DIXDC1

Summary

DIXDC1 (DIX domain containing 1, HGNC:23695) is a protein-coding gene on chromosome 11q23.1, encoding Dixin (Q155Q3). Positive effector of the Wnt signaling pathway; activates WNT3A signaling via DVL2.

The protein encoded by this gene is a positive regulator of the Wnt signaling pathway. The encoded protein is found associated with gamma tubulin at the centrosome. Alternative splicing results in multiple transcript variants encoding different isoforms.

Source: NCBI Gene 85458 — RefSeq curated summary.

At a glance

• GWAS associations: 4
• Clinical variants (ClinVar): 54 total — 1 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 1
• MANE Select transcript: NM_001037954

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:23695
Approved symbol	DIXDC1
Name	DIX domain containing 1
Location	11q23.1
Locus type	gene with protein product
Status	Approved
Aliases	KIAA1735, Dixin
Ensembl gene	ENSG00000150764
Ensembl biotype	protein_coding
OMIM	610493
Entrez	85458

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 5 protein_coding, 5 retained_intron

ENST00000440460, ENST00000526418, ENST00000526500, ENST00000528399, ENST00000529225, ENST00000530645, ENST00000614104, ENST00000615255, ENST00000618522, ENST00000941466

RefSeq mRNA: 3 — MANE Select: NM_001037954 NM_001037954, NM_001278542, NM_033425

CCDS: CCDS60957, CCDS73381, CCDS73382

Canonical transcript exons

ENST00000440460 — 20 exons

Exon	Start	End
ENSE00001273645	111982339	111982487
ENSE00001788348	112018956	112022653
ENSE00003472487	111995403	111995564
ENSE00003488449	111968513	111968638
ENSE00003498368	112017777	112017885
ENSE00003505848	111974876	111974983
ENSE00003510806	111996080	111996146
ENSE00003545711	111992951	111993004
ENSE00003570441	111980737	111980849
ENSE00003576013	111992415	111992519
ENSE00003591637	111993669	111993740
ENSE00003604036	111985232	111985321
ENSE00003606059	111974023	111974254
ENSE00003629430	111995019	111995108
ENSE00003644192	111937343	111937559
ENSE00003672460	111964549	111964678
ENSE00003672957	112016691	112016796
ENSE00003674765	111993496	111993588
ENSE00003693755	111986871	111986924
ENSE00003787677	111989005	111989055

Expression profiles

Bgee: expression breadth ubiquitous, 283 present calls, max score 98.06.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 11.3644 / max 219.9159, expressed in 1522 samples.

FANTOM5 promoters (20 alternative TSS)

Promoter ID	TPM avg	Samples expressed
116673	3.8684	882
116667	1.7318	905
116669	1.6483	720
116672	1.4880	590
116664	0.5504	218
116677	0.3391	123
116671	0.3383	188
116679	0.3153	52
116678	0.2295	100
116670	0.2097	76

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
calcaneal tendon	UBERON:0003701	98.06	gold quality
blood vessel layer	UBERON:0004797	96.42	gold quality
inferior vagus X ganglion	UBERON:0005363	96.29	gold quality
corpus callosum	UBERON:0002336	96.04	gold quality
urethra	UBERON:0000057	95.32	gold quality
saphenous vein	UBERON:0007318	95.17	gold quality
superficial temporal artery	UBERON:0001614	94.08	gold quality
subthalamic nucleus	UBERON:0001906	93.52	gold quality
ventral tegmental area	UBERON:0002691	93.17	gold quality
synovial joint	UBERON:0002217	93.09	gold quality
mucosa of paranasal sinus	UBERON:0005030	93.03	gold quality
cerebellar cortex	UBERON:0002129	93.02	gold quality
cerebellar hemisphere	UBERON:0002245	93.02	gold quality
mucosa of stomach	UBERON:0001199	92.99	gold quality
cerebellum	UBERON:0002037	92.74	gold quality
superior vestibular nucleus	UBERON:0007227	92.73	gold quality
right coronary artery	UBERON:0001625	92.62	gold quality
trigeminal ganglion	UBERON:0001675	92.52	gold quality
cauda epididymis	UBERON:0004360	92.36	gold quality
cortical plate	UBERON:0005343	92.36	gold quality
cartilage tissue	UBERON:0002418	92.34	gold quality
adult organism	UBERON:0007023	92.19	gold quality
right hemisphere of cerebellum	UBERON:0014890	92.09	gold quality
sural nerve	UBERON:0015488	92.04	gold quality
descending thoracic aorta	UBERON:0002345	92.03	gold quality
tendon	UBERON:0000043	92.02	gold quality
dorsal plus ventral thalamus	UBERON:0001897	91.38	gold quality
thoracic aorta	UBERON:0001515	91.28	gold quality
ascending aorta	UBERON:0001496	91.21	gold quality
aorta	UBERON:0000947	91.20	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.44

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

225 targeting DIXDC1, 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-3163	100.00	77.23	8605
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-432-3P	100.00	67.86	705
HSA-MIR-4673	100.00	66.64	1490
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-4645-5P	99.98	65.81	1284
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-499A-5P	99.98	70.79	1323
HSA-MIR-34C-5P	99.97	70.45	1577
HSA-MIR-449B-5P	99.97	70.26	1580
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-570-3P	99.96	72.41	4910

Literature-anchored findings (GeneRIF, showing 25)

• KIAA1735 maps to human chromosome 11q23.1 and encodes a novel protein with a myosine-tail homologous domain and C-terminal DIX domain (PMID:12792787)
• MTHDIX (KIAA1735) protein consists of Myosine-tail homologous (MTH) domain and C-terminal DIX domain. (PMID:12792787)
• Ccd1 inhibits Axin-mediated JNK activation by simultaneously adopting two distinct mechanisms, one through conformational changes that disallow MEKK1 binding and the other via direct sequestration of MEKK4. (PMID:15262978)
• Thus, our data provide the first evidence that l-DIXDC1 may act as a novel branching component in the Wnt signaling pathway targeting both beta-catenin-TCF complex for gene expression and cytoskeleton for regulating dynamics of actin filaments. (PMID:16814745)
• DIXDC1 might play an important role during neurogenesis, overexpression of DIXDC1 in embryonic carcinoma P19 cells promoted neuronal differentiation, and inhibited gliogenesis induced by retinoic acid. (PMID:18629627)
• The GFP-tag fused DIXDC1 exogenously expressed co-localize with gamma-tubulin both at interphase and mitotic phase in the centrosomes. (PMID:19375513)
• over-expression of DIXDC1 might target p21 and cyclin D1 to promote colon cancer cell proliferation and tumorigenesis at least partially through activation of the PI3K/Akt pathway. (PMID:19572978)
• Wnt/beta-catenin pathway activation might upregulate DIXDC1 through a post-translational mechanism by inhibiting the ubiquitin-mediated degradation of the DIXDC1 protein. (PMID:20085589)
• This study reveal that Dixdc1 integrates DISC1 into Wnt-GSK3beta/beta-catenin-dependent and -independent signaling pathways during cortical development and further delineate how DISC1 contributes to neuropsychiatric disorders. (PMID:20624590)
• a molecular mechanism for Ccd1-mediated Wnt activation in that Ccd1 converts latent polymeric Dvl to a biologically active oligomer(s). (PMID:21189423)
• Transgenic DIXDC1 might contribute to pathophysiology underlying abnormal behaviors in schizophrenia and other major psychiatric disorders in mice. (PMID:22832659)
• DIXDC1 is associated with stage and prognosis in non-small cell lung cancer, and may promote invasion and migration through PI3K-AKT/AP-1-dependent activation of metalloproteinases (PMID:23813858)
• DIXDC1 depletion results in upregulation of Snail1 in a FAK-dependent manner, leading to increased cell invasion. MARK1 phosphorylation of DIXDC1 is required for its localization to focal adhesions and ability to suppress metastasis in mice. (PMID:25042806)
• DIXDC1 was overexpressed in gastric cancer and correlated with poor prognosis. (PMID:25648220)
• Downregulated expression of DIXDC1 is associated with hepatocellular carcinoma. (PMID:27468723)
• Overexpression of DIXDC1 correlates with enhanced cell growth and poor prognosis in human pancreatic ductal adenocarcinoma. (PMID:27498060)
• found that DIXDC1 could promote cell proliferation via modulating cell cycle progression and PI3K/AKT signaling pathway in NHLs (PMID:27701018)
• DIXDC1 might participate in the development of glioma. (PMID:27817168)
• Taken together, our results suggest that DIXDC1 plays an important role in regulating prostate cancer cell proliferation and invasion. Targeting DIXDC1 by miR-1271 may be a promising therapeutic strategy for prostate cancer. (PMID:28153722)
• MiR-539 inhibits glioma cell proliferation and invasion by targeting DIXDC1. (PMID:28704799)
• High DIXDC1 expression is associated with Growth and Invasion of Gastric Cancer. (PMID:28800791)
• DIXDC1 silencing inhibited cell proliferation, invasion, and Wnt signaling in retinoblastoma cell lines. DIXDC1 was identified as a target gene of miR-186 (PMID:29264763)
• these results demonstrate that DIXDC1 promotes the growth of acute myeloid leukemia cells, possibly through upregulating the Wnt/beta-catenin signaling pathway (PMID:30257373)
• LncRNA SNHG20 enhances the progression of oral squamous cell carcinoma by regulating the miR-29a/DIXDC1/Wnt regulatory axis. (PMID:32495922)
• Circular RNA circ_0000423 promotes gastric cancer cell proliferation, migration and invasion via the microR-582-3p/Disheveled-Axin domain containing 1 axis. (PMID:34898351)

Cross-species orthologs

8 orthologs

Organism	Symbol	Gene ID
danio_rerio	dixdc1a	ENSDARG00000025302
danio_rerio	dixdc1b	ENSDARG00000056267
mus_musculus	Dixdc1	ENSMUSG00000032064
rattus_norvegicus	Dixdc1	ENSRNOG00000010260
drosophila_melanogaster	dsh	FBGN0000499
caenorhabditis_elegans		WBGENE00001101
caenorhabditis_elegans		WBGENE00001102
caenorhabditis_elegans		WBGENE00003241

Paralogs (3): DVL2 (ENSG00000004975), DVL1 (ENSG00000107404), DVL3 (ENSG00000161202)

Protein

Protein identifiers

Dixin — Q155Q3 (reviewed: Q155Q3)

Alternative names: Coiled-coil protein DIX1, DIX domain-containing protein 1

All UniProt accessions (2): Q155Q3, A0A087WVH1

UniProt curated annotations — full annotation on UniProt →

Function. Positive effector of the Wnt signaling pathway; activates WNT3A signaling via DVL2. Regulates JNK activation by AXIN1 and DVL2.

Subunit / interactions. Isoform 1 but not isoform 2 binds filamentous actin. Interacts with the complex composed of DVL2 and Rac. Interacts with AXIN1; competes with MAP3K1. Interacts with MAP3K4 preventing MAP3K4 interaction with AXIN1. Directly interacts (via DIX domain) with DVL2 (via DIX domain). Interacts with gamma-tubulin.

Subcellular location. Cell junction. Focal adhesion. Cytoplasm. Cytoskeleton. Stress fiber. Cytoplasm Cytoplasm.

Tissue specificity. Ubiquitously expressed with higher expression in cardiac and skeletal muscles.

Post-translational modifications. Phosphorylated on tyrosine and serine residues. Polyubiquitinated, leading to its proteasomal degradation. WNT3A signaling increases DIXDC1 protein levels by inhibiting its ubiquitination and subsequent degradation.

Domain organisation. The coiled-coil domain mediates interaction with MAP3K4 and inhibition of AXIN1-mediated JNK activation through MAP3K4. The DIX domain mediates interaction with AXIN1 and inhibition of AXIN1-mediated JNK activation through MAP3K1. Mediates interaction with DVL2; this interaction is required for activation of Wnt signaling.

Miscellaneous. Major isoform. Ubiquitously expressed. Major isoform. Preferentially expressed in cardiac and skeletal muscles.

Similarity. Belongs to the DIXDC1 family.

Isoforms (4)

UniProt ID	Names	Canonical?
Q155Q3-1	1, l-DIXDC1	yes
Q155Q3-2	2, s-DIXDC1
Q155Q3-4	3
Q155Q3-5	4

RefSeq proteins (3): NP_001033043, NP_001265471, NP_219493 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001158	DIX	Domain
IPR001715	CH_dom	Domain
IPR015506	Dsh/Dvl-rel	Family
IPR029071	Ubiquitin-like_domsf	Homologous_superfamily
IPR036872	CH_dom_sf	Homologous_superfamily
IPR038207	DIX_dom_sf	Homologous_superfamily

Pfam: PF00307, PF00778

UniProt features (35 total): splice variant 5, strand 5, sequence conflict 4, region of interest 4, modified residue 3, mutagenesis site 3, domain 2, compositionally biased region 2, chain 1, sequence variant 1, helix 1, turn 1, initiator methionine 1, lipid moiety-binding region 1, coiled-coil region 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
3PZ7	X-RAY DIFFRACTION	2.44

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q155Q3-F1	70.52	0.35

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 (4): 186, 231, 590, 2

Mutagenesis-validated functional residues (3):

Position	Phenotype
648	loss of interaction with dvl2. abolishes activation of wnt signaling.
651	loss of interaction with dvl2. abolishes activation of wnt signaling.
655	loss of interaction with dvl2. abolishes activation of wnt signaling.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 286 (showing top): GOBP_NEGATIVE_REGULATION_OF_NEURON_DIFFERENTIATION, GOBP_REGULATION_OF_MICROTUBULE_BASED_PROCESS, GOBP_NEUROGENESIS, GOBP_REGULATION_OF_WNT_SIGNALING_PATHWAY, LHX3_01, CHX10_01, GOBP_CELL_PROLIFERATION_IN_FOREBRAIN, GOBP_FOREBRAIN_DEVELOPMENT, FOXD3_01, SRF_Q5_01, GOBP_REGULATION_OF_ACTIN_FILAMENT_BASED_PROCESS, GOBP_FOREBRAIN_CELL_MIGRATION, SRF_01, GOBP_NEURAL_PRECURSOR_CELL_PROLIFERATION, CHEN_LVAD_SUPPORT_OF_FAILING_HEART_UP

GO Biological Process (11): cerebral cortex radially oriented cell migration (GO:0021799), forebrain ventricular zone progenitor cell division (GO:0021869), positive regulation of Wnt signaling pathway (GO:0030177), regulation of actin cytoskeleton organization (GO:0032956), negative regulation of neuron differentiation (GO:0045665), canonical Wnt signaling pathway (GO:0060070), regulation of microtubule cytoskeleton organization (GO:0070507), modification of postsynaptic actin cytoskeleton (GO:0098885), Wnt signaling pathway (GO:0016055), cerebral cortex cell migration (GO:0021795), cell proliferation in forebrain (GO:0021846)

GO Molecular Function (4): actin binding (GO:0003779), protein domain specific binding (GO:0019904), gamma-tubulin binding (GO:0043015), protein binding (GO:0005515)

GO Cellular Component (8): stress fiber (GO:0001725), cytosol (GO:0005829), focal adhesion (GO:0005925), postsynapse (GO:0098794), glutamatergic synapse (GO:0098978), cytoplasm (GO:0005737), cytoskeleton (GO:0005856), anchoring junction (GO:0070161)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
Wnt signaling pathway	2
regulation of cytoskeleton organization	2
synapse	2
cerebral cortex cell migration	1
cell proliferation in forebrain	1
cell division	1
positive regulation of signal transduction	1
regulation of Wnt signaling pathway	1
actin cytoskeleton organization	1
regulation of actin filament-based process	1
neuron differentiation	1
negative regulation of cell differentiation	1
regulation of neuron differentiation	1
microtubule cytoskeleton organization	1
regulation of microtubule-based process	1
modification of postsynaptic structure	1
cell surface receptor signaling pathway	1
cerebral cortex development	1
telencephalon cell migration	1
forebrain development	1
neural precursor cell proliferation	1
cytoskeletal protein binding	1
protein binding	1
tubulin binding	1
binding	1
actomyosin	1
contractile actin filament bundle	1
cytoplasm	1
cell-substrate junction	1
intracellular anatomical structure	1
intracellular membraneless organelle	1
cell junction	1

Protein interactions and networks

STRING

700 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DIXDC1	DISC1	Q9NRI5	957
DIXDC1	AXIN1	O15169	899
DIXDC1	DVL1	O14640	788
DIXDC1	DLAT	P10515	725
DIXDC1	MAP3K4	Q9Y6R4	697
DIXDC1	MYH2	Q9UKX2	639
DIXDC1	NDEL1	Q9GZM8	620
DIXDC1	AXIN2	Q9Y2T1	552
DIXDC1	VCL	P18206	514
DIXDC1	MYH1	P12882	497
DIXDC1	MAP3K1	Q13233	491
DIXDC1	GPRASP3	Q6PI77	478
DIXDC1	FZD6	O60353	462
DIXDC1	NDE1	Q9NXR1	450
DIXDC1	APCDD1	Q8J025	437

IntAct

39 interactions, top by confidence:

A	B	Type	Score
Dvl2	DIXDC1	psi-mi:“MI:0915”(physical association)	0.650
Dvl2	DIXDC1	psi-mi:“MI:0407”(direct interaction)	0.650
DIXDC1	Dvl2	psi-mi:“MI:0407”(direct interaction)	0.650
L3HYPDH	CCNE2	psi-mi:“MI:0914”(association)	0.530
NDEL1	OFD1	psi-mi:“MI:0914”(association)	0.530
DIXDC1	DVL2	psi-mi:“MI:0915”(physical association)	0.500
DIXDC1	DVL2	psi-mi:“MI:0914”(association)	0.500
DIXDC1	PKM	psi-mi:“MI:0217”(phosphorylation reaction)	0.440
Nde1	RPA2	psi-mi:“MI:0915”(physical association)	0.400
DIXDC1	ULK2	psi-mi:“MI:0915”(physical association)	0.370
DIXDC1	ATXN1	psi-mi:“MI:0915”(physical association)	0.370
MYH9	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
Flot2	ACTG1	psi-mi:“MI:0914”(association)	0.350
MYO1C	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
FLNA	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
Pafah1b1	ATXN3	psi-mi:“MI:0914”(association)	0.350
Ndel1	VEZF1	psi-mi:“MI:0914”(association)	0.350
Lima1	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
Calml3	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
DBN1	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
Myh9	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
CAPZA2	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
NDEL1	SHTN1	psi-mi:“MI:0914”(association)	0.350
CTBP1	TAF15	psi-mi:“MI:0914”(association)	0.350

BioGRID (43): DIXDC1 (Two-hybrid), DIXDC1 (Affinity Capture-MS), DIXDC1 (Affinity Capture-MS), DIXDC1 (Affinity Capture-MS), DIXDC1 (Affinity Capture-MS), DIXDC1 (Affinity Capture-MS), DIXDC1 (Affinity Capture-MS), DIXDC1 (Affinity Capture-MS), DIXDC1 (Affinity Capture-MS), DIXDC1 (Affinity Capture-MS), DIXDC1 (Affinity Capture-MS), DIXDC1 (Affinity Capture-MS), DIXDC1 (Affinity Capture-MS), DIXDC1 (Affinity Capture-MS), DIXDC1 (Affinity Capture-MS)

ESM2 similar proteins: A0A8I3PDQ1, A0M8S4, A0M8T5, A5GFW5, B6RSP1, B9EJA2, D4A039, E9Q0S6, O00750, O35177, Q00PJ1, Q07DV1, Q07DW4, Q07DX4, Q07DY4, Q07E15, Q07E28, Q07E41, Q08EC4, Q09YG9, Q09YI1, Q09YK4, Q09YM8, Q108T9, Q14511, Q155Q3, Q2IBA2, Q2IBB2, Q2IBD4, Q2IBE6, Q2IBF7, Q2QL82, Q2QLA2, Q2QLB3, Q2QLF8, Q2QLG9, Q2VUH7, Q3UIL6, Q5JV73, Q61140

Diamond homologs: A0A8C0TYJ0, B1WAP7, G5ECY0, O14640, O14641, O15018, O15169, O35625, O35889, O42400, O54824, O55164, O70239, O70240, O75970, O88566, P31007, P31016, P51140, P51141, P51142, P54792, P55196, P57094, P57105, P70175, P78352, Q05AS8, Q12923, Q12959, Q14005, Q155Q3, Q15700, Q22227, Q28C55, Q2VUH7, Q3T0C9, Q5IS48, Q5PYH5, Q5PYH6

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 39 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
Innate Immune System	6	6.4×	5e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	1
Uncertain significance	34
Likely benign	0
Benign	3

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
2424604	NC_000011.9:g.(?111171709)(111958707_?)del	Pathogenic
631529	NM_001037954.4(DIXDC1):c.793C>T (p.Arg265Ter)	Likely pathogenic

SpliceAI

2992 predictions. Top by Δscore:

Variant	Effect	Δscore
11:111964547:A:AG	acceptor_gain	1.0000
11:111964548:G:GG	acceptor_gain	1.0000
11:111964548:GCAAC:G	acceptor_gain	1.0000
11:111964671:GATT:G	donor_gain	1.0000
11:111964683:G:GG	donor_gain	1.0000
11:111964706:GA:G	donor_gain	1.0000
11:111964708:G:GG	donor_gain	1.0000
11:111968508:A:AG	acceptor_gain	1.0000
11:111968511:A:AG	acceptor_gain	1.0000
11:111968511:AGCAG:A	acceptor_gain	1.0000
11:111968512:G:GT	acceptor_gain	1.0000
11:111968512:GCA:G	acceptor_gain	1.0000
11:111968512:GCAGG:G	acceptor_gain	1.0000
11:111968635:AAAG:A	donor_loss	1.0000
11:111968636:AAGGT:A	donor_loss	1.0000
11:111968637:AG:A	donor_loss	1.0000
11:111968638:GG:G	donor_loss	1.0000
11:111968639:GTC:G	donor_loss	1.0000
11:111974252:GAG:G	donor_gain	1.0000
11:111974253:AGGT:A	donor_loss	1.0000
11:111974255:G:GC	donor_loss	1.0000
11:111974256:T:G	donor_loss	1.0000
11:111980729:A:AG	acceptor_gain	1.0000
11:111980735:A:AG	acceptor_gain	1.0000
11:111980736:G:GA	acceptor_gain	1.0000
11:111980736:GCC:G	acceptor_gain	1.0000
11:111980736:GCCT:G	acceptor_gain	1.0000
11:111982337:A:AG	acceptor_gain	1.0000
11:111982337:AGAAG:A	acceptor_gain	1.0000
11:111982338:G:GG	acceptor_gain	1.0000

AlphaMissense

4496 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:111964645:G:T	G53W	0.999
11:111964573:T:A	W29R	0.998
11:111964573:T:C	W29R	0.998
11:111964645:G:A	G53R	0.998
11:111964645:G:C	G53R	0.998
11:111964646:G:A	G53E	0.998
11:111964664:T:C	L59P	0.998
11:111968588:T:C	L89P	0.998
11:111974059:T:C	L118P	0.998
11:111964575:G:C	W29C	0.997
11:111964575:G:T	W29C	0.997
11:111964589:T:C	L34P	0.997
11:111964637:T:C	L50P	0.997
11:111974026:T:A	I107N	0.997
11:111974065:T:C	L120P	0.997
11:112017849:A:C	K645N	0.997
11:112017849:A:T	K645N	0.997
11:112019005:C:A	A674D	0.997
11:111964646:G:T	G53V	0.996
11:111968593:T:C	F91L	0.996
11:111968595:T:A	F91L	0.996
11:111968595:T:G	F91L	0.996
11:111974082:T:C	F126L	0.996
11:111974084:C:A	F126L	0.996
11:111974084:C:G	F126L	0.996
11:111995443:T:C	L523P	0.996
11:111995494:T:C	L540S	0.996
11:111974054:G:A	M116I	0.995
11:111974054:G:C	M116I	0.995
11:111974054:G:T	M116I	0.995

dbSNP variants (sampled 300 via entrez): RS1000118256 (11:112006498 C>T), RS1000163540 (11:111938414 G>T), RS1000194398 (11:111961011 G>A), RS1000196790 (11:111938748 G>A), RS1000301884 (11:112013855 C>T), RS1000303941 (11:111975451 G>A), RS1000350881 (11:111931717 T>G), RS1000358381 (11:112021754 T>A,G), RS1000412300 (11:112021516 G>A,C), RS1000501792 (11:111937227 G>C,T), RS1000534225 (11:111937446 G>A), RS1000546522 (11:111986508 G>A), RS1000613109 (11:111988034 C>G,T), RS1000692534 (11:111979326 C>T), RS1000761982 (11:111930851 T>C)

Disease associations

OMIM: gene MIM:610493 | disease phenotypes: MIM:171300, MIM:606864, MIM:615106

GenCC curated gene-disease

Mondo (4): pheochromocytoma (MONDO:0008233), Carney-Stratakis syndrome (MONDO:0011740), Cowden syndrome 3 (MONDO:0014045), obesity disorder (MONDO:0011122)

Orphanet (5): Cowden syndrome (Orphanet:201), Hereditary pheochromocytoma-paraganglioma (Orphanet:29072), Carney-Stratakis syndrome (Orphanet:97286), Obesity due to melanocortin 4 receptor deficiency (Orphanet:71529), NON RARE IN EUROPE: Non rare obesity (Orphanet:521399)

HPO phenotypes

1 total (1 of 1 shown, HPO-id order):

HPO	Term
HP:0001513	Obesity

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST010703_266	Brain morphology (MOSTest)	4.000000e-13
GCST011703_4	Smoking initiation	1.000000e-08
GCST90020025_653	Waist-to-hip ratio adjusted for BMI	1.000000e-08
GCST90020027_1631	Waist-hip index	9.000000e-09

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004346	neuroimaging measurement
EFO:0005670	smoking initiation
EFO:0007788	BMI-adjusted waist-hip ratio

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D010673	Pheochromocytoma	C04.557.465.625.650.700.725; C04.557.580.625.650.700.725
C564650	Carney-Stratakis Syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases expression, affects expression, decreases methylation	3
aristolochic acid I	decreases expression	1
triphenyl phosphate	affects expression	1
uranyl acetate	affects expression	1
bisphenol A	affects cotreatment, decreases methylation, increases methylation	1
methylselenic acid	increases expression	1
trichostatin A	affects expression	1
tris(2-butoxyethyl) phosphate	affects expression	1
beta-lapachone	decreases expression	1
afimoxifene	decreases expression, decreases reaction	1
sodium arsenite	decreases expression	1
cobaltous chloride	decreases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
aflatoxin B2	increases methylation	1
coumarin	increases phosphorylation	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
15-acetyldeoxynivalenol	increases expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	increases reaction, affects binding	1
abrine	decreases expression	1
licochalcone B	decreases expression	1
Sunitinib	decreases expression	1
Fulvestrant	affects cotreatment, decreases methylation	1
Leflunomide	increases expression	1
Ethanol	increases expression	1
Atrazine	decreases expression	1
Benzo(a)pyrene	affects methylation	1
Coumestrol	decreases expression	1
Estradiol	increases expression, affects cotreatment	1
Estrogens	decreases expression, decreases reaction	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01379898	PHASE4	COMPLETED	Phenoxybenzamine Versus Doxazosin in PCC Patients
NCT01959711	PHASE4	COMPLETED	Randomized Clinical Trial of Posterior Retroperitoneoscopic Adrenalectomy Versus Lateral Laparoscopic Adrenalectomy
NCT05702944	PHASE4	RECRUITING	The Effect and Safety of Omitting Preoperative Alpha-adrenergic Blockade for Normotensive Pheochromocytoma
NCT00076362	PHASE4	COMPLETED	Pediatric Hypothalamic Obesity
NCT00079547	PHASE4	COMPLETED	The Safety and Effectiveness of Low and High Carbohydrate Diets
NCT00115063	PHASE4	TERMINATED	LOSS- Louisiana Obese Subjects Study
NCT00134303	PHASE4	COMPLETED	Trial Comparing Metformin Versus Placebo in Non Alcoholic Steatohepatitis (NASH) Patients Receiving Bariatric Surgery for Obesity
NCT00143936	PHASE4	COMPLETED	The Safety and Efficacy of Low and High Carbohydrate Diets
NCT00143962	PHASE4	COMPLETED	Comparison of Two Approaches to Weight Loss Follow-Up Study
NCT00152360	PHASE4	COMPLETED	The Effect of Xenical on Weight and Risk Factors
NCT00176306	PHASE4	COMPLETED	Levofloxacin Pharmacokinetics (PK) in the Severely Obese
NCT00203450	PHASE4	COMPLETED	Zonegran for the Treatment of Weight Gain Associated With Psychotropic Medication Use: A Placebo-Controlled Trial
NCT00205504	PHASE4	COMPLETED	Oral Contraceptives in the Metabolic Syndrome
NCT00229229	PHASE4	TERMINATED	Comparison of 4 Diets in the Management of Overweight Patients With Vascular Disease
NCT00234988	PHASE4	COMPLETED	A Phase IV, Multi-Center, Open-Label Trial of Sibutramine in Combination With a Hypocaloric Diet in Obese and Overweight Thai Subjects.
NCT00264589	PHASE4	COMPLETED	Exercise Training and Cardiovascular Function in Obesity and in Type 2 Diabetes
NCT00288873	PHASE4	COMPLETED	Characterization of Hyperparathyroidism and Vitamin D Deficiency in Obesity
NCT00298857	PHASE4	TERMINATED	A Pharmacokinetic Study to Compare the Dosing of Valproic Acid in Subjects With Different Body Weights
NCT00315146	PHASE4	COMPLETED	Optimizing Body Composition for Function in Older Adults
NCT00319202	PHASE4	TERMINATED	Clinical Trial to Assess the Effects of Candesartan on the Carbohydrate Metabolism of Obese Subjects
NCT00327912	PHASE4	UNKNOWN	Laparoscopic Roux-en-Y Gastric Bypass Versus Laparoscopic Biliopancreatic Diversion (BPD)- Duodenal Switch for Superobesity
NCT00352287	PHASE4	COMPLETED	Study to Determine the Effects of Human Growth Hormone and Pioglitazone in Overweight, Prediabetic Adults
NCT00353054	PHASE4	COMPLETED	Effect of Calcium/Vitamin D Supplementation on Body Weight and Fat Loss.
NCT00390637	PHASE4	COMPLETED	Diet, Obesity and Genes (DiOGenes)
NCT00415688	PHASE4	COMPLETED	Lifestyle Modification for Obesity-Related Type 2 Diabetes
NCT00433641	PHASE4	COMPLETED	Weight Loss in Response to Sibutramine (MERIDIA) is Influenced by the Inherited Genes
NCT00440375	PHASE4	COMPLETED	Effects of Rosiglitazone on Bone in Postmenopausal Diabetic Women
NCT00453557	PHASE4	COMPLETED	Mechanism of Growth Hormone Effects on Adipose Tissue
NCT00456885	PHASE4	COMPLETED	The Effect of Exenatide on Weight and Hunger in Obese, Healthy Women
NCT00463112	PHASE4	COMPLETED	Effect of Diet Plus Sibutramine on Hormonal and Metabolic Features in Overweight and Obese Women With PCOS
NCT00512187	PHASE4	COMPLETED	Moderate Weight Loss Makes Obese Patients With Severe Chronic Plaque Psoriasis Responsive to Sub-Optimal Dose of Cyclosporine: an Investigator Blinded, Controlled, Randomized Clinical Trial
NCT00516919	PHASE4	COMPLETED	Study of Behavioral Weight Loss Therapy for Obesity and Binge Eating in Monolingual Hispanic Persons
NCT00522470	PHASE4	COMPLETED	Effects of Rosiglitazone on Serum Ghrelin and Peptide YY Levels
NCT00537810	PHASE4	COMPLETED	Treatment of Binge Eating in Obese Patients in Primary Care
NCT00538486	PHASE4	COMPLETED	A Randomized, Double-Blind, Active Control Trial Comparing Effects of Telmisartan, Candesartan and Amlodipine, Alone or Plus Metformin, on Non-Diabetic, Obese Hypertensive Patients
NCT00584389	PHASE4	TERMINATED	The Effect of Rimonabant on Energy Expenditure, Fat Metabolism and Body Composition
NCT00585182	PHASE4	COMPLETED	Study to Evaluate Weight-based Enoxaparin Dosing in Obese Medical Patients at Risk for DVT
NCT00632840	PHASE4	COMPLETED	Pharmacological Regulation of Fat Transport in Metabolic Syndrome
NCT00636142	PHASE4	COMPLETED	Effects of Infliximab on Insulin Sensitivity and Beta Cell Function in Insulin Resistant Human Obesity
NCT00675987	PHASE4	COMPLETED	A Randomized Clinical Trial To Study Losartan On Endothelial Dysfunction and Insulin Resistance In Obese Patients