DIAPH3

Summary

DIAPH3 (diaphanous related formin 3, HGNC:15480) is a protein-coding gene on chromosome 13q21.2, encoding Protein diaphanous homolog 3 (Q9NSV4). Actin nucleation and elongation factor required for the assembly of F-actin structures, such as actin cables and stress fibers.

This gene encodes a member of the diaphanous subfamily of the formin family. Members of this family are involved in actin remodeling and regulate cell movement and adhesion. Mutations in this gene are associated with autosomal dominant auditory neuropathy 1. Multiple transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 81624 — RefSeq curated summary.

At a glance

• Gene–disease (curated): autosomal dominant nonsyndromic hearing loss (Supportive, GenCC) — +2 more curated relationships
• GWAS associations: 15
• Clinical variants (ClinVar): 636 total — 2 pathogenic
• Phenotypes (HPO): 7
• MANE Select transcript: NM_001042517

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:15480
Approved symbol	DIAPH3
Name	diaphanous related formin 3
Location	13q21.2
Locus type	gene with protein product
Status	Approved
Aliases	DRF3, FLJ34705, AN, NSDAN
Ensembl gene	ENSG00000139734
Ensembl biotype	protein_coding
OMIM	614567
Entrez	81624

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 7 protein_coding, 2 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000267215, ENST00000377908, ENST00000400319, ENST00000400320, ENST00000400324, ENST00000465066, ENST00000470420, ENST00000498416, ENST00000615942, ENST00000649952

RefSeq mRNA: 7 — MANE Select: NM_001042517 NM_001042517, NM_001258366, NM_001258367, NM_001258368, NM_001258369, NM_001258370, NM_030932

CCDS: CCDS41898, CCDS58294, CCDS58295, CCDS58296, CCDS58297, CCDS73579, CCDS73580

Canonical transcript exons

ENST00000400324 — 28 exons

Exon	Start	End
ENSE00001475479	59774189	59774248
ENSE00001634806	60132957	60132989
ENSE00001660462	60015913	60015982
ENSE00001668777	60042690	60042820
ENSE00001678802	60016071	60016145
ENSE00001751108	60093628	60093732
ENSE00001806741	60112010	60112186
ENSE00001891196	60163587	60163928
ENSE00001892921	59665583	59666846
ENSE00003540828	60010533	60010669
ENSE00003553861	59861407	59861536
ENSE00003713074	59970852	59971160
ENSE00003715173	60008544	60008649
ENSE00003718160	59991158	59991274
ENSE00003725076	59833107	59833271
ENSE00003725145	59974352	59974456
ENSE00003726046	59774728	59774823
ENSE00003731831	59879229	59879468
ENSE00003733396	59992473	59992583
ENSE00003733540	59810788	59810923
ENSE00003733920	59992068	59992186
ENSE00003737799	59916155	59916249
ENSE00003741322	59983769	59983887
ENSE00003744869	59924775	59924870
ENSE00003747166	59911735	59911836
ENSE00003749783	59839324	59839448
ENSE00003751637	59969944	59970058
ENSE00003752503	59980795	59980859

Expression profiles

Bgee: expression breadth ubiquitous, 204 present calls, max score 91.48.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 16.3615 / max 261.8440, expressed in 1440 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
137465	14.3230	1411
137464	1.3254	555
137463	0.3856	216
137462	0.3141	168
137460	0.0134	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
sperm	CL:0000019	91.48	gold quality
ventricular zone	UBERON:0003053	90.46	gold quality
male germ cell	CL:0000015	87.91	gold quality
left testis	UBERON:0004533	84.80	gold quality
right testis	UBERON:0004534	84.35	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	84.34	gold quality
testis	UBERON:0000473	84.00	gold quality
secondary oocyte	CL:0000655	83.73	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	83.32	gold quality
ganglionic eminence	UBERON:0004023	82.78	gold quality
stromal cell of endometrium	CL:0002255	79.71	gold quality
buccal mucosa cell	CL:0002336	78.84	gold quality
trabecular bone tissue	UBERON:0002483	77.66	gold quality
oocyte	CL:0000023	76.93	gold quality
esophagus squamous epithelium	UBERON:0006920	76.33	gold quality
parietal pleura	UBERON:0002400	75.80	gold quality
cartilage tissue	UBERON:0002418	74.75	gold quality
tibia	UBERON:0000979	74.59	gold quality
placenta	UBERON:0001987	73.49	gold quality
oral cavity	UBERON:0000167	72.35	silver quality
epithelium of esophagus	UBERON:0001976	72.27	gold quality
adrenal tissue	UBERON:0018303	72.11	gold quality
pleura	UBERON:0000977	71.68	gold quality
bone marrow	UBERON:0002371	71.54	gold quality
amniotic fluid	UBERON:0000173	70.93	gold quality
caudate nucleus	UBERON:0001873	70.62	gold quality
anterior cingulate cortex	UBERON:0009835	70.22	gold quality
cingulate cortex	UBERON:0003027	70.15	gold quality
ascending aorta	UBERON:0001496	70.09	gold quality
mucosa of transverse colon	UBERON:0004991	70.00	gold quality

Single-cell (SCXA)

Detected in 6 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-MTAB-7051	yes	725.97
E-MTAB-11268	yes	632.36
E-MTAB-6678	yes	9.60
E-ANND-3	yes	6.29
E-CURD-119	no	743.28
E-MTAB-7249	no	370.14

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

95 targeting DIAPH3, 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-1277-5P	100.00	73.95	5056
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-548AT-5P	99.96	70.83	2666
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488
HSA-MIR-548AP-5P	99.94	71.14	3489
HSA-MIR-548AQ-5P	99.94	71.34	3426
HSA-MIR-548AR-5P	99.94	71.28	3515
HSA-MIR-548AS-5P	99.94	71.22	3482
HSA-MIR-548AU-5P	99.94	71.24	3488
HSA-MIR-548AY-5P	99.94	71.23	3502
HSA-MIR-548B-5P	99.94	71.23	3502
HSA-MIR-548BB-5P	99.94	71.27	3509
HSA-MIR-548C-5P	99.94	71.24	3488
HSA-MIR-548D-5P	99.94	71.23	3502
HSA-MIR-548H-5P	99.94	71.24	3488
HSA-MIR-548I	99.94	71.25	3481
HSA-MIR-548J-5P	99.94	71.14	3489
HSA-MIR-548O-5P	99.94	71.24	3488
HSA-MIR-548W	99.94	71.24	3488

Literature-anchored findings (GeneRIF, showing 31)

• These studies further suggest that Rho GTPases significantly influence the activity of mDia family formins in driving cellular membrane remodeling through the regulation of actin dynamics. (PMID:17198702)
• DIP-induced membrane blebbing was dependent on Diaphanous 2 but did not require the activities of either Diaphanous 1 or Actin-Related Protein 2-3 Complex. (PMID:17398099)
• Data show that Dia2 localizes in the lamella of migrating epithelial cells, where it is involved in the formation of a stable pool of cortical actin and in maintenance of polymerization-competent free filament barbed ends at focal adhesions. (PMID:17855386)
• Results suggest that WAVE and the Arp2/3 complex jointly orchestrate different types of actin-based plasma membrane protrusions by promoting ruffling and inhibiting mDia2-induced filopodia. (PMID:18516090)
• active Drf3 lacking the C-terminal regulatory region (Drf3DeltaDAD) induced the formation of filopodia and accumulated at their tips. (PMID:18755006)
• mDia2 is degraded at the end of mitosis; mDia2 is targeted for disposal by post-translational ubiquitin modification; forced expression of activated mDia2 yields binucleate cells due to failed cytokinesis (PMID:19457867)
• the amino terminus of mDia2 serves as a coincidence detection module, directing mDia2 to the plasma membrane through interactions with phospholipids and activated Rif (PMID:21119010)
• These findings reveal a key role for mDia3 and its regulation by Aurora B phosphorylation in achieving proper stable kinetochore microtubule attachment. (PMID:21397845)
• isoform-selective actin assembly by DIAPH3 exerts specific and differentially regulated functions during cell adhesion and motility. (PMID:22184005)
• In human tumours, DIAPH3 down-regulation was associated with aggressive or metastatic disease. (PMID:22593025)
• TGF-beta promotes association of mDia2 with actin stress fibers, which further drives stress fiber formation and myofibroblast differentiation (PMID:23580645)
• Dia1, Dia2, and Dia3 are involved in ErbB2-dependent capture of microtubules at the cell leading edge and ErbB2-driven guided migration. (PMID:24403606)
• An mDia2/ROCK signaling axis regulates invasive egress from epithelial ovarian cancer spheroids. (PMID:24587343)
• results suggest that inhibition of MT stability arising from DIAPH3 downregulation enhances susceptibility to MT poisons, and that the DIAPH3 network potentially reports taxane sensitivity in human tumors (PMID:26179371)
• we use a simple cellular system to examine fundamental features of formin-mediated filopodial assembly, using constitutively active constructs of the formins mDia2 and FMNL3 (PMID:26446836)
• Members of 3 generations of a family had dominant auditory neuropathy associated with a c.-172G>A point mutation in DIAPH3. (PMID:27658576)
• These data identify Diaph3 as a major guard of cortical progenitors, unravel novel functions of Diaphanous formins and add insights into the pathobiology of microcephaly. (PMID:27848932)
• mDia2 and CXCR4 associate in blebs upon CXCL12 stimulation. Both CXCR4 and RhoA are required for CXCL12-induced blebbing (PMID:28115158)
• DIAPH3 overexpression inhibits the migration and invasion of Triple-negative breast cancer by inhibiting RhoA-GTP expression. (PMID:28779705)
• study demonstrated the oncogenic activity of DIAPH3 in the progression of hepatocellular carcinoma and suggested that PDIAPH3 might be a therapeutic target. (PMID:28795316)
• through profilin-1 binding, CLIC4 functions in a RhoA-mDia2-regulated signaling network to integrate cortical actin assembly and membrane protrusion (PMID:30381396)
• Tropomyosin concentration but not formin nucleators mDia1 and mDia3 determines the level of tropomyosin incorporation into actin filaments. (PMID:31019238)
• The oncogenic roles of DIAPH3 in the tumorigenesis of lung cance. (PMID:31586548)
• Novel stromal biomarker screening in pancreatic cancer patients using the in vitro cancer-stromal interaction model. (PMID:33297976)
• DIAPH3 promotes pancreatic cancer progression by activating selenoprotein TrxR1-mediated antioxidant effects. (PMID:33345387)
• Diaph3 underlines tumor cell heterogeneity in glioblastoma with implications for treatment modalities resistance. (PMID:35380294)
• DIAPH3 is a prognostic biomarker and inhibit colorectal cancer progression through maintaining EGFR degradation. (PMID:35538918)
• DIAPH3 condensates formed by liquid-liquid phase separation act as a regulatory hub for stress-induced actin cytoskeleton remodeling. (PMID:36640348)
• The pan-cancer analysis identified DIAPH3 as a diagnostic biomarker of clinical cancer. (PMID:36750200)
• Super Enhancer-Regulated LncRNA LINC01089 Induces Alternative Splicing of DIAPH3 to Drive Hepatocellular Carcinoma Metastasis. (PMID:37756562)
• CircDiaph3 aggravates H/R-induced cardiomyocyte apoptosis and inflammation through miR-338-3p/SRSF1 axis. (PMID:38613636)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	diaph3	ENSDARG00000090785
mus_musculus	Diaph3	ENSMUSG00000022021
rattus_norvegicus	Diaph3	ENSRNOG00000008986
caenorhabditis_elegans		WBGENE00018976

Paralogs (18): DAAM1 (ENSG00000100592), FNBP4 (ENSG00000109920), DIAPH1 (ENSG00000131504), FHOD3 (ENSG00000134775), FHOD1 (ENSG00000135723), FHDC1 (ENSG00000137460), DAAM2 (ENSG00000146122), DIAPH2 (ENSG00000147202), FMN2 (ENSG00000155816), FMNL2 (ENSG00000157827), FMNL3 (ENSG00000161791), FMNL1 (ENSG00000184922), FAM47A (ENSG00000185448), SHTN1 (ENSG00000187164), FAM47B (ENSG00000189132), FAM47C (ENSG00000198173), INF2 (ENSG00000203485), GRID2IP (ENSG00000215045)

Protein

Protein identifiers

Protein diaphanous homolog 3 — Q9NSV4 (reviewed: Q9NSV4)

Alternative names: Diaphanous-related formin-3, MDia2

All UniProt accessions (1): Q9NSV4

UniProt curated annotations — full annotation on UniProt →

Function. Actin nucleation and elongation factor required for the assembly of F-actin structures, such as actin cables and stress fibers. Required for cytokinesis, stress fiber formation and transcriptional activation of the serum response factor. Binds to GTP-bound form of Rho and to profilin: acts in a Rho-dependent manner to recruit profilin to the membrane, where it promotes actin polymerization. DFR proteins couple Rho and Src tyrosine kinase during signaling and the regulation of actin dynamics. Also acts as an actin nucleation and elongation factor in the nucleus by promoting nuclear actin polymerization inside the nucleus to drive serum-dependent SRF-MRTFA activity.

Subcellular location. Cytoplasm. Nucleus.

Post-translational modifications. Ubiquitinated.

Disease relevance. Auditory neuropathy, autosomal dominant 1 (AUNA1) [MIM:609129] A form of sensorineural hearing loss with absent or severely abnormal auditory brainstem response, in the presence of normal cochlear outer hair cell function and normal otoacoustic emissions. Auditory neuropathies result from a lesion in the area including the inner hair cells, connections between the inner hair cells and the cochlear branch of the auditory nerve, the auditory nerve itself and auditory pathways of the brainstem. Affected individuals typically respond to sound but have difficulties in speech discrimination. The disease is caused by variants affecting the gene represented in this entry. A disease-causing mutation in the conserved 5’-UTR leads to increased protein expression.

Domain organisation. The DAD domain regulates activation via by an autoinhibitory interaction with the GBD/FH3 domain. This autoinhibition is released upon competitive binding of an activated GTPase. The release of DAD allows the FH2 domain to then nucleate and elongate nonbranched actin filaments.

Similarity. Belongs to the formin homology family. Diaphanous subfamily.

Isoforms (7)

UniProt ID	Names	Canonical?
Q9NSV4-3	3	yes
Q9NSV4-1	1
Q9NSV4-2	2
Q9NSV4-4	4
Q9NSV4-5	5
Q9NSV4-6	6
Q9NSV4-7	7

RefSeq proteins (7): NP_001035982, NP_001245295, NP_001245296, NP_001245297, NP_001245298, NP_001245299, NP_112194 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR010472	FH3_dom	Domain
IPR010473	GTPase-bd	Domain
IPR011989	ARM-like	Homologous_superfamily
IPR014767	DAD_dom	Domain
IPR014768	GBD/FH3_dom	Domain
IPR015425	FH2_Formin	Domain
IPR016024	ARM-type_fold	Homologous_superfamily
IPR042201	FH2_Formin_sf	Homologous_superfamily
IPR044933	DIA_GBD_sf	Homologous_superfamily
IPR051412	Formin_Homology_Diaphanous_sf	Family

Pfam: PF02181, PF06367, PF06371

UniProt features (39 total): splice variant 8, modified residue 7, sequence conflict 7, domain 4, sequence variant 3, short sequence motif 2, compositionally biased region 2, region of interest 2, coiled-coil region 2, chain 1, helix 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
5UWP	X-RAY DIFFRACTION	2.05
6X2Y	X-RAY DIFFRACTION	2.3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NSV4-F1	72.33	0.30

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 (7): 26, 68, 77, 175, 624, 1093, 1179

Function

Pathways and Gene Ontology

Reactome pathways

13 pathways

ID	Pathway
R-HSA-5663220	RHO GTPases Activate Formins
R-HSA-8980692	RHOA GTPase cycle
R-HSA-9013026	RHOB GTPase cycle
R-HSA-9013106	RHOC GTPase cycle
R-HSA-9013148	CDC42 GTPase cycle
R-HSA-9013149	RAC1 GTPase cycle
R-HSA-9013404	RAC2 GTPase cycle
R-HSA-9013405	RHOD GTPase cycle
R-HSA-9013406	RHOQ GTPase cycle
R-HSA-9013408	RHOG GTPase cycle
R-HSA-9013409	RHOJ GTPase cycle
R-HSA-9013423	RAC3 GTPase cycle
R-HSA-9035034	RHOF GTPase cycle

MSigDB gene sets: 349 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, chr13q21, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_ACTIN_FILAMENT_BUNDLE_ORGANIZATION, GOBP_MYELOID_CELL_HOMEOSTASIS, GOBP_ESTABLISHMENT_OR_MAINTENANCE_OF_CELL_POLARITY, GOBP_REGULATION_OF_MICROTUBULE_BASED_PROCESS, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, GOBP_MYELOID_CELL_DEVELOPMENT, GOBP_SENSORY_PERCEPTION_OF_MECHANICAL_STIMULUS, GOBP_VESICLE_ORGANIZATION, GOBP_ERYTHROCYTE_HOMEOSTASIS, GOBP_MEMBRANE_FUSION, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN

GO Biological Process (28): in utero embryonic development (GO:0001701), cytoskeleton organization (GO:0007010), negative regulation of microtubule depolymerization (GO:0007026), chromosome segregation (GO:0007059), integrin-mediated signaling pathway (GO:0007229), sensory perception of sound (GO:0007605), gene expression (GO:0010467), endosomal transport (GO:0016197), establishment of cell polarity (GO:0030010), cell projection organization (GO:0030030), actin cytoskeleton organization (GO:0030036), actin filament polymerization (GO:0030041), macrophage differentiation (GO:0030225), protein-containing complex remodeling (GO:0034367), erythrocyte enucleation (GO:0043131), actin nucleation (GO:0045010), microtubule polymerization (GO:0046785), actin filament bundle assembly (GO:0051017), actin crosslink formation (GO:0051764), inner ear receptor cell differentiation (GO:0060113), head development (GO:0060322), autophagosome-lysosome fusion (GO:0061909), podosome assembly (GO:0071800), microtubule cytoskeleton organization (GO:0000226), actin filament organization (GO:0007015), cellular component organization (GO:0016043), neuron differentiation (GO:0030182), erythrocyte differentiation (GO:0030218)

GO Molecular Function (6): actin binding (GO:0003779), microtubule binding (GO:0008017), small GTPase binding (GO:0031267), protein homodimerization activity (GO:0042803), cadherin binding (GO:0045296), cytoskeletal protein binding (GO:0008092)

GO Cellular Component (12): ESCRT I complex (GO:0000813), spindle pole (GO:0000922), nucleus (GO:0005634), cytoplasm (GO:0005737), microtubule organizing center (GO:0005815), cytosol (GO:0005829), actin filament (GO:0005884), filamentous actin (GO:0031941), cleavage furrow (GO:0032154), actin filament bundle (GO:0032432), ribbon synapse (GO:0097470), stereocilia tip-link density (GO:1990427)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
RHO GTPase cycle	12
RHO GTPase Effectors	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	6
protein polymerization	2
actin filament organization	2
actin cytoskeleton	2
actin filament	2
chordate embryonic development	1
organelle organization	1
microtubule depolymerization	1
negative regulation of microtubule polymerization or depolymerization	1
regulation of microtubule depolymerization	1
negative regulation of protein depolymerization	1
negative regulation of supramolecular fiber organization	1
cell cycle process	1
cell surface receptor signaling pathway	1
sensory perception of mechanical stimulus	1
macromolecule biosynthetic process	1
vesicle-mediated transport	1
intracellular transport	1
establishment or maintenance of cell polarity	1
cellular component organization	1
cytoskeleton organization	1
actin filament-based process	1
actin polymerization or depolymerization	1
myeloid leukocyte differentiation	1
mononuclear cell differentiation	1
protein-containing complex organization	1
enucleate erythrocyte maturation	1
enucleation	1
microtubule nucleation	1
microtubule polymerization or depolymerization	1
supramolecular fiber organization	1
cellular component assembly	1
actin filament bundle organization	1
mechanoreceptor differentiation	1
inner ear development	1
cytoskeletal protein binding	1
tubulin binding	1
GTPase binding	1
identical protein binding	1
protein dimerization activity	1

Protein interactions and networks

STRING

2171 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DIAPH3	ANLN	Q9NQW6	967
DIAPH3	RHOA	P06749	899
DIAPH3	PFN4	Q8NHR9	839
DIAPH3	BLVRB	P30043	828
DIAPH3	BLVRA	P53004	826
DIAPH3	PFN3	P60673	805
DIAPH3	CDC42	P21181	797
DIAPH3	PFN1	P07737	784
DIAPH3	WDHD1	O75717	745
DIAPH3	VASP	P50552	726
DIAPH3	RHOB	P01121	722
DIAPH3	WASF2	Q9Y6W5	676
DIAPH3	NCKIPSD	Q9NZQ3	654
DIAPH3	WASL	O00401	618
DIAPH3	SRC	P12931	616

IntAct

68 interactions, top by confidence:

A	B	Type	Score
HS2ST1	SLC7A1	psi-mi:“MI:0914”(association)	0.730
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
SCN2B	EXOC5	psi-mi:“MI:0914”(association)	0.640
ENPP6	SCAMP1	psi-mi:“MI:0914”(association)	0.640
EPHA1	EXOC5	psi-mi:“MI:0914”(association)	0.530
COMTD1	IFRD1	psi-mi:“MI:0914”(association)	0.530
VASN	AP3B1	psi-mi:“MI:0914”(association)	0.530
CAPN2	MYO9A	psi-mi:“MI:0914”(association)	0.530
S100A4	OIP5	psi-mi:“MI:0914”(association)	0.530
DIAPH3	Dlg4	psi-mi:“MI:0407”(direct interaction)	0.440
DIAPH3	PGRMC1	psi-mi:“MI:0915”(physical association)	0.400
SIRT1	KPNA3	psi-mi:“MI:0915”(physical association)	0.400
SMAD9	DIAPH3	psi-mi:“MI:0915”(physical association)	0.370
Xpo1	IFT56	psi-mi:“MI:0914”(association)	0.350
KATNAL1	CDK1	psi-mi:“MI:0914”(association)	0.350
KATNAL2	CDK1	psi-mi:“MI:0914”(association)	0.350
BCHE		psi-mi:“MI:0914”(association)	0.350
PNKD	EXOC5	psi-mi:“MI:0914”(association)	0.350
HS2ST1	USP9Y	psi-mi:“MI:0914”(association)	0.350
TPTE2	DNAJB5	psi-mi:“MI:0914”(association)	0.350
CCDC183	PCNT	psi-mi:“MI:0914”(association)	0.350
	ZFC3H1	psi-mi:“MI:0914”(association)	0.350
IMMP2L	ANKHD1-EIF4EBP3	psi-mi:“MI:0914”(association)	0.350

BioGRID (154): DIAPH3 (Affinity Capture-RNA), DIAPH3 (Affinity Capture-RNA), DIAPH3 (Affinity Capture-MS), DIAPH3 (Affinity Capture-MS), DIAPH3 (Affinity Capture-MS), DIAPH3 (Affinity Capture-MS), DIAPH3 (Affinity Capture-MS), DIAPH3 (Affinity Capture-MS), DIAPH3 (Co-fractionation), DIAPH3 (Co-fractionation), DIAPH3 (Proximity Label-MS), DIAPH3 (Proximity Label-MS), DIAPH3 (Proximity Label-MS), DIAPH3 (Proximity Label-MS), DIAPH3 (Proximity Label-MS)

ESM2 similar proteins: A0JM95, A1A4S6, A2A2Y4, A4II46, A4IJ06, A6NI28, B2RQE8, B5DFQ4, F1LVW7, O60879, O60890, O70566, O95267, P0C7A6, P0CAX5, Q02384, Q07889, Q07890, Q08DP6, Q0P4Q4, Q28EC1, Q4V7P7, Q566W7, Q5R6F6, Q5R803, Q5U4T3, Q62245, Q69ZK0, Q6DBW1, Q6DHR3, Q6NTL4, Q6PCS4, Q6Y5D8, Q6ZM89, Q7YQL5, Q7YQL6, Q8AVG0, Q8BHD4, Q8IV61, Q8N9B8

Diamond homologs: A3AB67, B0DOB5, F1LVW7, F1M775, O08808, O23373, O60610, O60879, O70566, P48608, Q0D519, Q0D5P3, Q10Q99, Q6H7U3, Q6MWG9, Q8H8K7, Q8S0F0, Q9FJX6, Q9MA60, Q9NSV4, Q9Z207, A0A1D5P556, O04532, Q10059, Q27J81, Q54N00, Q54WH2, Q69MT2, Q9XIE0, A2XUA1, A2YVG8, O22824, O48682, Q0DLG0, Q3ULZ2, Q6ZKB2, Q7XUV2, Q8GX37, Q94B77, Q9C0D6

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 87 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
Loss of Nlp from mitotic centrosomes	5	15.9×	2e-03
Loss of proteins required for interphase microtubule organization from the centrosome	5	15.9×	2e-03
AURKA Activation by TPX2	5	15.2×	2e-03
Recruitment of mitotic centrosome proteins and complexes	5	13.6×	3e-03
Regulation of PLK1 Activity at G2/M Transition	5	12.7×	3e-03
Recruitment of NuMA to mitotic centrosomes	5	11.7×	4e-03
Anchoring of the basal body to the plasma membrane	5	11.3×	4e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	0
Uncertain significance	346
Likely benign	178
Benign	60

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
625742	GRCh37/hg19 13q21.1-21.32(chr13:59424409-65723208)	Pathogenic
984530	NM_001042517.2(DIAPH3):c.2059del (p.Cys687fs)	Pathogenic

SpliceAI

7581 predictions. Top by Δscore:

Variant	Effect	Δscore
13:59696079:T:C	donor_gain	1.0000
13:59774819:ACCCT:A	acceptor_gain	1.0000
13:59774820:CCCT:C	acceptor_gain	1.0000
13:59774820:CCCTC:C	acceptor_gain	1.0000
13:59774821:CCT:C	acceptor_gain	1.0000
13:59774821:CCTC:C	acceptor_gain	1.0000
13:59774822:CT:C	acceptor_gain	1.0000
13:59774822:CTC:C	acceptor_gain	1.0000
13:59774823:TCTGT:T	acceptor_gain	1.0000
13:59774824:C:CC	acceptor_gain	1.0000
13:59774824:C:CG	acceptor_loss	1.0000
13:59774824:C:G	acceptor_gain	1.0000
13:59774825:T:A	acceptor_loss	1.0000
13:59774826:G:C	acceptor_gain	1.0000
13:59810780:GTACT:G	donor_loss	1.0000
13:59810784:TCAC:T	donor_loss	1.0000
13:59810785:CACCA:C	donor_loss	1.0000
13:59810786:A:AC	donor_gain	1.0000
13:59810786:AC:A	donor_gain	1.0000
13:59810787:C:CC	donor_gain	1.0000
13:59810787:CC:C	donor_gain	1.0000
13:59810787:CCA:C	donor_gain	1.0000
13:59810787:CCAGT:C	donor_gain	1.0000
13:59810920:CTTG:C	acceptor_gain	1.0000
13:59810921:TTG:T	acceptor_gain	1.0000
13:59810922:TG:T	acceptor_gain	1.0000
13:59810922:TGCTA:T	acceptor_loss	1.0000
13:59810924:C:CC	acceptor_gain	1.0000
13:59810924:CT:C	acceptor_loss	1.0000
13:59810925:T:C	acceptor_loss	1.0000

AlphaMissense

7950 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
13:59774762:G:C	F1075L	0.998
13:59774762:G:T	F1075L	0.998
13:59774764:A:G	F1075L	0.998
13:59774793:A:G	L1065P	0.998
13:60042720:A:G	L199P	0.998
13:60093670:T:A	K151N	0.998
13:60093670:T:G	K151N	0.998
13:59774785:C:G	A1068P	0.997
13:59924777:A:G	L723P	0.997
13:59992146:A:G	L389P	0.997
13:59992567:A:G	L344P	0.997
13:60015935:A:G	L250P	0.997
13:59970025:A:G	W665R	0.996
13:59970025:A:T	W665R	0.996
13:59970860:A:G	W651R	0.996
13:59970860:A:T	W651R	0.996
13:60015939:A:G	C249R	0.996
13:59774763:A:G	F1075S	0.995
13:59774781:A:G	L1069S	0.995
13:59992498:C:G	R367P	0.995
13:59992555:A:G	L348P	0.995
13:59992559:C:G	A347P	0.995
13:59992560:A:C	N346K	0.995
13:59992560:A:T	N346K	0.995
13:60010560:G:T	A294E	0.995
13:60093692:C:G	R144P	0.995
13:60093719:A:G	L135S	0.995
13:59774763:A:C	F1075C	0.994
13:59774766:G:T	A1074D	0.994
13:59774776:A:G	S1071P	0.994

dbSNP variants (sampled 300 via entrez): RS1000016943 (13:59977378 C>G,T), RS1000018857 (13:60088138 C>T), RS1000022476 (13:60099802 A>G), RS1000028517 (13:59698426 A>C), RS1000038965 (13:59806417 A>G), RS1000049519 (13:59926099 C>T), RS1000065724 (13:59791599 G>A), RS1000069660 (13:59835231 T>C), RS1000070112 (13:59782631 A>C,G), RS1000071664 (13:59999878 G>C), RS1000071992 (13:60043366 A>C), RS1000072635 (13:59876598 C>A), RS1000073013 (13:59740636 A>G), RS1000076322 (13:60059065 T>C,G), RS1000080688 (13:59835503 G>A,C,T)

Disease associations

OMIM: gene MIM:614567 | disease phenotypes: MIM:609129

GenCC curated gene-disease

Disease	Classification	Inheritance
autosomal dominant nonsyndromic hearing loss	Supportive	Autosomal dominant
autosomal dominant auditory neuropathy 1	Limited	Autosomal dominant
auditory neuropathy	Limited	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
auditory neuropathy	Limited	AD

Mondo (4): hearing loss disorder (MONDO:0005365), auditory neuropathy (MONDO:0021944), autosomal dominant auditory neuropathy 1 (MONDO:0012196), autosomal dominant nonsyndromic hearing loss (MONDO:0019587)

Orphanet (1): Rare autosomal dominant non-syndromic sensorineural deafness type DFNA (Orphanet:90635)

HPO phenotypes

7 total (7 of 7 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000407	Sensorineural hearing impairment
HP:0001963	Abnormal speech discrimination
HP:0003621	Juvenile onset
HP:0006958	Abnormal auditory evoked potentials
HP:0008529	Absence of acoustic reflex
HP:0011462	Young adult onset

GWAS associations

15 associations (top):

Study	Trait	p-value
GCST003854_44	Gut microbiota (functional units)	3.000000e-08
GCST004904_116	Body mass index	1.000000e-08
GCST005586_7	Breast milk fatty acid composition (maternal genotype effect)	5.000000e-09
GCST005587_6	Breast milk fatty acid composition (infant genotype effect)	5.000000e-07
GCST007325_120	General risk tolerance (MTAG)	3.000000e-11
GCST007326_49	Number of sexual partners	2.000000e-09
GCST007327_21	Smoking status (ever vs never smokers)	2.000000e-08
GCST007335_25	Age at first sexual intercourse	6.000000e-15
GCST007576_285	Chronotype	1.000000e-12
GCST007576_397	Chronotype	3.000000e-12
GCST009391_488	Metabolite levels	5.000000e-07
GCST010170_1	Neonatal total 25-hydroxyvitamin D levels (maternal genetic effect)	7.000000e-08
GCST010724_24	HOMA-B (corrected for HOMA-IR)	3.000000e-07
GCST011703_16	Smoking initiation	4.000000e-08
GCST90000047_241	Age at first sexual intercourse	9.000000e-13

EFO canonical traits (11, from GWAS)

EFO ID	Trait name
EFO:0007874	gut microbiome measurement
EFO:0004340	body mass index
EFO:0005939	parental genotype effect measurement
EFO:0007959	fetal genotype effect measurement
EFO:0008579	risk-taking behaviour
EFO:0004318	smoking behavior
EFO:0009749	age at first sexual intercourse measurement
EFO:0008328	chronotype measurement
EFO:0005001	phenylalanine measurement
EFO:0004469	HOMA-B
EFO:0005670	smoking initiation

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D034381	Hearing Loss	C09.218.458.341; C10.597.751.418.341; C23.888.592.763.393.341
C563790	Auditory Neuropathy, Autosomal Dominant, 1 (supp.)
C538268	Auditory neuropathy (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs77876672	Efficacy	3	hydrochlorothiazide	Essential hypertension

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs77876672	DIAPH3	3	0.00	1	hydrochlorothiazide

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	decreases expression, increases expression	5
bisphenol A	decreases expression, increases methylation	2
sodium arsenite	increases expression	2
potassium chromate(VI)	affects cotreatment, decreases expression	2
chromium hexavalent ion	decreases expression, increases abundance	2
bisphenol S	affects cotreatment, decreases expression, decreases methylation	2
Acetaminophen	increases expression, decreases expression	2
Silicon Dioxide	decreases expression	2
Tobacco Smoke Pollution	decreases expression, increases methylation	2
Valproic Acid	affects expression, decreases methylation	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	2
Cyclosporine	increases expression, decreases expression	2
Aflatoxin B1	affects expression, decreases methylation, increases expression	2
aristolochic acid I	decreases expression	1
afuresertib	decreases expression	1
FR900359	decreases phosphorylation	1
fluorene-9-bisphenol	increases expression	1
methylmercuric chloride	increases expression	1
propionaldehyde	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
zinc chromate	decreases expression, increases abundance	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, increases expression	1
2-amino-3,8-dimethylimidazo(4,5-f)quinoxaline	increases expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine	increases expression	1
perfluorooctane sulfonic acid	decreases expression	1
jinfukang	affects cotreatment, decreases expression	1
incobotulinumtoxinA	decreases expression	1
sparstolonin B	decreases expression	1
(+)-JQ1 compound	decreases expression	1

Cellosaurus cell lines

4 cell lines: 4 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_E1VP	HAP1 DIAPH3 (-) 1	Cancer cell line	Male
CVCL_E1VQ	HAP1 DIAPH3 (-) 2	Cancer cell line	Male
CVCL_E1VR	HAP1 DIAPH3 (-) 3	Cancer cell line	Male
CVCL_E1VS	HAP1 DIAPH3 (-) 4	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00205881	PHASE4	COMPLETED	Bilateral Benefit in Adult Users of the HiRes 90K Bionic Ear System
NCT00331539	PHASE4	UNKNOWN	Relationship Between Auto NRT and Behavioural T & C Levels With the Nucleus Freedom Cochlear Implant
NCT00424307	PHASE4	UNKNOWN	Bilateral Cochlear Implant Benefit in Young Children
NCT00765635	PHASE4	COMPLETED	Chlorobutanol, Potassium Carbonate, and Irrigation in Cerumen Removal
NCT03321006	PHASE4	COMPLETED	Treating Hearing Loss to Improve Mood and Cognition in Older Adults
NCT01499901	PHASE3	WITHDRAWN	Comparison of the Bilateral Sequential and Simultaneous Cochlear Implantation in the Deaf Children
NCT02561091	PHASE3	COMPLETED	AM-111 in the Treatment of Acute Inner Ear Hearing Loss
NCT03331627	PHASE3	COMPLETED	Safety and Efficacy of STR001-IT and STR001-ER in Patients With SSHL
NCT05532657	PHASE3	ACTIVE_NOT_RECRUITING	ACHIEVE Brain Health Follow-Up Study
NCT00013455	PHASE2	COMPLETED	Quantifying Auditory Perceptual Learning Following Hearing Aid Fitting
NCT00323427	PHASE2	COMPLETED	Clinical Trial of the Living Well With Hearing Loss Workshop
NCT00552786	PHASE2	COMPLETED	Antioxidation Medication for Noise-induced Hearing Loss
NCT00802425	PHASE2	COMPLETED	Efficacy of AM-111 in Patients With Acute Sensorineural Hearing Loss
NCT01139281	PHASE2	COMPLETED	The Protective Effect of Ginkgo Biloba Extract on Cisplatin-induced Ototoxicity in Humans
NCT01451853	PHASE2	UNKNOWN	SPI-1005 for Prevention and Treatment of Chemotherapy Induced Hearing Loss
NCT01588925	PHASE2	COMPLETED	Hearing Preservation Using Dexamethasone and Hyaluronic Acid for Cochlear Implantation
NCT01773278	PHASE2	RECRUITING	Cholesterol and Antioxidant Treatment in Patients With Smith-Lemli-Opitz Syndrome (SLOS)
NCT02832128	PHASE2	COMPLETED	Evaluating Possible Improvement in Speech and Hearing Tests After 28 Days of Dosing of the Study Drug AUT00063 Compared to Placebo (QuicKfire)
NCT04915183	PHASE2	RECRUITING	Atorvastatin to Reduce Cisplatin-Induced Hearing Loss Among Individuals With Head and Neck Cancer
NCT05258773	PHASE2	COMPLETED	Evaluation of the Presence of SENS-401 in the Perilymph
NCT06340633	PHASE2	RECRUITING	SPI-1005 in Adults Receiving Cochlear Implant
NCT00582946	PHASE1	COMPLETED	Wide-Bandwidth Open Canal Hearing Aid For Better Multitalker Speech Understanding
NCT00584155	PHASE1	WITHDRAWN	Protection From Cisplatin Ototoxicity by Lactated Ringers
NCT01206829	PHASE1	UNKNOWN	Hearing Impairment, Cognitive Therapy and Coping
NCT01256229	PHASE1	COMPLETED	Outcomes In Children With Developmental Delay And Deafness
NCT01343394	PHASE1	WITHDRAWN	Safety of Autologous Human Umbilical Cord Blood Mononuclear Fraction to Treat Acquired Hearing Loss in Children
NCT01452607	PHASE1	COMPLETED	Study to Evaluate the Safety and Pharmacokinetics of SPI-1005
NCT02259595	PHASE1	COMPLETED	Study to Determine the Safety, Tolerability, and Pharmacokinetic Profile of HPN-07 and HPN-07 Plus NAC
NCT04041440	PHASE1	COMPLETED	Speech Recognition Training in Children With Hearing Loss
NCT07218913	PHASE1	RECRUITING	Testing the Addition of Pedmark to Cisplatin Chemotherapy for Reducing Drug-Induced Ear Damage in Men With Stage II-III Metastatic Testicular Germ Cell Tumors
NCT07032038	PHASE1/PHASE2	NOT_YET_RECRUITING	First In Human Randomised Trial of Rincell-1 in Adults With a Cochlear Implant
NCT01023932	Not specified	COMPLETED	Auditory Neuropathy and Cochlear Implants
NCT05666466	Not specified	UNKNOWN	Noninvasive Diagnostic Techniques in Determination of Site of Lesion of Auditory Neuropathy Spectrum Disorder
NCT06125015	Not specified	COMPLETED	Unexpected ABR Results in Patients Suspected With Auditory Neuropathy Spectrum Disorder
NCT00486577	PHASE2/PHASE3	COMPLETED	Chronic Electrical Stimulation of the Auditory Cortex for Intractable Tinnitus
NCT00789061	PHASE2/PHASE3	UNKNOWN	Applying Proton Pump Inhibitor to Prevent and Treat Acute Fluctuating Hearing Loss in Patients With SLC26A4 Mutation
NCT01423409	PHASE2/PHASE3	COMPLETED	Multicenter Trial Assessing an Innovative VAS of Pain Among Deaf People
NCT05786378	PHASE2/PHASE3	UNKNOWN	Assessment of The Efficacy of Intratympanic Platelet Rich Plasma for Treatment of Sensorineural Hearing Loss.
NCT01108601	PHASE1/PHASE2	UNKNOWN	Transtympanic Ringer’s Lactate for the Prevention of Cisplatin Ototoxicity
NCT01621256	PHASE1/PHASE2	COMPLETED	Efficacy, Safety, and Tolerability of Ancrod in Patients With Sudden Hearing Loss