DIAPH1

Summary

DIAPH1 (diaphanous related formin 1, HGNC:2876) is a protein-coding gene on chromosome 5q31.3, encoding Protein diaphanous homolog 1 (O60610). Actin nucleation and elongation factor required for the assembly of F-actin structures, such as actin cables and stress fibers.

This gene is a homolog of the Drosophila diaphanous gene, and has been linked to autosomal dominant, fully penetrant, nonsyndromic sensorineural progressive low-frequency hearing loss. Actin polymerization involves proteins known to interact with diaphanous protein in Drosophila and mouse. It has therefore been speculated that this gene may have a role in the regulation of actin polymerization in hair cells of the inner ear. Alternatively spliced transcript variants encoding distinct isoforms have been found for this gene.

Source: NCBI Gene 1729 — RefSeq curated summary.

At a glance

• Gene–disease (curated): progressive microcephaly-seizures-cortical blindness-developmental delay syndrome (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 7
• Clinical variants (ClinVar): 1,947 total — 36 pathogenic, 33 likely-pathogenic (top 1% of genes corpus-wide)
• GTEx eGene: eQTL in 17 tissues, sQTL in 7 (q < 0.05)
• Phenotypes (HPO): 47
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• Constraint (gnomAD): pLI 1.00 (loss-of-function intolerant), LOEUF 0.37 (moderately constrained)
• MANE Select transcript: NM_005219
• Interaction hub: 1,819 STRING partners (top 9% of genes corpus-wide)

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2876
Approved symbol	DIAPH1
Name	diaphanous related formin 1
Location	5q31.3
Locus type	gene with protein product
Status	Approved
Aliases	hDIA1, LFHL1, mDia1
Ensembl gene	ENSG00000131504
Ensembl biotype	protein_coding
OMIM	602121
Entrez	1729

Gene structure

Transcript identifiers

Ensembl transcripts: 16 — 7 protein_coding, 4 protein_coding_CDS_not_defined, 3 retained_intron, 2 nonsense_mediated_decay

MANE Select: ENST00000389054

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 2: 4, TSL 4: 4, TSL 5: 3

ENST00000389054, ENST00000448451, ENST00000468119, ENST00000472516, ENST00000476339, ENST00000491754, ENST00000494967, ENST00000518047, ENST00000518484, ENST00000523100, ENST00000524301, ENST00000643312, ENST00000643718, ENST00000647330, ENST00000647433, ENST00001139609

RefSeq mRNA: 3 — MANE Select: NM_005219 NM_001079812, NM_001314007, NM_005219

CCDS: CCDS43373, CCDS43374, CCDS87331

Canonical transcript exons

ENST00000389054 — 28 exons

Exon	Start	End
ENSE00001504786	141571926	141572040
ENSE00002433803	141583485	141583615
ENSE00002447549	141583206	141583292
ENSE00002453535	141577475	141577591
ENSE00002467863	141584124	141584225
ENSE00002468421	141582312	141582375
ENSE00002474822	141574967	141575146
ENSE00002484253	141576756	141576871
ENSE00002486835	141573492	141574208
ENSE00002505979	141580744	141580883
ENSE00002524976	141576230	141576294
ENSE00003460486	141578515	141578625
ENSE00003463207	141578225	141578343
ENSE00003478221	141579088	141579196
ENSE00003489171	141528453	141528582
ENSE00003491307	141528702	141528941
ENSE00003517610	141515021	141517008
ENSE00003541262	141526038	141526173
ENSE00003548898	141587042	141587197
ENSE00003584222	141527573	141527697
ENSE00003593301	141534335	141534433
ENSE00003598560	141524143	141524229
ENSE00003605990	141529603	141529697
ENSE00003677015	141526297	141526461
ENSE00003690253	141529172	141529273
ENSE00003723728	141588224	141588250
ENSE00003769475	141571428	141571436
ENSE00003847922	141618798	141619000

Expression profiles

Bgee: expression breadth ubiquitous, 291 present calls, max score 98.43.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 37.4788 / max 1070.9863, expressed in 1817 samples.

Highest expression (Bgee): granulocyte, lower esophagus mucosa, leukocyte, monocyte, mononuclear cell.

Genetic regulation across tissues (GTEx eQTL / sQTL)

DIAPH1 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 17 tissues and its splicing (sQTL) in 7 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 24 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Artery Tibial	eqtl	3.1e-18	+0.27	5:141534095:T:A
Adipose Subcutaneous	eqtl	1.1e-15	+0.26	5:141631910:A:ATAT
Esophagus Gastroesophageal Junction	eqtl	9.1e-11	+0.28	5:141525582:A:G
Testis	sqtl	1.6e-10	-1.13	5:141572979:G:C
Artery Aorta	eqtl	1.8e-09	+0.28	5:141626120:A:G
Esophagus Muscularis	eqtl	4.2e-09	+0.23	5:141626120:A:G
Adipose Visceral Omentum	eqtl	6.5e-07	+0.18	5:141631309:T:C
Nerve Tibial	eqtl	7.4e-06	+0.18	5:141626120:A:G
Artery Tibial	sqtl	1.1e-05	-0.56	5:141519037:G:A
Muscle Skeletal	sqtl	2.5e-05	-0.34	5:141635675:G:T
Skin Sun Exposed Lower leg	sqtl	2.0e-04	-0.54	5:141536209:G:C
Esophagus Mucosa	sqtl	7.8e-04	-0.58	5:141567421:C:T
Artery Coronary	eqtl	8.6e-04	+0.32	5:141631910:A:ATAT
Lung	eqtl	2.3e-03	+0.11	5:141631309:T:C
Heart Atrial Appendage	eqtl	4.0e-03	+0.20	5:141519701:T:C
Thyroid	eqtl	7.2e-03	+0.13	5:141626120:A:G
Brain Cortex	eqtl	7.4e-03	+0.20	5:141513528:G:A
Pancreas	eqtl	8.9e-03	-0.11	5:141393821:G:T
Brain Hypothalamus	eqtl	1.6e-02	+0.41	5:142598623:C:T
Breast Mammary Tissue	eqtl	2.3e-02	+0.32	5:141469212:G:A

FANTOM5 promoters

8 alternative TSS:

Promoter ID	TPM avg	Samples expressed
63852	29.6259	1812
63853	3.7285	1455
63850	1.9398	1126
63854	1.1095	700
63851	0.6310	405
63845	0.2055	76
63855	0.1643	57
63843	0.0744	33

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	98.43	gold quality
lower esophagus mucosa	UBERON:0035834	97.96	gold quality
leukocyte	CL:0000738	97.38	gold quality
monocyte	CL:0000576	97.31	gold quality
mononuclear cell	CL:0000842	97.27	gold quality
calcaneal tendon	UBERON:0003701	97.14	gold quality
right lobe of liver	UBERON:0001114	97.12	gold quality
gastrocnemius	UBERON:0001388	97.09	gold quality
muscle of leg	UBERON:0001383	96.60	gold quality
esophagus mucosa	UBERON:0002469	96.25	gold quality
skin of leg	UBERON:0001511	96.05	gold quality
right lung	UBERON:0002167	96.03	gold quality
upper lobe of left lung	UBERON:0008952	95.96	gold quality
blood	UBERON:0000178	95.90	gold quality
amniotic fluid	UBERON:0000173	95.83	gold quality
hindlimb stylopod muscle	UBERON:0004252	95.40	gold quality
upper lobe of lung	UBERON:0008948	95.38	gold quality
islet of Langerhans	UBERON:0000006	95.32	gold quality
body of pancreas	UBERON:0001150	95.32	gold quality
skin of abdomen	UBERON:0001416	95.31	gold quality
tendon	UBERON:0000043	95.07	gold quality
liver	UBERON:0002107	94.97	gold quality
tonsil	UBERON:0002372	94.96	gold quality
lymph node	UBERON:0000029	94.94	gold quality
pancreas	UBERON:0001264	94.93	gold quality
metanephros cortex	UBERON:0010533	94.79	gold quality
gingival epithelium	UBERON:0001949	94.76	gold quality
apex of heart	UBERON:0002098	94.66	gold quality
colonic epithelium	UBERON:0000397	94.65	gold quality
bone marrow cell	CL:0002092	94.64	gold quality
esophagus squamous epithelium	UBERON:0006920	94.61	gold quality
adenohypophysis	UBERON:0002196	94.60	gold quality
zone of skin	UBERON:0000014	94.40	gold quality
gingiva	UBERON:0001828	94.38	gold quality
mouth mucosa	UBERON:0003729	94.33	gold quality
minor salivary gland	UBERON:0001830	94.27	gold quality
popliteal artery	UBERON:0002250	94.25	gold quality
tibial artery	UBERON:0007610	94.25	gold quality
left lobe of thyroid gland	UBERON:0001120	94.14	gold quality
body of stomach	UBERON:0001161	94.07	gold quality
muscle organ	UBERON:0001630	94.01	gold quality
skeletal muscle organ	UBERON:0014892	94.01	gold quality
oral cavity	UBERON:0000167	94.00	gold quality
pituitary gland	UBERON:0000007	93.95	gold quality
right lobe of thyroid gland	UBERON:0001119	93.94	gold quality
aorta	UBERON:0000947	93.91	gold quality
right coronary artery	UBERON:0001625	93.85	gold quality
mucosa of transverse colon	UBERON:0004991	93.77	gold quality
tongue squamous epithelium	UBERON:0006919	93.73	gold quality
ascending aorta	UBERON:0001496	93.62	gold quality
endometrium epithelium	UBERON:0004811	93.62	gold quality
epithelium of esophagus	UBERON:0001976	93.60	gold quality
thyroid gland	UBERON:0002046	93.60	gold quality
thoracic aorta	UBERON:0001515	93.58	gold quality
pharyngeal mucosa	UBERON:0000355	93.57	gold quality
squamous epithelium	UBERON:0006914	93.54	gold quality
spleen	UBERON:0002106	93.52	gold quality
ectocervix	UBERON:0012249	93.47	gold quality
stomach	UBERON:0000945	93.40	gold quality
descending thoracic aorta	UBERON:0002345	93.38	gold quality
adult mammalian kidney	UBERON:0000082	93.16	gold quality
esophagus	UBERON:0001043	93.09	gold quality
left coronary artery	UBERON:0001626	93.05	gold quality
gall bladder	UBERON:0002110	92.91	gold quality
synovial joint	UBERON:0002217	92.89	gold quality
ventricular zone	UBERON:0003053	92.82	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	92.77	gold quality
coronary artery	UBERON:0001621	92.72	gold quality
type B pancreatic cell	CL:0000169	92.71	silver quality
rectum	UBERON:0001052	92.70	gold quality
small intestine Peyer’s patch	UBERON:0003454	92.68	gold quality
stromal cell of endometrium	CL:0002255	92.49	gold quality
vermiform appendix	UBERON:0001154	92.49	gold quality
mucosa of stomach	UBERON:0001199	92.47	gold quality
heart left ventricle	UBERON:0002084	92.43	gold quality
bone marrow	UBERON:0002371	92.32	gold quality
skin of hip	UBERON:0001554	92.27	gold quality
vagina	UBERON:0000996	92.22	gold quality
cardiac ventricle	UBERON:0002082	92.17	gold quality
small intestine	UBERON:0002108	92.03	gold quality
ganglionic eminence	UBERON:0004023	92.00	gold quality
right uterine tube	UBERON:0001302	91.97	gold quality
right hemisphere of cerebellum	UBERON:0014890	91.80	gold quality
tibial nerve	UBERON:0001323	91.78	gold quality
lung	UBERON:0002048	91.77	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	91.74	gold quality
saliva-secreting gland	UBERON:0001044	91.67	gold quality
endocervix	UBERON:0000458	91.65	gold quality
cerebellar hemisphere	UBERON:0002245	91.63	gold quality
cerebellar cortex	UBERON:0002129	91.51	gold quality
trabecular bone tissue	UBERON:0002483	91.38	gold quality
tibialis anterior	UBERON:0001385	91.32	gold quality
left adrenal gland cortex	UBERON:0035825	91.32	gold quality
thymus	UBERON:0002370	91.26	gold quality
right adrenal gland cortex	UBERON:0035827	91.21	gold quality
caecum	UBERON:0001153	91.18	gold quality
subcutaneous adipose tissue	UBERON:0002190	91.18	gold quality
left adrenal gland	UBERON:0001234	91.17	gold quality
right frontal lobe	UBERON:0002810	91.12	gold quality
body of tongue	UBERON:0011876	91.05	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

HPA expression

RNA tissue specificity: Low tissue specificity

showing 60 of 79 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Liver	tissue	85.9	medium
Bone marrow	tissue	85.4	low
Choroid plexus	tissue	66.3
Thymus	tissue	63.9
Lymph node	tissue	62.7	low
Tonsil	tissue	62.3	low
Tongue	tissue	51.9
Esophagus	tissue	51.0	not detected
Pituitary gland	tissue	48.7
Lung	tissue	48.4	high
Vagina	tissue	46.7	not detected
Skin 1	tissue	44.8	low
Urinary bladder	tissue	44.0	medium
Stomach 1	tissue	43.5	high
Epididymis	tissue	42.3	medium
Parathyroid gland	tissue	41.9	not detected
Appendix	tissue	39.8	low
Duodenum	tissue	38.2	high
Kidney	tissue	36.0	low
Skeletal muscle	tissue	34.7	low
Spleen	tissue	34.7	low
Small intestine	tissue	34.5	medium
Thyroid gland	tissue	31.0	medium
Pancreas	tissue	29.9	high
Rectum	tissue	29.2	medium
Colon	tissue	29.2	medium
Gallbladder	tissue	28.2	high
Caudate putamen	tissue	27.4
Retina	tissue	26.5
Frontal cortex	tissue	25.5
Nucleus accumbens	tissue	24.7
Heart muscle	tissue	24.1	not detected
Fallopian tube	tissue	23.7	low
Placenta	tissue	23.6	high
Breast	tissue	22.7	medium
Locus coeruleus	tissue	22.1
Salivary gland	tissue	21.2	high
Postcentral gyrus	tissue	21.2
Cervix	tissue	20.7	medium
Adrenal gland	tissue	19.1	high
Seminal vesicle	tissue	18.2	high
Hippocampus	tissue	18.1	medium
Testis	tissue	17.6	high
Smooth muscle	tissue	17.5	not detected
Adipose tissue	tissue	17.3	not detected
Basal ganglia	tissue	17.2	low
Superior colliculi	tissue	16.8
Hypothalamus	tissue	16.6
Spinal cord	tissue	16.6
Amygdala	tissue	16.4
Hippocampal formation	tissue	16.4
Septum	tissue	16.0
Putamen	tissue	15.7
Entorhinal cortex	tissue	15.3
Cerebral cortex	tissue	15.2	high
Insular cortex	tissue	15.2
Endometrium 1	tissue	15.1	low
Prefrontal cortex	tissue	15.0
Temporal cortex	tissue	14.7
Motor cortex	tissue	14.6

Brain sub-regions (HPA Brain Atlas): detected in 192; highest nTPM — Blood vessel (49.4), Ventromedial nucleus (37.2), Arcuate nucleus (33.6), Caudate nucleus (26.5), Hippocampus, CA3 (24.6).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): MITF, TBXT

miRNA regulators (miRDB)

Targeting DIAPH1 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 100 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-6851-5P	100.00	65.63	1294
HSA-MIR-3689D	100.00	66.14	1181
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-4673	100.00	66.64	1490
HSA-MIR-4425	100.00	67.59	1049
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-485-3P	99.98	70.68	1585
HSA-MIR-539-3P	99.98	70.74	1616
HSA-MIR-4645-5P	99.98	65.81	1284
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-3910	99.95	71.13	2227
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-450B-5P	99.92	71.48	3175
HSA-MIR-4753-3P	99.90	71.03	3786
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057
HSA-MIR-3919	99.87	69.45	2489
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-221-5P	99.86	65.45	1052
HSA-MIR-8073	99.86	65.21	1118
HSA-MIR-4779	99.86	66.50	1583
HSA-MIR-6817-3P	99.79	68.35	2126
HSA-MIR-548AJ-5P	99.78	71.12	3085
HSA-MIR-548F-5P	99.78	71.02	3093
HSA-MIR-548G-5P	99.78	71.12	3085

Functional genomics

gnomAD constraint: pLI 1, LOEUF 0.367, missense Z 2.45 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD)

ENST00000389054 splits into 3 regions with different missense tolerance; 0 are missense-constrained. Missense variants in a constrained region (low observed/expected) are more likely to be pathogenic. gnomAD

Region (GRCh38)	Missense obs / exp	o/e	Constrained
5:141,516,854–141,534,347	344 / 512.2	0.67	no
5:141,534,348–141,577,554	589 / 549.3	1.07	no
5:141,577,555–141,618,914	377 / 497.1	0.76	no
ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• ROCK and Dia have opposing effects on adherens junctions downstream of Rho. (PMID:11992112)
• mDia influences Pax6-induced transcriptional activity and axonal pathfinding in a way opposite from ROCK (Rho kinase) and that it may act via Pax6 to modulate early neuronal development (PMID:12324464)
• pertains to studies in mouse (PMID:12324464)
• mDia is present in very small amounts in freshly isolated peripheral blood lymphocytes, is induced in vivo and in vitro during T cell activation, and is involved in regulating the F-actin/G-actin balance critical for T cell motility. (PMID:12847276)
• RhoA, mDia, and ROCK have roles in cell shape-dependent control of the Skp2-p27kip1 pathway and the G1/S transition (PMID:15096506)
• Results show that mDia1 and PKD2 interact in native and in transfected cells, and binding is mediated by the cytoplasmic C terminus of PKD2 binding to the mDia1 N terminus. (PMID:15123714)
• findings show that in melanomas invasiveness can be regulated epigenetically by the microphthalmia-associated transcription factor, Mitf, by regulation of the DIAPH1 gene; Mitf, via regulation of Dia1, can both inhibit invasiveness & promote proliferation (PMID:17182868)
• Increases in GTP-bound RHOA and DIAPH1 expression may contribute to the increase in uterine activity in idiopathic preterm labor. (PMID:17301291)
• Data suggest that Dia1 localizes to and controls E-cadherin-mediated junctions in a RhoA-dependent manner. (PMID:17940061)
• Angiopoietin 1 promotes the activation of mDia through RhoA, resulting in the association of mDia with Src. [mD1a] (PMID:18194650)
• mDia1 and Daam1 are platelet actin assembly factors having distinct efficiencies, and they are directly regulated by Rho GTPases (PMID:18218625)
• the interaction of the RAGE cytoplasmic domain with Dia-1 is required to transduce extracellular environmental cues evoked by binding of RAGE ligands to their cell surface receptor, resulting in Rac-1 and Cdc42 activation and cellular migration (PMID:18922799)
• Memo-RhoA-mDia1 signaling coordinates the organization of the lamellipodial actin network, adhesion site formation, and microtubule outgrowth within the cell leading edge to sustain cell motility. (PMID:18955552)
• Flies with mutations affecting the diaphanous,forked, and CG12026/TMHS genes displayed significant reductions in the amplitude of sound-evoked potentials compared to wild-type flies (PMID:19102128)
• These findings uncover a novel link between cadherin-mediated adhesion and the regulation of actin dynamics through the requirement for an Abi/Dia complex for the formation and stability of cell-cell junctions. (PMID:19158278)
• Rho mediates various phenotypes of malignant transformation by Ras and Src through its effectors, ROCK and mDia [review] (PMID:19160018)
• mDia1 was shown to translocate to the platelet cytoskeleton following thrombin stimulation, in a phosphoinositide 3-kinase (PI 3-kinase)-dependent manner. (PMID:19470376)
• loss of hDia1 did not disrupt actin assembly at the lytic synapse. Instead, loss of hDia1 led to perturbations in the microtubule cytoskeleton, including the targeting of microtubules to the lytic synapse (PMID:19913427)
• PI3-kinase regulates the thrombin-induced actin cytoskeleton reconstitution in platelets by the RhoA-mDia1 pathway. (PMID:20030946)
• mDia plays an important role in the development of force-induced transcriptional activation of SMA and myofibroblast differentiation (PMID:20071339)
• Fli-I promotes the GTP-bound active Rho-mediated relief of the autoinhibition of Daam1 and mDia1. Thus, Fli-I is a novel positive regulator of Rho-induced linear actin assembly mediated by DRFs. (PMID:20223827)
• Data show that expression of a dominant-negative RhoA mutant or silencing DIAPH1 impaired mitochondrial trafficking and cortisol biosynthesis. (PMID:20591975)
• mDia1 regulates Golgi architecture and dynamics in a Rho-dependent manner (PMID:21680709)
• mDia1 and WAVE2 are important Src homology 3 domain partners of IRSp53 in forming filopodia. (PMID:22179776)
• a novel mechanism through which an extracellular signal initiated by RAGE ligands regulates RAGE signaling in a manner requiring mDia1. (PMID:22194616)
• Liprin-alpha negatively regulates the activity of mDia in the cell by displacing it from the plasma membrane through binding to the N-terminal Dia-inhibitory domain (DID) and dimerization domain (DD) of mDia (PMID:22266902)
• mDia1 knockdown results in Cav1/caveolae clustering and defective inward trafficking upon loss of cell adhesion. (PMID:22454521)
• findings show that DIAPH1 interacts with multiple proteins in H295R human adrenocortical cells and that cAMP signaling modulates the interaction of a subset of proteins with DIAPH1 (PMID:23325789)
• Depletion of DIAPH1 reduced metastasis 60-fold. (PMID:24105619)
• Recruitment of Syx to the cell membrane, the selective activation of Dia1 signaling, coupled with the suppression of ROCK and actin reorganization, plays a key role in establishing cell polarity during directed cell migration. (PMID:24126053)
• The results revealed that treatment with siRNA-mDRF1 significantly inhibited tumor growth and led to a decrease in the weight of the transplanted tumor. In conclusion, our data demonstrate that mDRF1 is highly expressed in human glioma tissue. (PMID:24317603)
• Dia1, Dia2, and Dia3 are involved in ErbB2-dependent capture of microtubules at the cell leading edge and ErbB2-driven guided migration. (PMID:24403606)
• Patients with a homozygous nonsense DIAPH1 alteration (p.Gln778*) have MCP as well as reduced height and weight. (PMID:24781755)
• Mechanistically, mDia1 deficiency led to a downregulation of membrane-associated genes and a specific upregulation of CD14 messenger RNA in granulocytes, but not in other lineages. (PMID:24891322)
• the RhoA-regulated formin Dia1 is involved in entosis downstream of LPAR2 (PMID:24950964)
• DIAPH1 has a critical role in generating F-actin structures and assisting the microtubule stabilization underlying proplatelet formation and platelet production (PMID:25298036)
• Data indicate that diaphanous homolog 1 (Drosophila) protein (DIAPH1) stabilizes microtubules and reduces microtubule dynamics. (PMID:26124177)
• The Rho-mDia1 signaling pathway is involved in the cytoskeletal rearrangement of human periodontal ligament cells induced by cyclic strain. (PMID:26201082)
• functional complementation experiments and optogenetics to show that mDia1 cooperates with the Arp2/3 complex in initiating lamellipodia and ruffles. (PMID:26349808)
• Loss-of-function variants in DIAPH1 is associated with syndromic microcephaly, blindness, and early onset seizures. (PMID:26463574)

Cross-species orthologs

9 orthologs

Organism	Symbol	Gene ID
danio_rerio		ENSDARG00000115082
mus_musculus	Diaph1	ENSMUSG00000024456
rattus_norvegicus	Diaph1	ENSRNOG00000019688
drosophila_melanogaster	Frl	FBGN0267795
caenorhabditis_elegans	fhod-1	WBGENE00016735
caenorhabditis_elegans		WBGENE00018976
caenorhabditis_elegans		WBGENE00019030
caenorhabditis_elegans	sydn-1	WBGENE00021473
caenorhabditis_elegans		WBGENE00021698

Paralogs (18): DAAM1 (ENSG00000100592), FNBP4 (ENSG00000109920), FHOD3 (ENSG00000134775), FHOD1 (ENSG00000135723), FHDC1 (ENSG00000137460), DIAPH3 (ENSG00000139734), DAAM2 (ENSG00000146122), DIAPH2 (ENSG00000147202), FMN2 (ENSG00000155816), FMNL2 (ENSG00000157827), FMNL3 (ENSG00000161791), FMNL1 (ENSG00000184922), FAM47A (ENSG00000185448), SHTN1 (ENSG00000187164), FAM47B (ENSG00000189132), FAM47C (ENSG00000198173), INF2 (ENSG00000203485), GRID2IP (ENSG00000215045)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:1194490) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 45 distinct phenotype terms.

Mouse phenotype (MP)	Records
increased central memory CD4-positive, alpha-beta T cell number	2
increased central memory CD8-positive, alpha-beta T cell number	2
malocclusion	1
increased leukocyte cell number	1
increased neutrophil cell number	1
increased monocyte cell number	1
extramedullary hematopoiesis	1
echinocytosis	1
increased bone marrow cell number	1
increased granulocyte number	1
alopecia	1
abnormal spleen morphology	1
abnormal skin condition	1
dermatitis	1
dehydration	1
anemia	1
postnatal growth retardation	1
abnormal humoral immune response	1
abnormal definitive hematopoiesis	1
abnormal lymph node morphology	1
abnormal spleen germinal center morphology	1
abnormal bone marrow cell morphology/development	1
decreased IgE level	1
abnormal leukocyte migration	1
abnormal vertebral arch morphology	1

+20 more (showing top 25).

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Gallus gallus	A0A1D5P556	77.8%	Diamond
Arabidopsis thaliana	O04532	66.6%	Diamond
Oryza sativa Japonica Group	Q6MWG9	64.6%	Diamond
Dictyostelium discoideum	Q54WH2	34.0%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
DIAPH1-AS1	ncRNA	100505658
DIAPH1-AS2	ncRNA	124901091
RELL2	protein-coding	285613
HDAC3	protein-coding	8841
FCHSD1	protein-coding	89848
PCDHGA12	protein-coding	26025
PCDHGC3	protein-coding	5098
PCDHGC5	protein-coding	56097
PCDHGC4	protein-coding	56098
PCDHGB7	protein-coding	56099
PCDHGB6	protein-coding	56100
PCDHGB5	protein-coding	56101
PCDHGB3	protein-coding	56102
PCDHGB2	protein-coding	56103
PCDHGB1	protein-coding	56104
PCDHGA11	protein-coding	56105
PCDHGA10	protein-coding	56106
PCDHGA9	protein-coding	56107
PCDHGA7	protein-coding	56108
PCDHGA6	protein-coding	56109
PCDHGA5	protein-coding	56110
PCDHGA4	protein-coding	56111
PCDHGA3	protein-coding	56112
PCDHGA2	protein-coding	56113
PCDHGA1	protein-coding	56114
PCDHGB4	protein-coding	8641
PCDHGA8	protein-coding	9708
ARAP3	protein-coding	64411
TAF7	protein-coding	6879
SLC25A2	protein-coding	83884

Protein

Protein identifiers

Protein diaphanous homolog 1 — O60610 (reviewed: O60610)

Alternative names: Diaphanous-related formin-1

All UniProt accessions (5): A0A2R8Y5N1, A0A2R8YEF8, B4E2I7, H7C2W8, O60610

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. Binds to the barbed end of the actin filament and slows down actin polymerization and depolymerization. Required for cytokinesis, and transcriptional activation of the serum response factor. DFR proteins couple Rho and Src tyrosine kinase during signaling and the regulation of actin dynamics. Functions as a scaffold protein for MAPRE1 and APC to stabilize microtubules and promote cell migration. Has neurite outgrowth promoting activity. Acts in a Rho-dependent manner to recruit PFY1 to the membrane. In hear cells, it may play a role in the regulation of actin polymerization in hair cells. The MEMO1-RHOA-DIAPH1 signaling pathway plays an important role in ERBB2-dependent stabilization of microtubules at the cell cortex. It controls the localization of APC and CLASP2 to the cell membrane, via the regulation of GSK3B activity. In turn, membrane-bound APC allows the localization of the MACF1 to the cell membrane, which is required for microtubule capture and stabilization. Plays a role in the regulation of cell morphology and cytoskeletal organization. Required in the control of cell shape. Plays a role in brain development. 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.

Subunit / interactions. Homodimer. Interacts with the GTP-bound form of RHOA. Interacts with RHOC, PFY1, MAPRE1 and BAIAP2. Interacts with APC; acts as a scaffold protein for MAPRE1 and APC to stabilize microtubules and promote cell migration. Interacts with SCAI. Interacts with DCAF7, via FH2 domain. Interacts with NCDN. Interacts with OSBPL10, OSBPL2, VIM, TUBB and DYN1.

Subcellular location. Cell membrane. Cell projection. Ruffle membrane. Cytoplasm. Cytoskeleton. Microtubule organizing center. Centrosome. Spindle. Nucleus.

Tissue specificity. Expressed in brain, heart, placenta, lung, kidney, pancreas, liver, skeletal muscle and cochlea. Expressed in platelets.

Post-translational modifications. Phosphorylation at Thr-768 is stimulated by cAMP and regulates stability, complex formation and mitochondrial movement.

Disease relevance. Deafness, autosomal dominant 1, with or without thrombocytopenia (DFNA1) [MIM:124900] A form of non-syndromic sensorineural hearing loss. Sensorineural deafness results from damage to the neural receptors of the inner ear, the nerve pathways to the brain, or the area of the brain that receives sound information. Patients may have mild thrombocytopenia and enlarged platelets, although most of DFNA1 affected individuals do not have significant bleeding tendencies. The disease is caused by variants affecting the gene represented in this entry. Seizures, cortical blindness, and microcephaly syndrome (SCBMS) [MIM:616632] A severe autosomal recessive neurodevelopmental disorder characterized by microcephaly, early-onset seizures, severely delayed psychomotor development, short stature, and cortical blindness. The disease is caused by variants affecting the gene represented in this entry.

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 (3)

UniProt ID	Names	Canonical?
O60610-1	1	yes
O60610-2	2
O60610-3	3

RefSeq proteins (3): NP_001073280, NP_001300936, NP_005210* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR010465	Drf_DAD	Domain
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

Pfam: PF02181, PF06345, PF06346, PF06367, PF06371

UniProt features (58 total): helix 16, modified residue 10, compositionally biased region 8, domain 4, mutagenesis site 4, sequence conflict 4, splice variant 3, sequence variant 2, turn 2, region of interest 2, coiled-coil region 2, chain 1

Structure

Experimental structures (PDB)

1 structures by resolution:

PDB	Title	Method	Resolution (Å)
8FG1	Human diaphanous inhibitory domain bound to diaphanous autoregulatory domain	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O60610-F1	74.04	0.33

Human Protein Atlas

Protein class: Predicted intracellular proteins, Plasma proteins, Cancer-related genes, Mutated cancer genes, Disease related genes, Human disease related genes, Ear disease

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): cytosol; plasma membrane

Antibody reliability (HPA): IH approved · IF uncertain

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 (10)

Type	Positions
N-acetylmethionine	1
Phosphoserine	7, 22, 36, 1251, 1254
Phosphothreonine	768
N6-acetyllysine	1057, 1103
Phosphotyrosine	1121

Mutagenesis-validated functional residues (4)

Position	Phenotype
154	partial decrease of phosphorylation.
768	substantial loss of phosphorylation, no increase of phosphorylation in response to camp, increased stability, reduced interaction with …
1091	substantial loss of phosphorylation.
1238	substantial loss of phosphorylation.

Function

Pathways and Gene Ontology

Reactome pathways

9 curated (TAS) of 21; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

21 pathways:

ID	Pathway	Evidence
R-HSA-6785631	ERBB2 Regulates Cell Motility	curated
R-HSA-6798695	Neutrophil degranulation	curated
R-HSA-5663220	RHO GTPases Activate Formins	curated
R-HSA-8980692	RHOA GTPase cycle	curated
R-HSA-9013026	RHOB GTPase cycle	curated
R-HSA-9013106	RHOC GTPase cycle	curated
R-HSA-9013405	RHOD GTPase cycle	curated
R-HSA-9035034	RHOF GTPase cycle	curated
R-HSA-9854909	Regulation of MITF-M dependent genes involved in invasion	curated
R-HSA-1266738	Developmental Biology	—
R-HSA-168256	Immune System	—
R-HSA-168249	Innate Immune System	—
R-HSA-9856651	MITF-M-dependent gene expression	—
R-HSA-9730414	MITF-M-regulated melanocyte development	—
R-HSA-195258	RHO GTPase Effectors	—
R-HSA-9012999	RHO GTPase cycle	—
R-HSA-162582	Signal Transduction	—
R-HSA-1227986	Signaling by ERBB2	—
R-HSA-9006934	Signaling by Receptor Tyrosine Kinases	—
R-HSA-194315	Signaling by Rho GTPases	—
R-HSA-9716542	Signaling by Rho GTPases, Miro GTPases and RHOBTB3	—

MSigDB gene sets: 461 (showing top): BIOCARTA_RHO_PATHWAY, RNGTGGGC_UNKNOWN, AGGAAGC_MIR5163P, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_PROTEIN_LOCALIZATION_TO_CYTOSKELETON, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_REGULATION_OF_CELL_MORPHOGENESIS, GOBP_REGULATION_OF_MICROTUBULE_BASED_PROCESS, BIOCARTA_MAL_PATHWAY, GOBP_SENSORY_PERCEPTION_OF_MECHANICAL_STIMULUS, GOCC_SECRETORY_GRANULE, MORF_SNRP70, MORF_HDAC1, ACEVEDO_NORMAL_TISSUE_ADJACENT_TO_LIVER_TUMOR_DN, AREB6_01

GO Biological Process (13): cytoskeleton organization (GO:0007010), sensory perception of sound (GO:0007605), actin cytoskeleton organization (GO:0030036), actin filament polymerization (GO:0030041), regulation of microtubule-based process (GO:0032886), protein localization to microtubule (GO:0035372), regulation of release of sequestered calcium ion into cytosol (GO:0051279), regulation of cytoskeleton organization (GO:0051493), cellular response to histamine (GO:0071420), brain development (GO:0007420), cellular component organization (GO:0016043), neuron projection development (GO:0031175), synaptic vesicle endocytosis (GO:0048488)

GO Molecular Function (8): RNA binding (GO:0003723), actin binding (GO:0003779), signaling receptor binding (GO:0005102), small GTPase binding (GO:0031267), transmembrane transporter binding (GO:0044325), protein binding (GO:0005515), profilin binding (GO:0005522), identical protein binding (GO:0042802)

GO Cellular Component (14): nucleus (GO:0005634), cytoplasm (GO:0005737), centrosome (GO:0005813), cytosol (GO:0005829), actin filament (GO:0005884), plasma membrane (GO:0005886), secretory granule membrane (GO:0030667), ruffle membrane (GO:0032587), mitotic spindle (GO:0072686), ficolin-1-rich granule membrane (GO:0101003), spindle (GO:0005819), cytoskeleton (GO:0005856), brush border (GO:0005903), neuron projection (GO:0043005)

Reactome top-level categories

11 top-level categories:

Category	Pathways
RHO GTPase cycle	5
Signaling by Rho GTPases	2
Signal Transduction	2
RHO GTPase Effectors	1
Signaling by ERBB2	1
Innate Immune System	1
MITF-M-dependent gene expression	1
Signaling by Receptor Tyrosine Kinases	1
Immune System	1
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1
Developmental Biology	1

GO top-level categories

53 GO namespaces:

Category	Terms
protein binding	4
cytoskeleton organization	2
cellular anatomical structure	2
intracellular membraneless organelle	2
organelle organization	1
sensory perception of mechanical stimulus	1
actin filament-based process	1
actin polymerization or depolymerization	1
protein polymerization	1
microtubule-based process	1
regulation of cellular process	1
protein localization to microtubule cytoskeleton	1
release of sequestered calcium ion into cytosol	1
regulation of calcium ion transmembrane transport	1
regulation of organelle organization	1
response to histamine	1
cellular response to nitrogen compound	1
central nervous system development	1
animal organ development	1
head development	1
cellular component organization or biogenesis	1
neuron development	1
plasma membrane bounded cell projection organization	1
synaptic vesicle recycling	1
presynaptic endocytosis	1
nucleic acid binding	1
cytoskeletal protein binding	1
GTPase binding	1
binding	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
centriole	1
microtubule organizing center	1
cytoplasm	1
actin cytoskeleton	1
polymeric cytoskeletal fiber	1
membrane	1
cell periphery	1
secretory granule	1
cytoplasmic vesicle membrane	1
bounding membrane of organelle	1
ruffle	1
cell projection membrane	1
leading edge membrane	1
spindle	1
secretory granule membrane	1
tertiary granule	1
ficolin-1-rich granule	1
microtubule cytoskeleton	1
microvillus	1
apical part of cell	1
cluster of actin-based cell projections	1
plasma membrane bounded cell projection	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 8 of 35 annotations. The rest are phylogenetic / computational / electronic (IEA).

8 experimentally-supported GO terms:

GO term	NS	Evidence
cellular response to histamine	BP	mutant phenotype
protein localization to microtubule	BP	mutant phenotype
regulation of cytoskeleton organization	BP	mutant phenotype
regulation of microtubule-based process	BP	mutant phenotype
regulation of release of sequestered calcium ion into cytosol	BP	mutant phenotype
mitotic spindle	CC	direct assay
RNA binding	MF	high-throughput assay
transmembrane transporter binding	MF	physical interaction

Protein interactions and networks

STRING

showing 15 of 1,819 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DIAPH1	SAV1	Q9H4B6	843
DIAPH1	RHOC	P08134	757
DIAPH1	EIF3M	Q7L2H7	752
DIAPH1	WFS1	O76024	749
DIAPH1	GFER	P55789	725
DIAPH1	RHOD	O00212	698
DIAPH1	PCSK9	Q8NBP7	665
DIAPH1	POU4F3	Q15319	664
DIAPH1	LIMK1	P53667	640
DIAPH1	MYO7A	P78427	608
DIAPH1	CFL2	Q9Y281	572
DIAPH1	CFL1	P23528	571
DIAPH1	SRF	P11831	567
DIAPH1	CDC42	P21181	545
DIAPH1	RHOA	P06749	543

IntAct

Human interaction partners of DIAPH1 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

26 partners by confidence:

Partner	Interaction type	MIscore	Records
DCAF7	association	0.730	3
RHOA	association	0.600	3
RHOC	direct interaction	0.590	1
RHOD	direct interaction	0.590	1
AGER	physical association	0.580	3
PPM1F	physical association	0.540	3
PKD2	colocalization	0.530	2
ORF	physical association	0.500	1
RHOB	direct interaction	0.440	1
RHOF	direct interaction	0.440	1
CALU	physical association	0.400	1
CLIP1	physical association	0.400	1
GAS7	physical association	0.400	1
H2BC9	physical association	0.400	1
H3C13	physical association	0.400	1
IQGAP1	physical association	0.400	1
WBP4	physical association	0.400	1
EGFR	physical association	0.370	1
PRPF40A	physical association	0.370	1
CSPG5	association	0.350	1
HCK	association	0.350	1
PABPN1	association	0.350	1
PFN2	association	0.350	1
SOWAHB	association	0.350	1
ZNF284	association	0.350	1
CDC5L	physical association	0.000	1

BioGRID (198 interactions; top human partners by supporting records): DCAF7 (Affinity Capture-MS; 6 records), RHOD (Affinity Capture-MS; 4 records), HSP90AA1 (Cross-Linking-MS (XL-MS); 3 records), RHOA (Reconstituted Complex; 3 records), RHOC (Affinity Capture-MS; 3 records), IQGAP1 (Co-fractionation; 2 records), KIAA1429 (Affinity Capture-RNA; 2 records), PFN2 (Affinity Capture-MS; 2 records), PRPF40A (Two-hybrid; 2 records), PTPRF (Affinity Capture-MS; 2 records), RHOB (Proximity Label-MS; 2 records), SNW1 (Affinity Capture-MS; 2 records), SOWAHC (Affinity Capture-MS; 2 records), TCERG1 (Affinity Capture-Western; 2 records), UPF1 (Co-fractionation; 2 records)

SIGNOR signaling

6 signaling interactions:

A	Effect	B	Mechanism
RHOA	“up-regulates activity”	DIAPH1
DIAPH1	“up-regulates activity”	CDH4
ERK1/2	“up-regulates quantity by stabilization”	DIAPH1	phosphorylation
PKA	“up-regulates quantity by stabilization”	DIAPH1	phosphorylation
CHEK1	“down-regulates activity”	DIAPH1	phosphorylation
CDK1	“down-regulates activity”	DIAPH1	phosphorylation

Protein complexes (CORUM) (1)

Experimentally-characterized complexes this protein is a subunit of (★ = the complex contains a known drug target).

1 complexes by size:

Complex	Subunits	Members
★ LGR4-RSPO supercomplex	10	PXN, RSPO3, DVL2, IQGAP1, MAP2K2, PTK2, WASL, DIAPH1, LGR4, MAP2K1

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 26 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
RHO GTPases Activate Formins	6	21.2×	6e-05

GO biological processes:

GO term	Partners	Fold	FDR
regulation of actin cytoskeleton organization	6	41.1×	2e-06
cell migration	5	13.4×	2e-03

Disease & clinical

Genetic variants

Variant evidence for DIAPH1: 1,947 ClinVar records (69 pathogenic / likely pathogenic); 7 GWAS associations. Per-variant detail is on Sugi Variant.

ClinVar

1,947 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	36
Likely pathogenic	33
Uncertain significance	993
Likely benign	720
Benign	42

Top pathogenic / likely-pathogenic (15)

Showing the 15 best-reviewed of 69 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
228577	NM_005219.5(DIAPH1):c.3637C>T (p.Arg1213Ter)	Pathogenic	criteria provided, multiple submitters, no conflicts	9
217754	NM_005219.5(DIAPH1):c.3145C>T (p.Arg1049Ter)	Pathogenic	criteria provided, multiple submitters, no conflicts	5
1990251	NM_005219.5(DIAPH1):c.1051C>T (p.Arg351Ter)	Pathogenic	criteria provided, multiple submitters, no conflicts	3
946228	NM_005219.5(DIAPH1):c.2540_2541del (p.Lys847fs)	Pathogenic	criteria provided, multiple submitters, no conflicts	2
2935331	NM_005219.5(DIAPH1):c.684+1G>A	Pathogenic	criteria provided, multiple submitters, no conflicts	2
3748740	NM_005219.5(DIAPH1):c.991C>T (p.Arg331Ter)	Pathogenic	criteria provided, multiple submitters, no conflicts	2
1030893	NM_005219.5(DIAPH1):c.145-1G>A	Likely pathogenic	criteria provided, multiple submitters, no conflicts	2
7528	NM_005219.5(DIAPH1):c.3661+1G>T	Pathogenic	criteria provided, single submitter	2
1027661	NM_005219.5(DIAPH1):c.3490C>T (p.Arg1164Ter)	Pathogenic	criteria provided, single submitter	2
391928	NM_005219.5(DIAPH1):c.2794C>T (p.Arg932Ter)	Pathogenic	criteria provided, single submitter	1
419689	NM_005219.5(DIAPH1):c.1971_1972delinsT (p.Leu657fs)	Pathogenic	criteria provided, single submitter	1
504168	NM_005219.5(DIAPH1):c.2905_2906dup (p.Ser970fs)	Pathogenic	criteria provided, single submitter	1
522646	NM_005219.5(DIAPH1):c.627C>A (p.Tyr209Ter)	Pathogenic	criteria provided, single submitter	1
839955	NM_005219.5(DIAPH1):c.1549C>T (p.Gln517Ter)	Pathogenic	criteria provided, single submitter	1
1070912	NM_005219.5(DIAPH1):c.108dup (p.Lys37Ter)	Pathogenic	criteria provided, single submitter	1

Per-variant reference — Sugi Variant

Explore DIAPH1’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 30 predictions of 2,214):

Position(s)	Effect	Δscore	Sites
5:141524141–141524142	donor_loss	1.0000	5
5:141524230–141524231	acceptor_loss	1.0000	6
5:141524233	acceptor_gain	1.0000
5:141526036–141526037	donor_loss	1.0000	4
5:141526174–141526175	acceptor_loss	1.0000	6
5:141526181	acceptor_gain	1.0000
5:141527531–141527532	donor_gain	1.0000	2
5:141527590	donor_gain	1.0000
5:141527699	acceptor_loss	1.0000	3
5:141528431	donor_gain	1.0000

AlphaMissense

3,265 missense substitutions predicted likely pathogenic (of 8,377 scored), across 777 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
M124	9	0.989	1.000
M99	9	0.964	0.999
M1199	9	0.962	0.999
M103	9	0.953	0.999
M256	9	0.945	0.993
M1107	9	0.916	0.995
M225	9	0.911	0.997
M1111	9	0.905	0.989
D1200	8	0.998	1.000
N226	8	0.996	1.000
D372	8	0.995	0.999
N988	8	0.994	0.999
F96	8	0.993	0.999
F1212	8	0.991	1.000
F295	8	0.990	0.999
F183	8	0.989	0.999
N985	8	0.984	0.999
H333	8	0.979	0.996
F365	8	0.977	0.998
N859	8	0.977	0.998

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

4 prognostic cancer types:

Cancer	Prognostic	p-value
Kidney Renal Clear Cell Carcinoma (TCGA)	favorable	9.37e-07
Pancreatic Adenocarcinoma (validation)	unfavorable	0.000379
Pancreatic Adenocarcinoma (TCGA)	unfavorable	0.000607
Kidney Renal Clear Cell Carcinoma (validation)	favorable	0.00071

Disease associations

OMIM: gene MIM:602121 | disease phenotypes: MIM:616632, MIM:124900, MIM:274600

GenCC curated gene-disease

3 curated gene-disease records:

Disease	Classification	Inheritance	Records
DIAPH1-related sensorineural hearing loss-thrombocytopenia syndrome	Definitive	Autosomal dominant	3
autosomal dominant nonsyndromic hearing loss 1	Strong	Autosomal dominant
progressive microcephaly-seizures-cortical blindness-developmental delay syndrome	Strong	Autosomal recessive	3

ClinGen Gene-Disease Validity

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

2 validity classifications:

Disease	Classification	Inheritance
progressive microcephaly-seizures-cortical blindness-developmental delay syndrome	Definitive	AR
DIAPH1-related sensorineural hearing loss-thrombocytopenia syndrome	Definitive	AD

Genomics England panels (PanelApp)

Clinical diagnostic gene panels including this gene (13 panels, 12 green/diagnostic-grade). Confidence: green = diagnostic, amber = moderate.

13 panels:

Panel	Rating
Bleeding and platelet disorders	green
Early onset or syndromic epilepsy	green
Fetal anomalies	green
Hypotonic infant	green
Inherited bleeding disorders	green
Intellectual disability	green
Leukodystrophy, childhood onset	green
Monogenic hearing loss	green
Paediatric disorders	green
Primary immunodeficiency or monogenic inflammatory bowel disease	green
Severe microcephaly	green
Unexplained death in infancy and sudden unexplained death in childhood	green
Cerebral vascular malformations	amber

Mondo (7): progressive microcephaly-seizures-cortical blindness-developmental delay syndrome (MONDO:0014714), autosomal dominant nonsyndromic hearing loss 1 (MONDO:0007424), Pendred syndrome (MONDO:0010134), microcephaly (MONDO:0001149), epilepsy (MONDO:0005027), hearing loss disorder (MONDO:0005365), DIAPH1-related sensorineural hearing loss-thrombocytopenia syndrome (MONDO:0044635)

Orphanet (4): Progressive microcephaly-seizures-cortical blindness-developmental delay syndrome (Orphanet:477814), Rare autosomal dominant non-syndromic sensorineural deafness type DFNA (Orphanet:90635), Pendred syndrome (Orphanet:705), Rare genetic deafness (Orphanet:96210)

HPO phenotypes

47 phenotypes (HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000132	Menorrhagia
HP:0000252	Microcephaly
HP:0000253	Progressive microcephaly
HP:0000407	Sensorineural hearing impairment
HP:0000408	Progressive sensorineural hearing impairment
HP:0000648	Optic atrophy
HP:0000823	Delayed puberty
HP:0001009	Telangiectasia
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001510	Growth delay
HP:0001531	Failure to thrive in infancy
HP:0001873	Thrombocytopenia
HP:0001875	Decreased total neutrophil count
HP:0001891	Iron deficiency anemia
HP:0002079	Hypoplasia of the corpus callosum
HP:0002110	Bronchiectasis
HP:0002119	Ventriculomegaly
HP:0002187	Profound intellectual disability
HP:0002465	Poor speech
HP:0002665	Lymphoma
HP:0002719	Recurrent infections
HP:0003202	Skeletal muscle atrophy
HP:0003540	Impaired platelet aggregation
HP:0003593	Infantile onset
HP:0003621	Juvenile onset
HP:0003623	Neonatal onset
HP:0004322	Short stature
HP:0004325	Decreased body weight
HP:0005387	Combined immunodeficiency
HP:0006285	Enamel hypomineralization
HP:0011330	Metopic synostosis
HP:0011463	Childhood onset
HP:0011877	Increased mean platelet volume
HP:0011891	Post-partum hemorrhage
HP:0012191	B-cell lymphoma
HP:0012444	Brain atrophy
HP:0032218	Decreased total CD4+ T cell proportion
HP:0033725	Thin corpus callosum
HP:0034311	Hypoplastic optic chiasm
HP:0040185	Macrothrombocytopenia
HP:0100659	Abnormal cerebral vascular morphology
HP:0100704	Cerebral visual impairment

GWAS associations

7 associations:

Study	Trait	p-value
GCST010002_114	Refractive error	2e-14
GCST010244_205	Triglyceride levels	4e-11
GCST005038_89	Allergic disease (asthma, hay fever or eczema)	6e-11
GCST004599_111	Mean platelet volume	4e-10
GCST90002395_18	Mean platelet volume	6e-10
GCST012490_363	Femur bone mineral density x serum urate levels interaction	9e-9
GCST90000050_37	Age at first birth	1e-8

EFO canonical traits (from GWAS)

3 canonical traits:

EFO ID	Trait name
EFO:0004530	triglyceride measurement
EFO:0004531	urate measurement
EFO:0009101	age at first birth measurement

MeSH disease descriptors

5 disease descriptors:

Descriptor	Name	Tree numbers
D004827	Epilepsy	C10.228.140.490
D034381	Hearing Loss	C09.218.458.341; C10.597.751.418.341; C23.888.592.763.393.341
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500
C565121	Deafness, Autosomal Dominant 1 *(supp.)*
C536648	Pendred syndrome *(supp.)*

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL4295668 (SINGLE PROTEIN), CHEMBL4523648 (PROTEIN COMPLEX)

PharmGKB: 1 entry (CPIC guideline: no)

Binding affinities (BindingDB)

1 measured of 1 human assays (2 total across all organisms); most potent 1 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
CHEMBL5653589	KD	1440 nM

ChEMBL bioactivities

4 potent at pChembl≥5 of 4 total, top 4 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.28	Kd	5.213	nM	CHEMBL3752910
8.28	ED50	5.213	nM	CHEMBL3752910
5.84	Kd	1440	nM	CHEMBL5653589
5.84	ED50	1440	nM	CHEMBL5653589

PubChem BioAssay actives

2 with measured affinity, of 5 total; 2 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148239: Binding affinity to human DIAPH1 incubated for 45 mins by Kinobead based pull down assay	kd	0.0052	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148239: Binding affinity to human DIAPH1 incubated for 45 mins by Kinobead based pull down assay	kd	1.4396	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects cotreatment, decreases methylation, decreases expression	4
sodium arsenite	increases abundance, increases expression, decreases expression	2
Tobacco Smoke Pollution	affects expression, increases expression	2
Valproic Acid	affects expression, increases expression	2
FR900359	decreases phosphorylation	1
dicrotophos	increases expression	1
2,4,6-tribromophenol	decreases expression	1
triphenyl phosphate	affects expression	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	decreases expression	1
CGP 52608	affects binding, increases reaction	1
2-palmitoylglycerol	increases expression	1
PCB 180	decreases expression	1
ICG 001	decreases expression	1
pentabrominated diphenyl ether 100	decreases expression	1
hexabrominated diphenyl ether 153	decreases expression	1
bisphenol S	affects cotreatment, decreases expression	1
bisphenol AF	increases expression	1
Sunitinib	decreases expression	1
Arsenic Trioxide	decreases expression	1
Fulvestrant	affects cotreatment, decreases methylation	1
Acetaminophen	decreases expression	1
Arsenic	increases abundance, decreases expression	1
Atrazine	increases expression	1
Caffeine	decreases phosphorylation	1
Cisplatin	decreases expression	1
Dexamethasone	affects cotreatment, decreases expression	1
Diethylhexyl Phthalate	increases expression	1
Dinitrochlorobenzene	affects binding	1
Endosulfan	decreases expression	1

ChEMBL screening assays

3 unique, capped per target: 3 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4119004	Binding	Binding affinity to DIAPH1 in human NCI-H358 cells at 1 uM by mass spectrometry based pull down assay	Studies of TAK1-centered polypharmacology with novel covalent TAK1 inhibitors. — *Bioorg Med Chem*

Cellosaurus cell lines

5 cell lines: 3 cancer cell line, 2 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B1DD	Abcam HCT 116 DIAPH1 KO	Cancer cell line	Male
CVCL_B2VW	Abcam HEK293T DIAPH1 KO	Transformed cell line	Female
CVCL_E1FP	Abcam HEK293 DIAPH1 KO	Transformed cell line	Female
CVCL_SK82	HAP1 DIAPH1 (-) 1	Cancer cell line	Male
CVCL_SK83	HAP1 DIAPH1 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.

showing 60 of 300 trials:

NCT	Phase	Status	Title
NCT00205881	Phase 4	COMPLETED	Bilateral Benefit in Adult Users of the HiRes 90K Bionic Ear System
NCT00331539	Phase 4	UNKNOWN	Relationship Between Auto NRT and Behavioural T & C Levels With the Nucleus Freedom Cochlear Implant
NCT00424307	Phase 4	UNKNOWN	Bilateral Cochlear Implant Benefit in Young Children
NCT00765635	Phase 4	COMPLETED	Chlorobutanol, Potassium Carbonate, and Irrigation in Cerumen Removal
NCT03321006	Phase 4	COMPLETED	Treating Hearing Loss to Improve Mood and Cognition in Older Adults
NCT01499901	Phase 3	WITHDRAWN	Comparison of the Bilateral Sequential and Simultaneous Cochlear Implantation in the Deaf Children
NCT02561091	Phase 3	COMPLETED	AM-111 in the Treatment of Acute Inner Ear Hearing Loss
NCT03331627	Phase 3	COMPLETED	Safety and Efficacy of STR001-IT and STR001-ER in Patients With SSHL
NCT05532657	Phase 3	ACTIVE_NOT_RECRUITING	ACHIEVE Brain Health Follow-Up Study
NCT00013455	Phase 2	COMPLETED	Quantifying Auditory Perceptual Learning Following Hearing Aid Fitting
NCT00323427	Phase 2	COMPLETED	Clinical Trial of the Living Well With Hearing Loss Workshop
NCT00552786	Phase 2	COMPLETED	Antioxidation Medication for Noise-induced Hearing Loss
NCT00802425	Phase 2	COMPLETED	Efficacy of AM-111 in Patients With Acute Sensorineural Hearing Loss
NCT01139281	Phase 2	COMPLETED	The Protective Effect of Ginkgo Biloba Extract on Cisplatin-induced Ototoxicity in Humans
NCT01451853	Phase 2	WITHDRAWN	SPI-1005 for Prevention and Treatment of Chemotherapy Induced Hearing Loss
NCT01588925	Phase 2	COMPLETED	Hearing Preservation Using Dexamethasone and Hyaluronic Acid for Cochlear Implantation
NCT01773278	Phase 2	UNKNOWN	Cholesterol and Antioxidant Treatment in Patients With Smith-Lemli-Opitz Syndrome (SLOS)
NCT02832128	Phase 2	COMPLETED	Evaluating Possible Improvement in Speech and Hearing Tests After 28 Days of Dosing of the Study Drug AUT00063 Compared to Placebo (QuicKfire)
NCT04915183	Phase 2	RECRUITING	Atorvastatin to Reduce Cisplatin-Induced Hearing Loss Among Individuals With Head and Neck Cancer
NCT05258773	Phase 2	COMPLETED	Evaluation of the Presence of SENS-401 in the Perilymph
NCT06340633	Phase 2	RECRUITING	SPI-1005 in Adults Receiving Cochlear Implant
NCT00582946	Phase 1	COMPLETED	Wide-Bandwidth Open Canal Hearing Aid For Better Multitalker Speech Understanding
NCT00584155	Phase 1	WITHDRAWN	Protection From Cisplatin Ototoxicity by Lactated Ringers
NCT01206829	Phase 1	UNKNOWN	Hearing Impairment, Cognitive Therapy and Coping
NCT01256229	Phase 1	COMPLETED	Outcomes In Children With Developmental Delay And Deafness
NCT01343394	Phase 1	WITHDRAWN	Safety of Autologous Human Umbilical Cord Blood Mononuclear Fraction to Treat Acquired Hearing Loss in Children
NCT01452607	Phase 1	COMPLETED	Study to Evaluate the Safety and Pharmacokinetics of SPI-1005
NCT02259595	Phase 1	COMPLETED	Study to Determine the Safety, Tolerability, and Pharmacokinetic Profile of HPN-07 and HPN-07 Plus NAC
NCT04041440	Phase 1	COMPLETED	Speech Recognition Training in Children With Hearing Loss
NCT07218913	Phase 1	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
NCT00486577	Phase 2/3	COMPLETED	Chronic Electrical Stimulation of the Auditory Cortex for Intractable Tinnitus
NCT00789061	Phase 2/3	UNKNOWN	Applying Proton Pump Inhibitor to Prevent and Treat Acute Fluctuating Hearing Loss in Patients With SLC26A4 Mutation
NCT01423409	Phase 2/3	COMPLETED	Multicenter Trial Assessing an Innovative VAS of Pain Among Deaf People
NCT05786378	Phase 2/3	UNKNOWN	Assessment of The Efficacy of Intratympanic Platelet Rich Plasma for Treatment of Sensorineural Hearing Loss.
NCT01108601	Phase 1/2	UNKNOWN	Transtympanic Ringer’s Lactate for the Prevention of Cisplatin Ototoxicity
NCT01621256	Phase 1/2	COMPLETED	Efficacy, Safety, and Tolerability of Ancrod in Patients With Sudden Hearing Loss
NCT06370351	Phase 1/2	ACTIVE_NOT_RECRUITING	A Phase I/II Clinical Trial With SENS-501 in Children Suffering From Severe to Profound Hearing Loss Due to Otoferlin (OTOF) Mutations
NCT06545175	Phase 1/2	ACTIVE_NOT_RECRUITING	Intracochlear Application of VSF1.01 for the Reduction of Cochlear Implant Surgery Related Trauma
NCT07304024	Phase 1/2	RECRUITING	A Treatment for a Form of Age-Related Central Auditory Processing Disorder Consisting of Clemastine Fumarate Plus Engineered Sound
NCT01109576	Early Phase 1	COMPLETED	Workshops for Veterans With Vision and Hearing Loss
NCT03300687	Early Phase 1	COMPLETED	First in Human Safety Study of FX-322 in Adults Undergoing Cochlear Implantation
NCT04777669	Early Phase 1	UNKNOWN	Removing Background Talker Noise for Cochlear Implant Users
NCT06025032	Early Phase 1	WITHDRAWN	a Study in Subjects With Otoferlin Mutation-related Hearing Loss Using RNA Base-eDiting Therapy(SOUND)
NCT00001668	Not specified	COMPLETED	Endolymphatic Sac Tumors in a Population of Patients With Von Hippel-Lindau Disease:The Natural History and Pathobiology, and a Prospective Non-Randomized Clinical Trial of Hearing Preservation Surgery in Patients With Early Stage Endolymphatic Sac Tumors
NCT00001782	Not specified	COMPLETED	Areas of Brain Responsible for Understanding American Sign Language
NCT00013468	Not specified	COMPLETED	Early Diagnosis of Steroid-Responsive & No-Responsive Hearing Loss
NCT00016471	Not specified	COMPLETED	A Genetic Analysis of Usher Syndrome in Ashkenazi Jews
NCT00018486	Not specified	COMPLETED	Epidemiology of Hearing Loss in Diabetic and Non-Diabetic Veterans
NCT00106743	Not specified	COMPLETED	Natural History and Genetic Studies of Usher Syndrome
NCT00110604	Not specified	COMPLETED	The Effect of Folic Acid on Atherosclerosis, Cognitive Performance and Hearing
NCT00126113	Not specified	COMPLETED	The Performance-Perceptual Test as a Counseling Tool
NCT00260663	Not specified	COMPLETED	The Hearing Aid Effectiveness After Aural Rehabilitation (HEAR) Trial
NCT00371436	Not specified	COMPLETED	Progressive Intervention Program for Tinnitus Management
NCT00371449	Not specified	COMPLETED	Predicting Success With Hearing Aids
NCT00371839	Not specified	COMPLETED	Clinical Applications for Time-Compressed Speech Tests
NCT00400413	Not specified	COMPLETED	Neuroanatomy of Reading in Congenital Deafness.
NCT00438334	Not specified	COMPLETED	Real-World Benefit From Directional Hearing Aids
NCT00451503	Not specified	COMPLETED	Evaluation of Middle Ear Implantation
NCT00484224	Not specified	UNKNOWN	Audiological Disturbances in Vitiligo
NCT00511381	Not specified	COMPLETED	Genetic Testing in Detection of Late-Onset Hearing Loss

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for DIAPH1 across ~30M SureChEMBL compounds — explore on Sugi Predict.