DOCK9

Summary

DOCK9 (dedicator of cytokinesis 9, HGNC:14132) is a protein-coding gene on chromosome 13q32.3, encoding Dedicator of cytokinesis protein 9 (Q9BZ29). Guanine nucleotide-exchange factor (GEF) that activates CDC42 by exchanging bound GDP for free GTP.

Enables cadherin binding activity. Predicted to be involved in positive regulation of GTPase activity and regulation of Rho protein signal transduction. Located in membrane.

Source: NCBI Gene 23348 — RefSeq curated summary.

At a glance

• Gene–disease (curated): keratoconus (Limited, GenCC)
• GWAS associations: 17
• Clinical variants (ClinVar): 309 total
• MANE Select transcript: NM_001366683

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:14132
Approved symbol	DOCK9
Name	dedicator of cytokinesis 9
Location	13q32.3
Locus type	gene with protein product
Status	Approved
Aliases	KIAA1058, ZIZ1
Ensembl gene	ENSG00000088387
Ensembl biotype	protein_coding
OMIM	607325
Entrez	23348

Gene structure

Transcript identifiers

Ensembl transcripts: 26 — 19 protein_coding, 3 nonsense_mediated_decay, 3 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000339416, ENST00000340449, ENST00000376460, ENST00000400228, ENST00000419908, ENST00000427887, ENST00000448493, ENST00000449796, ENST00000450257, ENST00000472874, ENST00000473165, ENST00000479769, ENST00000481051, ENST00000627024, ENST00000630992, ENST00000638020, ENST00000652315, ENST00000682017, ENST00000703210, ENST00000703211, ENST00000703216, ENST00000703227, ENST00000903387, ENST00000903388, ENST00000903389, ENST00000903390

RefSeq mRNA: 14 — MANE Select: NM_001366683 NM_001130048, NM_001130049, NM_001130050, NM_001318849, NM_001366676, NM_001366677, NM_001366678, NM_001366679, NM_001366680, NM_001366681, NM_001366682, NM_001366683, NM_001366684, NM_015296

CCDS: CCDS45062, CCDS45063, CCDS76645, CCDS91827, CCDS91828, CCDS91829

Canonical transcript exons

ENST00000682017 — 53 exons

Exon	Start	End
ENSE00001604599	98797389	98797489
ENSE00001613480	98898179	98898261
ENSE00001617245	98885708	98885831
ENSE00001619529	98925837	98925919
ENSE00001624954	98902972	98903112
ENSE00001638130	98804999	98805209
ENSE00001640495	98886532	98886624
ENSE00001648093	98914328	98914395
ENSE00001652140	98888632	98888711
ENSE00001656237	98930168	98930257
ENSE00001658439	98923302	98923371
ENSE00001658649	98879898	98879969
ENSE00001681410	98867928	98868011
ENSE00001692370	98904632	98904706
ENSE00001700069	98809352	98809465
ENSE00001705363	98883813	98883899
ENSE00001709892	98883042	98883131
ENSE00001726163	98902288	98902491
ENSE00001727581	98915329	98915503
ENSE00001731729	98901778	98901900
ENSE00001741422	98867425	98867536
ENSE00001741729	98868231	98868377
ENSE00001749158	98884971	98885092
ENSE00001755179	98797115	98797253
ENSE00001759171	98897488	98897610
ENSE00001761450	98881558	98881627
ENSE00001788257	98860405	98860522
ENSE00001792695	98880547	98880672
ENSE00001802923	98881892	98882007
ENSE00001806091	98920954	98921088
ENSE00001806198	98888158	98888223
ENSE00003478553	98863019	98863132
ENSE00003520983	98824398	98824504
ENSE00003545726	98853408	98853522
ENSE00003562505	98845924	98846060
ENSE00003568470	98850047	98850113
ENSE00003577746	98955435	98955551
ENSE00003583878	98863370	98863548
ENSE00003611793	98855898	98856031
ENSE00003622646	98848592	98848639
ENSE00003681092	98826830	98826887
ENSE00003682519	98888360	98888547
ENSE00003714306	98831348	98831530
ENSE00003721279	98837494	98837609
ENSE00003740447	98810169	98810291
ENSE00003740647	98831649	98831786
ENSE00003741492	98829643	98829756
ENSE00003745091	98829307	98829522
ENSE00003768577	98922051	98922146
ENSE00003786933	98807661	98807807
ENSE00003789891	98800288	98800478
ENSE00003791925	98793429	98794748
ENSE00003919285	98977784	98978064

Expression profiles

Bgee: expression breadth ubiquitous, 293 present calls, max score 98.55.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 12.8779 / max 492.8985, expressed in 1432 samples.

FANTOM5 promoters (13 alternative TSS)

Promoter ID	TPM avg	Samples expressed
137964	7.2126	618
137977	3.4053	1235
137968	0.9881	106
137976	0.5527	295
137971	0.3034	74
137963	0.1851	75
137961	0.0650	32
137974	0.0580	21
137970	0.0292	17
137962	0.0227	10

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
calcaneal tendon	UBERON:0003701	98.55	gold quality
right lung	UBERON:0002167	98.54	gold quality
corpus callosum	UBERON:0002336	98.48	gold quality
CA1 field of hippocampus	UBERON:0003881	98.04	gold quality
lower lobe of lung	UBERON:0008949	97.97	gold quality
oral cavity	UBERON:0000167	97.84	gold quality
lower esophagus mucosa	UBERON:0035834	97.69	gold quality
tongue squamous epithelium	UBERON:0006919	97.55	gold quality
sural nerve	UBERON:0015488	97.49	gold quality
skin of hip	UBERON:0001554	97.47	gold quality
inferior olivary complex	UBERON:0002127	97.38	gold quality
upper lobe of lung	UBERON:0008948	97.27	gold quality
penis	UBERON:0000989	97.21	gold quality
upper lobe of left lung	UBERON:0008952	97.21	gold quality
tibial nerve	UBERON:0001323	97.18	gold quality
upper leg skin	UBERON:0004262	97.16	gold quality
subthalamic nucleus	UBERON:0001906	97.00	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	96.87	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	96.79	gold quality
inferior vagus X ganglion	UBERON:0005363	96.76	gold quality
esophagus mucosa	UBERON:0002469	96.74	gold quality
lung	UBERON:0002048	96.70	gold quality
orbitofrontal cortex	UBERON:0004167	96.65	gold quality
skin of leg	UBERON:0001511	96.46	gold quality
spinal cord	UBERON:0002240	96.36	gold quality
visceral pleura	UBERON:0002401	96.36	gold quality
medulla oblongata	UBERON:0001896	96.30	gold quality
esophagus	UBERON:0001043	96.19	gold quality
zone of skin	UBERON:0000014	96.14	gold quality
pharyngeal mucosa	UBERON:0000355	96.14	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-CURD-119	yes	2011.42
E-HCAD-35	yes	17.81
E-CURD-112	no	3.07
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): TAL1

miRNA regulators (miRDB)

115 targeting DOCK9, 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-3924	100.00	72.09	2394
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-363-3P	99.98	74.72	1821
HSA-MIR-367-3P	99.98	74.83	1819
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-493-5P	99.96	72.47	2382
HSA-MIR-96-5P	99.95	72.80	2140
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-548AQ-3P	99.93	72.66	4867
HSA-MIR-6835-3P	99.93	70.49	2904
HSA-MIR-218-5P	99.93	72.22	2103
HSA-MIR-145-5P	99.92	71.13	1836
HSA-MIR-5195-3P	99.92	70.92	1877
HSA-MIR-12133	99.92	71.82	2006
HSA-MIR-5680	99.91	69.83	3421

Literature-anchored findings (GeneRIF, showing 9)

• Sequence comparison combined with mutational analysis identified a new domain, which we named CZH2, that mediates direct interaction with Cdc42 (PMID:12172552)
• DOCK9 contributes to both risk and increased illness severity in bipolar disorder. (PMID:17728666)
• novel functions for the N-terminal region of zizimin1. (PMID:17935486)
• DOCK2 and DOCK9 specifically recognize Rac2 and Cdc42 through their switch 1 as well as beta2-beta3 regions and the mode of recognition via switch 1 appears to be conserved among diverse Rac-specific DHR-2 GEFs (PMID:18056264)
• interaction between Smad2/3 and the Cdc42 guanine nucleotide exchange factor, Zizimin1, in response to TGF-beta1 (PMID:18729074)
• through structural analysis of DOCK9-Cdc42 complexes, we identify a nucleotide sensor within the alpha10 helix of the DHR2 domain that contributes to release of guanine diphosphate (GDP) and then to discharge of the activated GTP-bound Cdc42 (PMID:19745154)
• Studies indicate that that many of the mechanistic principles of the exchange process are conserved in the DOCK9-catalyzed reaction. (PMID:19809089)
• c.2262A>C substitution in DOCK9 leads to a splicing aberration. However, because the mutation effect was observed in vitro, a definitive relationship between DOCK9 and KTCN phenotype could not be established. (PMID:26641546)
• Genome-wide analysis of 53,400 people with irritable bowel syndrome highlights shared genetic pathways with mood and anxiety disorders. (PMID:34741163)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	dock9b	ENSDARG00000016311
danio_rerio	dock9a	ENSDARG00000114086
mus_musculus	Dock9	ENSMUSG00000025558
rattus_norvegicus	Dock9	ENSRNOG00000011969
drosophila_melanogaster	Zir	FBGN0031216
caenorhabditis_elegans		WBGENE00000419
caenorhabditis_elegans		WBGENE00018520

Paralogs (10): DOCK3 (ENSG00000088538), DOCK8 (ENSG00000107099), DOCK7 (ENSG00000116641), DOCK4 (ENSG00000128512), DOCK6 (ENSG00000130158), DOCK2 (ENSG00000134516), DOCK10 (ENSG00000135905), DOCK11 (ENSG00000147251), DOCK5 (ENSG00000147459), DOCK1 (ENSG00000150760)

Protein

Protein identifiers

Dedicator of cytokinesis protein 9 — Q9BZ29 (reviewed: Q9BZ29)

Alternative names: Cdc42 guanine nucleotide exchange factor zizimin-1

All UniProt accessions (16): Q9BZ29, A0A088AWN3, A0A0A0MT38, A0A0D9SF41, A0A0D9SFH5, A0A1B0GVL8, A0A804HIE8, A0A8V8TQS9, A0A8V8TR95, A0A8V8TRI9, H0Y3S1, H0Y572, H7BZ79, Q5JUD8, Q6ZSL5, X6RGR3

UniProt curated annotations — full annotation on UniProt →

Function. Guanine nucleotide-exchange factor (GEF) that activates CDC42 by exchanging bound GDP for free GTP. Overexpression induces filopodia formation.

Subunit / interactions. Homodimer. Interacts preferentially with nucleotide-depleted CDC42.

Subcellular location. Endomembrane system.

Tissue specificity. Widely expressed, with highest expression in heart and placenta. Expressed at intermediate level in kidney, brain, lung and skeletal muscle.

Domain organisation. The DOCKER domain is necessary and sufficient for the GEF activity.

Miscellaneous. ‘Zizim’ means ‘spike’ in Hebrew. Produced by exon skipping that results in a frameshift.

Similarity. Belongs to the DOCK family.

Isoforms (5)

UniProt ID	Names	Canonical?
Q9BZ29-1	1	yes
Q9BZ29-5	2
Q9BZ29-3	3
Q9BZ29-4	4
Q9BZ29-6	5

RefSeq proteins (14): NP_001123520, NP_001123521, NP_001123522, NP_001305778, NP_001353605, NP_001353606, NP_001353607, NP_001353608, NP_001353609, NP_001353610, NP_001353611, NP_001353612, NP_001353613, NP_056111 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001849	PH_domain	Domain
IPR011993	PH-like_dom_sf	Homologous_superfamily
IPR016024	ARM-type_fold	Homologous_superfamily
IPR021816	DOCK_C/D_N	Domain
IPR026791	DOCK	Family
IPR027007	C2_DOCK-type_domain	Domain
IPR027357	DOCKER_dom	Domain
IPR035892	C2_domain_sf	Homologous_superfamily
IPR037809	C2_Dock-D	Domain
IPR043161	DOCK_C_lobe_A	Homologous_superfamily
IPR043162	DOCK_C_lobe_C	Homologous_superfamily
IPR046769	DOCKER_Lobe_A	Domain
IPR046770	DOCKER_Lobe_B	Domain
IPR046773	DOCKER_Lobe_C	Domain

Pfam: PF00169, PF06920, PF11878, PF14429, PF20421, PF20422

UniProt features (79 total): helix 22, strand 19, modified residue 12, splice variant 6, turn 5, domain 3, region of interest 3, compositionally biased region 2, sequence variant 2, sequence conflict 2, coiled-coil region 2, chain 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
2WM9	X-RAY DIFFRACTION	2.2
2WMO	X-RAY DIFFRACTION	2.2
2WMN	X-RAY DIFFRACTION	2.39
1WG7	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9BZ29-F1	79.68	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 (12): 21, 32, 167, 170, 433, 443, 927, 1235, 1241, 1255, 1261, 1264

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-9013148	CDC42 GTPase cycle
R-HSA-9013149	RAC1 GTPase cycle
R-HSA-983231	Factors involved in megakaryocyte development and platelet production

MSigDB gene sets: 240 (showing top): MULLIGHAN_NPM1_SIGNATURE_3_UP, MYOGENIN_Q6, GCM_PTPRD, DACOSTA_UV_RESPONSE_VIA_ERCC3_XPCS_DN, GOLDRATH_IMMUNE_MEMORY, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GOBP_REGULATION_OF_GTPASE_ACTIVITY, GOBP_REGULATION_OF_SMALL_GTPASE_MEDIATED_SIGNAL_TRANSDUCTION, CAGCTG_AP4_Q5, GOBP_POSITIVE_REGULATION_OF_CATALYTIC_ACTIVITY, CHEN_LVAD_SUPPORT_OF_FAILING_HEART_UP, GOBP_REGULATION_OF_HYDROLASE_ACTIVITY, ONKEN_UVEAL_MELANOMA_UP, GOBP_POSITIVE_REGULATION_OF_MOLECULAR_FUNCTION, KESHELAVA_MULTIPLE_DRUG_RESISTANCE

GO Biological Process (3): small GTPase-mediated signal transduction (GO:0007264), regulation of Rho protein signal transduction (GO:0035023), positive regulation of GTPase activity (GO:0043547)

GO Molecular Function (3): guanyl-nucleotide exchange factor activity (GO:0005085), cadherin binding (GO:0045296), protein binding (GO:0005515)

GO Cellular Component (3): cytosol (GO:0005829), endomembrane system (GO:0012505), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
RHO GTPase cycle	2
Hemostasis	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
intracellular signaling cassette	1
Rho protein signal transduction	1
regulation of small GTPase mediated signal transduction	1
GTPase activity	1
regulation of GTPase activity	1
positive regulation of hydrolase activity	1
GTP binding	1
GDP binding	1
GTPase regulator activity	1
cell adhesion molecule binding	1
binding	1
cytoplasm	1
vacuole	1
plasma membrane	1

Protein interactions and networks

STRING

950 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DOCK9	DHX8	Q14562	935
DOCK9	DHX37	Q8IY37	896
DOCK9	CDC42	P21181	842
DOCK9	RABIF	P47224	665
DOCK9	VSX1	Q9NZR4	643
DOCK9	RHOJ	Q9H4E5	541
DOCK9	PLEK2	Q9NYT0	520
DOCK9	RAB3GAP1	Q15042	520
DOCK9	ZNF469	Q96JG9	513
DOCK9	PLEK	P08567	510
DOCK9	DOCK5	Q9H7D0	509
DOCK9	MCF2	P10911	508
DOCK9	IPO5	O00410	507
DOCK9	EPHB2	P29323	504
DOCK9	DOCK1	Q14185	493

IntAct

44 interactions, top by confidence:

A	B	Type	Score
SMAD3	SMAD4	psi-mi:“MI:0914”(association)	0.980
SMAD2	SMAD4	psi-mi:“MI:0914”(association)	0.970
PAAT	CLTC	psi-mi:“MI:0914”(association)	0.740
YWHAH	PLEKHG3	psi-mi:“MI:0914”(association)	0.610
SMAD2	DOCK9	psi-mi:“MI:0915”(physical association)	0.580
DOCK9	SMAD3	psi-mi:“MI:0915”(physical association)	0.580
SMAD3	DOCK9	psi-mi:“MI:0915”(physical association)	0.580
DOCK10	HAL	psi-mi:“MI:0914”(association)	0.530
GIPC1	APPL2	psi-mi:“MI:0914”(association)	0.480
DOCK9	HTT	psi-mi:“MI:0915”(physical association)	0.370
	NAP1L1	psi-mi:“MI:0914”(association)	0.350
BFRF1A	SHTN1	psi-mi:“MI:0914”(association)	0.350
CUL4B	APBB1	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
	IPO5	psi-mi:“MI:0914”(association)	0.350
DOCK9	CHD1	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
YWHAH	FOXO6	psi-mi:“MI:0914”(association)	0.350
YWHAZ	HECTD4	psi-mi:“MI:0914”(association)	0.350
NEB	DOCK9	psi-mi:“MI:2364”(proximity)	0.270
BUD13	RPSA2	psi-mi:“MI:2364”(proximity)	0.270
HNRNPC	SBNO1	psi-mi:“MI:2364”(proximity)	0.270
SBDS	RPSA2	psi-mi:“MI:2364”(proximity)	0.270
SRSF7	ESYT2	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (84): DOCK9 (Proximity Label-MS), DOCK9 (Affinity Capture-MS), DOCK9 (Affinity Capture-MS), DOCK9 (Proximity Label-MS), DOCK9 (Affinity Capture-MS), DOCK9 (Proximity Label-MS), DOCK9 (Proximity Label-MS), DOCK9 (Affinity Capture-RNA), DOCK9 (Affinity Capture-RNA), DOCK9 (Affinity Capture-MS), DOCK9 (Proximity Label-MS), NEB (Two-hybrid), ATG12 (Two-hybrid), NEDD9 (Two-hybrid), NUCKS1 (Two-hybrid)

ESM2 similar proteins: A0A4X1TB62, A4VCH4, G3V7Q0, O14795, O35841, O43237, O70585, P23116, P48553, Q0P5J8, Q14152, Q15542, Q1JU68, Q3TLI0, Q3UHE1, Q4R5P6, Q5R660, Q5R7S4, Q5R7U7, Q5RE09, Q5RE70, Q5VSL9, Q5XI83, Q658Y4, Q68E01, Q6IQ26, Q6PAL8, Q6PDL0, Q6TEP1, Q6WKZ8, Q7SYD9, Q7TPD0, Q8BIK4, Q8BWQ6, Q8C079, Q8C092, Q8C9H6, Q8CBY8, Q8IWV8, Q8K400

Diamond homologs: A2AF47, B0R034, Q5JSL3, Q63603, Q8BIK4, Q8BZN6, Q8C147, Q8NF50, Q96BY6, Q9BZ29, Q9VZZ9, Q8R1A4, Q8VDR9, Q96HP0, Q96N67

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 47 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
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	6	126.0×	1e-09
FOXO-mediated transcription	6	63.0×	5e-08
SARS-CoV-1-host interactions	6	32.9×	1e-06
SARS-CoV-1 Infection	6	26.8×	2e-06
Cell Cycle Checkpoints	5	13.8×	3e-04
RHO GTPase Effectors	5	10.6×	7e-04
SARS-CoV Infections	6	10.4×	2e-04
Transcriptional Regulation by TP53	5	9.7×	9e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	228
Likely benign	10
Benign	4

Top pathogenic / likely-pathogenic (0)

SpliceAI

8469 predictions. Top by Δscore:

Variant	Effect	Δscore
13:98794744:CAGAT:C	acceptor_gain	1.0000
13:98794745:AGAT:A	acceptor_gain	1.0000
13:98794746:GAT:G	acceptor_gain	1.0000
13:98794746:GATC:G	acceptor_loss	1.0000
13:98794747:AT:A	acceptor_gain	1.0000
13:98794749:C:A	acceptor_loss	1.0000
13:98794749:C:CC	acceptor_gain	1.0000
13:98794750:T:C	acceptor_gain	1.0000
13:98794750:T:TC	acceptor_gain	1.0000
13:98797111:TCACC:T	donor_loss	1.0000
13:98797112:CACCT:C	donor_loss	1.0000
13:98797113:ACCT:A	donor_loss	1.0000
13:98797114:CCTG:C	donor_gain	1.0000
13:98797176:T:TA	donor_gain	1.0000
13:98797249:ATTGC:A	acceptor_gain	1.0000
13:98797250:TTGC:T	acceptor_gain	1.0000
13:98797251:TGC:T	acceptor_gain	1.0000
13:98797252:GC:G	acceptor_gain	1.0000
13:98797253:CC:C	acceptor_gain	1.0000
13:98797254:C:CC	acceptor_gain	1.0000
13:98797254:CTGG:C	acceptor_loss	1.0000
13:98797259:A:C	acceptor_gain	1.0000
13:98797262:G:C	acceptor_gain	1.0000
13:98797262:G:GC	acceptor_gain	1.0000
13:98797265:C:CT	acceptor_gain	1.0000
13:98797266:A:T	acceptor_gain	1.0000
13:98797269:C:CT	acceptor_gain	1.0000
13:98797270:G:T	acceptor_gain	1.0000
13:98797383:CTTTA:C	donor_loss	1.0000
13:98797384:TTTAC:T	donor_loss	1.0000

AlphaMissense

13935 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
13:98800310:A:G	L1980P	1.000
13:98800316:A:G	L1978P	1.000
13:98807686:A:T	V1845D	1.000
13:98807725:A:G	L1832P	1.000
13:98809371:C:G	R1784P	1.000
13:98829353:A:G	L1618P	1.000
13:98829357:A:G	W1617R	1.000
13:98829357:A:T	W1617R	1.000
13:98829368:A:G	L1613P	1.000
13:98829410:A:G	L1599P	1.000
13:98915472:A:G	L251P	1.000
13:98797137:A:G	L2060P	0.999
13:98797404:A:G	L2016P	0.999
13:98797455:A:G	F1999S	0.999
13:98800322:A:G	L1976P	0.999
13:98800397:G:T	A1951D	0.999
13:98800449:G:T	R1934S	0.999
13:98805004:A:G	L1922P	0.999
13:98805016:C:G	R1918P	0.999
13:98805157:A:T	V1871D	0.999
13:98805169:T:G	Q1867P	0.999
13:98805172:A:T	I1866N	0.999
13:98805178:G:T	A1864E	0.999
13:98805193:A:G	L1859P	0.999
13:98807727:T:A	R1831S	0.999
13:98807727:T:G	R1831S	0.999
13:98807766:C:A	K1818N	0.999
13:98807766:C:G	K1818N	0.999
13:98807771:A:C	Y1817D	0.999
13:98809356:C:T	G1789E	0.999

dbSNP variants (sampled 300 via entrez): RS1000000649 (13:98812122 A>C), RS1000017445 (13:99006194 T>A), RS1000086386 (13:99064052 T>G), RS1000091243 (13:98886705 G>A,T), RS1000108830 (13:99089172 A>G), RS1000138143 (13:98958603 G>A), RS1000138590 (13:98937949 G>C,T), RS1000141008 (13:99067599 G>A), RS1000150791 (13:98803425 T>C), RS1000157605 (13:98983299 G>T), RS1000214944 (13:99067869 GCTT>G), RS1000230738 (13:98983040 T>C), RS1000253304 (13:99006970 T>C), RS1000253981 (13:98896802 G>T), RS1000254655 (13:98854543 C>A)

Disease associations

OMIM: gene MIM:607325 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
keratoconus	Limited	Autosomal dominant

Mondo (1): keratoconus (MONDO:0015486)

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

17 associations (top):

Study	Trait	p-value
GCST004033_18	QRS interval (sulfonylurea treatment interaction)	2.000000e-07
GCST005986_19	Blood urea nitrogen levels	1.000000e-13
GCST006288_160	Heel bone mineral density	1.000000e-16
GCST006288_399	Heel bone mineral density	4.000000e-13
GCST006288_429	Heel bone mineral density	8.000000e-29
GCST006979_1036	Heel bone mineral density	9.000000e-67
GCST007159_10	Corneal astigmatism	7.000000e-07
GCST007431_18	Lung function (FEV1/FVC)	5.000000e-12
GCST007432_51	FEV1	2.000000e-06
GCST007995_42	Asthma (childhood onset)	5.000000e-13
GCST008062_66	Blood urea nitrogen levels	6.000000e-16
GCST009356_13	Nonsyndromic cleft palate	5.000000e-12
GCST010002_194	Refractive error	2.000000e-76
GCST011365_107	Myocardial infarction	7.000000e-07
GCST90000025_1055	Appendicular lean mass	2.000000e-18
GCST90002401_61	Platelet distribution width	3.000000e-09
GCST90002407_612	White blood cell count	1.000000e-09

EFO canonical traits (7, from GWAS)

EFO ID	Trait name
EFO:0007922	response to sulfonylurea
EFO:0009270	heel bone mineral density
EFO:1002040	Corneal astigmatism
EFO:0004713	FEV/FVC ratio
EFO:0004314	forced expiratory volume
EFO:0004980	appendicular lean mass
EFO:0007984	platelet component distribution width

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D007640	Keratoconus	C11.204.627

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, increases methylation	7
trichostatin A	increases expression, affects cotreatment	3
methylmercuric chloride	decreases expression	2
bisphenol A	affects cotreatment, increases methylation, increases expression	2
mercuric bromide	increases expression, affects cotreatment	2
Panobinostat	increases expression, affects cotreatment	2
Nickel	decreases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Aflatoxin B1	affects methylation, increases methylation	2
aristolochic acid I	decreases expression	1
FR900359	affects phosphorylation	1
2,4,6-tribromophenol	decreases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
decabromobiphenyl ether	increases expression	1
beta-lapachone	decreases expression, increases expression	1
arsenite	affects binding, decreases reaction	1
sodium arsenite	increases reaction, affects binding	1
cobaltous chloride	decreases expression	1
butyraldehyde	decreases expression	1
benzo(e)pyrene	decreases methylation	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
methacrylaldehyde	increases oxidation, increases abundance, affects cotreatment	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
pentanal	decreases expression	1
perfluorooctane sulfonic acid	increases expression	1
2-palmitoylglycerol	increases expression	1
monomethylarsonous acid	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
abrine	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01485211	PHASE4	COMPLETED	Corneal Thickness Changes During Corneal Collagen Cross-linking With Ultraviolet-A Irradiation and Riboflavin
NCT02119039	PHASE4	COMPLETED	Effect of CACICOL20 on Corneal Epithelial Healing After Cross-linking in Patients With Keratoconus
NCT03245853	PHASE4	COMPLETED	Epi-On Corneal Crosslinking for Keratoconus
NCT03429569	PHASE4	UNKNOWN	Cross-Linking ACcéléré Iontophorèse Confocal kératocONE
NCT04427956	PHASE4	COMPLETED	Corneal Crosslinking Treatment Study
NCT07474870	PHASE4	NOT_YET_RECRUITING	Outcomes of CTAK Surgery
NCT00371202	PHASE3	UNKNOWN	Comparison of Penetrating Keratoplasty and Deep Lamellar Keratoplasty With the Big Bubble Technique for Keratoconus
NCT00647699	PHASE3	COMPLETED	Corneal Collagen Cross-linking for Progressive Keratoconus
NCT00815256	PHASE3	UNKNOWN	Safety and Effectiveness of Collagen Cross Linking in Progressive Mild and Moderate Keratoconus
NCT00887900	PHASE3	COMPLETED	Deep Anterior Lamellar Keratoplasty (DALK)
NCT01112072	PHASE3	UNKNOWN	Corneal Collagen Crosslinking and Intacs for Keratoconus and Ectasia
NCT01152541	PHASE3	UNKNOWN	Corneal Collagen Crosslinking for Progressive Keratoconus and Ectasia Using Riboflavin/Dextran and Hypotonic Riboflavin
NCT01190306	PHASE3	TERMINATED	Safety Study of the VEGA UV-A System to Treat Keratoconus
NCT01344187	PHASE3	COMPLETED	Safety and Efficacy Study of Corneal Collagen Cross-Linking in Eyes With Keratoconus
NCT01459679	PHASE3	TERMINATED	Safety & Efficacy of Corneal Collagen Cross-Linking in Eyes With Keratoconus or Corneal Ectasia After Refractive Surgery
NCT01464268	PHASE3	UNKNOWN	Transepithelial Corneal Collagen Crosslinking for Keratoconus and Corneal Ectasia
NCT01604135	PHASE3	ACTIVE_NOT_RECRUITING	Collagen Crosslinking for Keratoconus - a Randomized Controlled Clinical Trial
NCT01643226	PHASE3	COMPLETED	Safety and Efficacy Study of Corneal Collagen Cross-Linking in Eyes With Keratoconus
NCT01672814	PHASE3	COMPLETED	Microwave Treatment and Corneal Collagen Crosslinking for Keratoconus
NCT01682993	PHASE3	TERMINATED	Corneal Cross Linking and Topography Guided Excimer Laser Treatment
NCT01972854	PHASE3	TERMINATED	Safety and Efficacy of Corneal Collagen Cross-Linking in Eyes With Keratoconus
NCT02613780	PHASE3	UNKNOWN	Refractive Treatment of Early Keratoconus
NCT02638376	PHASE3	UNKNOWN	Evaluating the Safety and Efficacy of the KXL System for Corneal Collagen Cross-Linking in Eyes Having Keratoconus
NCT03080077	PHASE3	UNKNOWN	Safety and Effectiveness of Corneal Crosslinking (CXL): Keratoconus and Post-Refractive Ectasia
NCT03187912	PHASE3	COMPLETED	Accelerated Corneal Cross-linking With Different Riboflavin Solutions
NCT03442751	PHASE3	COMPLETED	Study to Evaluate the Safety and Efficacy of Epi-on Corneal Cross-linking in Eyes With Progressive Keratoconus
NCT03858036	PHASE3	UNKNOWN	Corneal Collagen Cross-Linking (CXL) Performed With Epi-ON Versus Epi-OFF in Eyes With Keratoconus and Other Corneal Ectatic Disorders
NCT04897503	PHASE3	UNKNOWN	Corneal Collagen Crosslinking for Keratoconus and Ectasia Using Riboflavin/Dextran or Riboflavin/Methylcellulose
NCT04905108	PHASE3	UNKNOWN	Transepithelial (Epi-on) Corneal Collagen Crosslinking to Treat Keratoconus and Corneal Ectasia
NCT05027295	PHASE3	UNKNOWN	Accelerated Corneal Collagen Crosslinking for Keratoconus and Ectasia Using Pulse or Continuous UV-A Light
NCT06100939	PHASE3	ACTIVE_NOT_RECRUITING	Epithelium-On Corneal Cross-linking in Subjects 8 to 45 Years of Age With Keratoconus
NCT06100952	PHASE3	ACTIVE_NOT_RECRUITING	Epithelium-On Corneal Cross-linking in Subjects 8 to 45 Years of Age with Keratoconus
NCT06450470	PHASE3	RECRUITING	Use of a Freeze-dried Amniotic Membrane Post Crosslinking in Subjects With Progressive Keratoconus
NCT06601101	PHASE3	RECRUITING	Effects of Topical Insulin on Corneal Epithelium Healing After Corneal Crosslinking in Patients With Keratoconus
NCT07124910	PHASE3	RECRUITING	Comparison of Epi-ON Corneal Collagen Crosslinking Performed Using an 18-Minute UVA Exposure vs. a 24-Minute UVA Exposure on Eyes With Ectatic Corneal Diseases
NCT07135167	PHASE3	RECRUITING	Compassionate Use Study of Epi-ON Corneal Collagen Crosslinking Performed Using UVA Exposure on Eyes With Ectatic Corneal Diseases for Subjects With Down Syndrome
NCT00409955	PHASE2	COMPLETED	Lamellar Transplant With Lyophilized Corneas
NCT00925327	PHASE2	UNKNOWN	Safety and Effectiveness of the UV-X System for Corneal Collagen Cross-Linking for Compassionate Treatment in Pediatric Patients With Progressive Keratoconus
NCT01143389	PHASE2	COMPLETED	Corneal Crosslinking in Patients With Keratoconus and Post-Refractive Ectasia
NCT01181219	PHASE2	COMPLETED	Transepithelial Corneal Collagen Cross-linking (CXL) in Treatment of Keratoconus