BCAP31	P51572	991
PACS2	CANX	P27824	948
PACS2	MFN2	O95140	936
PACS2	RMDN3	Q96TC7	821
PACS2	PKD2	Q13563	789
PACS2	ITPR3	Q14573	781
PACS2	HSPA9	P30036	780
PACS2	VAPB	O95292	768
PACS2	ITPR1	Q14643	763
PACS2	BCL2L11	O43521	726
PACS2	SIGMAR1	Q99720	681
PACS2	ARF6	P26438	667
PACS2	CSNK2A1	P19138	666
PACS2	ATG14	Q6ZNE5	636
PACS2	VDAC1	P21796	614

IntAct

27 interactions, top by confidence:

A	B	Type	Score
LRRC46	TFPT	psi-mi:“MI:0914”(association)	0.640
YWHAZ	PACS2	psi-mi:“MI:0914”(association)	0.640
YWHAH	PLEKHG3	psi-mi:“MI:0914”(association)	0.610
YWHAQ	IGLC7	psi-mi:“MI:0914”(association)	0.530
WDR37	CLUH	psi-mi:“MI:0914”(association)	0.530
PACS2	SFN	psi-mi:“MI:0915”(physical association)	0.400
NBPF15	PACS2	psi-mi:“MI:0915”(physical association)	0.370
Mad2l1bp	ARHGAP32	psi-mi:“MI:0914”(association)	0.350
ASPM		psi-mi:“MI:0914”(association)	0.350
RSRP1	DMWD	psi-mi:“MI:0914”(association)	0.350
Wipi2	MACF1	psi-mi:“MI:0914”(association)	0.350
ANAPC15		psi-mi:“MI:0914”(association)	0.350
TINF2	SIRT2	psi-mi:“MI:0914”(association)	0.350
YWHAB	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
YWHAG	C1orf226	psi-mi:“MI:0914”(association)	0.350
YWHAZ	SPEG	psi-mi:“MI:0914”(association)	0.350
M		psi-mi:“MI:0914”(association)	0.350
YWHAB	FOXO6	psi-mi:“MI:0914”(association)	0.350
YWHAG	FOXO6	psi-mi:“MI:0914”(association)	0.350
YWHAQ	FOXO6	psi-mi:“MI:0914”(association)	0.350
YWHAH	FOXO6	psi-mi:“MI:0914”(association)	0.350
YWHAZ	HECTD4	psi-mi:“MI:0914”(association)	0.350
LEAP2	PACS1	psi-mi:“MI:0914”(association)	0.350
CREB3L2	PLEKHG3	psi-mi:“MI:0914”(association)	0.350

BioGRID (35): PACS2 (Affinity Capture-MS), PACS2 (Affinity Capture-MS), PACS2 (Affinity Capture-MS), PACS2 (Affinity Capture-MS), PACS2 (Affinity Capture-MS), PACS2 (Affinity Capture-MS), PACS2 (Affinity Capture-MS), PACS2 (Affinity Capture-MS), PACS2 (Affinity Capture-MS), PACS2 (Affinity Capture-MS), PACS2 (Proximity Label-MS), PACS2 (Reconstituted Complex), PACS2 (Positive Genetic), PACS2 (Affinity Capture-MS), PACS2 (Affinity Capture-MS)

ESM2 similar proteins: A6QR40, A7UA95, B0V207, E7F221, O08764, O94810, P70218, Q05AA6, Q08DJ7, Q09M05, Q13474, Q2HJJ0, Q3TJ91, Q3UFQ8, Q3UMR0, Q499U2, Q4U2V3, Q5FVC2, Q5PQM2, Q5REW9, Q5SQE2, Q5XHY1, Q60875, Q6F6B3, Q6NWA8, Q6P9Q4, Q6V7V2, Q7TQI7, Q80TR8, Q80YR2, Q86VP3, Q8BYZ7, Q8C6B2, Q8CDM8, Q8K2Z4, Q8N961, Q8ND23, Q96BJ8, Q96NW4, Q99M76

Diamond homologs: O88588, Q3V3Q7, Q6VY07, Q86VP3, Q8K212

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
BIRC2	“down-regulates quantity by destabilization”	PACS2	ubiquitination
BIRC2	“down-regulates quantity by destabilization”	PACS2	polyubiquitination
BIRC3	“down-regulates quantity by destabilization”	PACS2	polyubiquitination

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 31 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
Activation of BAD and translocation to mitochondria	6	285.5×	8e-13
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	6	251.9×	1e-12
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	6	251.9×	1e-12
Activation of BH3-only proteins	6	186.2×	8e-12
RHO GTPases activate PKNs	6	119.0×	1e-10
Intrinsic Pathway for Apoptosis	6	109.8×	2e-10
FOXO-mediated transcription	5	105.0×	9e-09
SARS-CoV-1-host interactions	6	65.9×	4e-09

GO biological processes:

GO term	Partners	Fold	FDR
intracellular protein localization	6	26.2×	2e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

1229 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	1
Uncertain significance	392
Likely benign	599
Benign	131

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
2844831	NM_001100913.3(PACS2):c.623C>G (p.Ser208Cys)	Likely pathogenic

SpliceAI

5646 predictions. Top by Δscore:

Variant	Effect	Δscore
14:105348578:CAGGT:C	donor_loss	1.0000
14:105348579:AGG:A	donor_loss	1.0000
14:105348580:GG:G	donor_loss	1.0000
14:105348581:G:A	donor_loss	1.0000
14:105348582:T:A	donor_loss	1.0000
14:105355046:CCACA:C	acceptor_loss	1.0000
14:105355050:A:AG	acceptor_gain	1.0000
14:105355050:AGTAT:A	acceptor_loss	1.0000
14:105355051:G:GA	acceptor_gain	1.0000
14:105355051:GT:G	acceptor_gain	1.0000
14:105355051:GTAT:G	acceptor_gain	1.0000
14:105355051:GTATC:G	acceptor_gain	1.0000
14:105355174:TGAGG:T	donor_loss	1.0000
14:105355176:AGG:A	donor_loss	1.0000
14:105355178:GTGA:G	donor_loss	1.0000
14:105355179:T:A	donor_loss	1.0000
14:105367372:ACGGG:A	donor_loss	1.0000
14:105367373:CGG:C	donor_gain	1.0000
14:105367374:GG:G	donor_gain	1.0000
14:105367374:GGG:G	donor_gain	1.0000
14:105367375:GG:G	donor_gain	1.0000
14:105367376:G:GG	donor_gain	1.0000
14:105368060:T:TA	acceptor_gain	1.0000
14:105368065:A:AG	acceptor_gain	1.0000
14:105368066:T:G	acceptor_gain	1.0000
14:105368069:CGCA:C	acceptor_loss	1.0000
14:105368070:GCAG:G	acceptor_loss	1.0000
14:105368072:A:AG	acceptor_gain	1.0000
14:105368072:A:C	acceptor_loss	1.0000
14:105368073:G:GC	acceptor_gain	1.0000

AlphaMissense

5948 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
14:105314989:T:C	L24P	1.000
14:105315000:T:A	W28R	1.000
14:105315000:T:C	W28R	1.000
14:105348519:T:C	L49P	1.000
14:105348570:T:A	V66D	1.000
14:105352394:T:C	L75P	1.000
14:105352451:T:C	L94P	1.000
14:105355086:T:A	L111H	1.000
14:105355086:T:C	L111P	1.000
14:105355098:T:C	L115P	1.000
14:105355104:G:C	R117P	1.000
14:105355107:G:C	R118T	1.000
14:105355108:A:C	R118S	1.000
14:105355108:A:T	R118S	1.000
14:105355109:A:G	K119E	1.000
14:105355111:G:C	K119N	1.000
14:105355111:G:T	K119N	1.000
14:105355136:G:C	G128R	1.000
14:105355137:G:A	G128D	1.000
14:105367315:A:C	S176R	1.000
14:105367317:C:A	S176R	1.000
14:105367317:C:G	S176R	1.000
14:105383477:T:A	W578R	1.000
14:105383477:T:C	W578R	1.000
14:105389995:T:C	F675L	1.000
14:105389997:T:A	F675L	1.000
14:105389997:T:G	F675L	1.000
14:105393297:T:C	L838P	1.000
14:105394589:T:C	F863L	1.000
14:105394591:C:A	F863L	1.000

dbSNP variants (sampled 300 via entrez): RS1000019252 (14:105342062 G>A,C), RS1000029395 (14:105312315 T>C), RS1000044446 (14:105351013 C>T), RS1000064351 (14:105345729 T>A,C), RS1000070576 (14:105318450 T>TTTTTG), RS1000089080 (14:105317966 G>A), RS1000102669 (14:105313581 G>A), RS1000137640 (14:105331805 T>C), RS1000198051 (14:105356333 G>A), RS1000202966 (14:105317701 G>A), RS1000225677 (14:105333039 C>T), RS1000317041 (14:105312659 C>T), RS1000357969 (14:105313820 GA>G), RS1000395586 (14:105351133 C>T), RS1000493482 (14:105361148 T>A,C)

Disease associations

OMIM: gene MIM:610423 | disease phenotypes: MIM:618067, MIM:308350

GenCC curated gene-disease

Disease	Classification	Inheritance
developmental and epileptic encephalopathy, 66	Strong	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
genetic developmental and epileptic encephalopathy	Definitive	AD

Mondo (4): developmental and epileptic encephalopathy, 66 (MONDO:0054845), intellectual disability (MONDO:0001071), developmental and epileptic encephalopathy, 1 (MONDO:0010632), cleft palate (MONDO:0016064)

Orphanet (2): Cleft palate (Orphanet:2014), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

89 total (30 of 89 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000028	Cryptorchidism
HP:0000154	Wide mouth
HP:0000219	Thin upper lip vermilion
HP:0000232	Everted lower lip vermilion
HP:0000252	Microcephaly
HP:0000280	Coarse facial features
HP:0000316	Hypertelorism
HP:0000348	High forehead
HP:0000431	Wide nasal bridge
HP:0000483	Astigmatism
HP:0000486	Strabismus
HP:0000494	Downslanted palpebral fissures
HP:0000504	Abnormality of vision
HP:0000508	Ptosis
HP:0000540	Hypermetropia
HP:0000545	Myopia
HP:0000546	Retinal degeneration
HP:0000639	Nystagmus
HP:0000648	Optic atrophy
HP:0000664	Synophrys
HP:0000668	Hypodontia
HP:0000675	Macrodontia of permanent maxillary central incisor
HP:0000687	Widely spaced teeth
HP:0000708	Atypical behavior
HP:0000717	Autism
HP:0000729	Autistic behavior
HP:0000733	Motor stereotypy
HP:0000750	Delayed speech and language development
HP:0001249	Intellectual disability

GWAS associations

0 associations (top):

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D002972	Cleft Palate	C05.500.460.185; C05.660.207.540.460.185; C07.320.440.185; C07.465.525.185; C07.650.500.460.185; C07.650.525.185; C16.131.621.207.540.460.185; C16.131.850.500.460.185; C16.131.850.525.185
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

29 total (human), top 29 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	increases methylation, affects methylation, decreases expression	3
Acetaminophen	decreases expression, increases expression	2
Tobacco Smoke Pollution	decreases expression, increases methylation	2
aristolochic acid I	decreases expression	1
afuresertib	increases expression	1
FR900359	affects phosphorylation	1
methylmercuric chloride	decreases expression	1
bisphenol A	decreases methylation	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
butyraldehyde	decreases expression	1
perfluorooctanoic acid	decreases expression	1
aflatoxin B2	decreases methylation	1
perfluorooctane sulfonic acid	decreases expression	1
perfluoro-n-nonanoic acid	decreases expression	1
perfluorohexanesulfonic acid	decreases expression	1
abrine	decreases expression	1
jinfukang	increases expression	1
Sunitinib	increases expression	1
Atrazine	increases expression	1
Caffeine	decreases phosphorylation	1
Dichlorodiphenyl Dichloroethylene	decreases expression	1
Doxorubicin	decreases expression	1
Homocysteine	increases expression	1
Lead	increases expression	1
Phthalic Acids	increases methylation	1
Rotenone	increases expression	1
Smoke	decreases expression	1
Valproic Acid	increases expression	1
Aflatoxin B1	decreases methylation	1

Cellosaurus cell lines

2 cell lines: 1 finite cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_C7P2	GM28610	Finite cell line	Female
CVCL_C7P6	GM28627	Transformed cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT02422056	PHASE4	COMPLETED	Acid Tranexamic Effectiveness in Reducing the Intraoperative Bleeding in Palatoplasty
NCT02915042	PHASE4	WITHDRAWN	Dexmedetomidine vs Placebo for Pediatric Cleft Palate Repair
NCT02953145	PHASE4	WITHDRAWN	The Use of Fibrin Sealant to Reduce Post Operative Pain in Cleft Palate Surgery
NCT03632044	PHASE4	ACTIVE_NOT_RECRUITING	Evaluation of Trigeminal Nerve Blockade
NCT06962306	PHASE4	RECRUITING	Optimizing Perioperative Analgesia to Lower Pain Following Cleft Palate Surgery
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT00098319	PHASE3	COMPLETED	Oral Cleft Prevention Trial in Brazil
NCT00397917	PHASE3	COMPLETED	Oral Cleft Prevention Program
NCT04928352	PHASE3	RECRUITING	Nebulized Bupivacaine Analgesia for Cleft Palate Repair
NCT04928391	PHASE3	COMPLETED	A Single Bolus of Dexmedetomidine Versus Normal Saline in Postoperative Agitation
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT00004639	PHASE2	COMPLETED	Cleft Palate Surgery and Speech Development
NCT00760006	PHASE2	COMPLETED	Preventing Complications in Cleft Palate Repair With Antibiotics
NCT01760330	PHASE2	WITHDRAWN	IV Acetaminophen in Children Undergoing Palatoplasty
NCT02350803	PHASE2	COMPLETED	Does Use of Rigid Fixation After Removing Distraction Osteogenesis Device Reduce the Relapse?
NCT03412474	PHASE2	COMPLETED	Suprazygomatic Block in Cleft Palate Surgery in Children
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT03479476	PHASE2/PHASE3	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome
NCT02616796	PHASE1/PHASE2	COMPLETED	Effects of Social Gaze Training on Brain and Behavior in Fragile X Syndrome
NCT06860672	EARLY_PHASE1	RECRUITING	Clinical Trial of the Dual Vector Base Editor for the Treatment of the CHD3-R1025W Mutation
NCT00597948	Not specified	COMPLETED	Healthy Lifestyles for People With Intellectual Disabilities
NCT01087320	Not specified	RECRUITING	Genome Medical Sequencing for Gene Discovery
NCT01652963	Not specified	UNKNOWN	Picture-based Computerised Assessment and Training of Cognitive Behaviour Therapy Skills
NCT01695395	Not specified	COMPLETED	Mental Health Care Provision for Adults With Intellectual Disability and a Mental Disorder
NCT01867554	Not specified	COMPLETED	Research and Characterization of New Genes Involved in Intellectual Disability
NCT01915381	Not specified	COMPLETED	Improving Adherence Healthy Lifestyle With a Smartphone Application Based on Adults With Intellectual Disabilities
NCT01988623	Not specified	COMPLETED	Pivotal Response Treatment for Individuals With Intellectual Disabilities
NCT02099773	Not specified	COMPLETED	Support Staff-client Interactions With Augmentative and Alternative Communication
NCT02136849	Not specified	COMPLETED	Inter-regional Project of the Great Western Exploration Approach for Exome Molecular Causes Severe Intellectual Disability Isolated or Syndromic