DIAPH2

Summary

DIAPH2 (diaphanous related formin 2, HGNC:2877) is a protein-coding gene on chromosome Xq21.33, encoding Protein diaphanous homolog 2 (O60879). Could be involved in oogenesis.

The product of this gene belongs to the diaphanous subfamily of the formin homology family of proteins. This gene may play a role in the development and normal function of the ovaries. Defects in this gene have been linked to premature ovarian failure 2. Alternatively spliced transcript variants encoding different isoforms have been identified.

Source: NCBI Gene 1730 — RefSeq curated summary.

At a glance

• Gene–disease (curated): premature ovarian failure 2A (Limited, GenCC)
• Clinical variants (ClinVar): 356 total — 5 pathogenic, 1 likely-pathogenic (top 9% of genes corpus-wide)
• GTEx eGene: eQTL in 18 tissues, sQTL in 10 (q < 0.05)
• Phenotypes (HPO): 6
• MANE Select transcript: NM_006729
• Notable: 356 clinical variants but no curated precision-oncology (CIViC) evidence yet

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2877
Approved symbol	DIAPH2
Name	diaphanous related formin 2
Location	Xq21.33
Locus type	gene with protein product
Status	Approved
Aliases	POF, DIA, POF2, DIA2
Ensembl gene	ENSG00000147202
Ensembl biotype	protein_coding
OMIM	300108
Entrez	1730

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 5 protein_coding, 2 nonsense_mediated_decay

MANE Select: ENST00000324765

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

ENST00000324765, ENST00000373049, ENST00001001844, ENST00001027915, ENST00001106826, ENST00001116041, ENST00001133523

RefSeq mRNA: 2 — MANE Select: NM_006729 NM_006729, NM_007309

CCDS: CCDS14467, CCDS14468

Canonical transcript exons

ENST00000324765 — 27 exons

Exon	Start	End
ENSE00000673299	97114726	97114965
ENSE00000673301	97099694	97099795
ENSE00000673302	97075167	97075261
ENSE00000673303	97072941	97073042
ENSE00001291044	96918509	96918617
ENSE00001291397	96957828	96958148
ENSE00001294364	96912328	96912402
ENSE00001297290	96945527	96945591
ENSE00001298907	96948935	96949039
ENSE00001307197	96912483	96912552
ENSE00001307924	97599253	97604997
ENSE00001310717	96965093	96965207
ENSE00001319230	96881579	96881718
ENSE00001319497	96942018	96942136
ENSE00001325833	96930733	96930843
ENSE00001329256	96916438	96916574
ENSE00001435159	96937233	96937351
ENSE00001435438	96939266	96939382
ENSE00001617272	97429650	97429745
ENSE00001647562	96758154	96758258
ENSE00001651913	96735758	96735790
ENSE00001685643	97247715	97247839
ENSE00001699194	96738586	96738762
ENSE00001764776	97348116	97348280
ENSE00001783804	97383909	97384044
ENSE00002289605	97141665	97141794
ENSE00003845498	96684842	96685190

Expression profiles

Bgee: expression breadth ubiquitous, 286 present calls, max score 93.05.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 19.7800 / max 639.9673, expressed in 1722 samples.

Highest expression (Bgee): buccal mucosa cell, parietal pleura, bronchial epithelial cell, pleura, lower lobe of lung.

Genetic regulation across tissues (GTEx eQTL / sQTL)

DIAPH2 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 18 tissues and its splicing (sQTL) in 10 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 28 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Muscle Skeletal	eqtl	1.0e-17	-0.21	X:96735534:G:A
Artery Aorta	eqtl	3.2e-16	-0.24	X:96532834:A:G
Esophagus Mucosa	eqtl	5.7e-13	+0.21	X:96701722:T:G
Cells Cultured fibroblasts	sqtl	1.7e-09	+0.34	X:96759612:G:C
Whole Blood	eqtl	2.8e-05	+0.11	X:96415516:T:C
Artery Tibial	sqtl	4.0e-05	+0.35	X:96687348:A:G
Brain Cerebellar Hemisphere	eqtl	2.8e-04	+0.29	X:96406563:A:T
Artery Aorta	sqtl	6.0e-04	-1.07	X:97419125:T:C
Adipose Subcutaneous	eqtl	1.5e-03	+0.13	X:96979080:A:C
Adipose Visceral Omentum	sqtl	3.2e-03	+0.31	X:96743100:T:A
Brain Hypothalamus	eqtl	5.3e-03	+0.32	X:95848076:C:T
Nerve Tibial	eqtl	6.2e-03	-0.07	X:96389854:C:T
Cells EBV-transformed lymphocytes	eqtl	7.6e-03	-0.45	X:97427597:T:C
Esophagus Muscularis	sqtl	9.3e-03	+0.27	X:96756803:T:C
Brain Cerebellum	eqtl	9.3e-03	+0.45	X:97000402:C:T
Spleen	eqtl	1.0e-02	-0.40	X:97402463:G:A
Cells Cultured fibroblasts	eqtl	1.4e-02	+0.08	X:96790228:C:T
Heart Left Ventricle	eqtl	1.7e-02	-0.36	X:95696127:G:A
Thyroid	sqtl	2.1e-02	+0.26	X:96701722:T:G
Brain Anterior cingulate cortex BA24	eqtl	2.1e-02	-0.80	X:96002110:A:G

FANTOM5 promoters

6 alternative TSS:

Promoter ID	TPM avg	Samples expressed
196906	16.2512	1708
196905	2.0888	962
196904	0.8185	462
196907	0.3024	98
196908	0.3011	113
196910	0.0180	4

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
buccal mucosa cell	CL:0002336	93.05	gold quality
parietal pleura	UBERON:0002400	91.33	gold quality
bronchial epithelial cell	CL:0002328	90.79	gold quality
pleura	UBERON:0000977	90.56	gold quality
lower lobe of lung	UBERON:0008949	90.24	gold quality
epithelium of bronchus	UBERON:0002031	89.87	gold quality
visceral pleura	UBERON:0002401	89.61	gold quality
bronchus	UBERON:0002185	89.40	gold quality
hair follicle	UBERON:0002073	89.02	gold quality
calcaneal tendon	UBERON:0003701	88.95	gold quality
blood vessel layer	UBERON:0004797	88.29	gold quality
choroid plexus epithelium	UBERON:0003911	87.87	gold quality
tendon	UBERON:0000043	87.74	gold quality
placenta	UBERON:0001987	87.69	gold quality
sperm	CL:0000019	87.51	gold quality
male germ cell	CL:0000015	87.46	gold quality
parotid gland	UBERON:0001831	87.45	gold quality
tendon of biceps brachii	UBERON:0008188	87.45	gold quality
mucosa of paranasal sinus	UBERON:0005030	87.44	gold quality
vastus lateralis	UBERON:0001379	86.75	gold quality
layer of synovial tissue	UBERON:0007616	86.72	gold quality
monocyte	CL:0000576	86.63	gold quality
cervix squamous epithelium	UBERON:0006922	86.60	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	86.59	gold quality
synovial joint	UBERON:0002217	86.45	gold quality
mononuclear cell	CL:0000842	86.39	gold quality
cauda epididymis	UBERON:0004360	86.32	gold quality
skin of hip	UBERON:0001554	86.07	gold quality
mucosa of sigmoid colon	UBERON:0004993	85.97	gold quality
upper leg skin	UBERON:0004262	85.90	gold quality
leukocyte	CL:0000738	85.89	gold quality
cartilage tissue	UBERON:0002418	85.86	gold quality
quadriceps femoris	UBERON:0001377	85.70	gold quality
colonic mucosa	UBERON:0000317	85.63	gold quality
epithelium of nasopharynx	UBERON:0001951	85.49	gold quality
secondary oocyte	CL:0000655	85.37	gold quality
seminal vesicle	UBERON:0000998	85.36	gold quality
tongue squamous epithelium	UBERON:0006919	85.35	gold quality
biceps brachii	UBERON:0001507	85.33	gold quality
superficial temporal artery	UBERON:0001614	85.10	gold quality
skeletal muscle tissue	UBERON:0001134	85.06	gold quality
oviduct epithelium	UBERON:0004804	84.89	gold quality
urethra	UBERON:0000057	84.84	gold quality
colonic epithelium	UBERON:0000397	84.78	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	84.70	gold quality
pigmented layer of retina	UBERON:0001782	84.45	gold quality
vena cava	UBERON:0004087	84.39	gold quality
bone marrow	UBERON:0002371	84.22	gold quality
popliteal artery	UBERON:0002250	84.17	gold quality
nasal cavity epithelium	UBERON:0005384	84.15	gold quality
tibial artery	UBERON:0007610	84.15	gold quality
muscle organ	UBERON:0001630	83.98	gold quality
saphenous vein	UBERON:0007318	83.93	gold quality
muscle tissue	UBERON:0002385	83.91	gold quality
connective tissue	UBERON:0002384	83.81	gold quality
adipose tissue	UBERON:0001013	83.72	gold quality
diaphragm	UBERON:0001103	83.71	silver quality
gastrocnemius	UBERON:0001388	83.70	gold quality
muscle of leg	UBERON:0001383	83.41	gold quality
pylorus	UBERON:0001166	83.30	gold quality
mucosa of stomach	UBERON:0001199	83.30	gold quality
adrenal tissue	UBERON:0018303	83.23	gold quality
aorta	UBERON:0000947	83.19	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	83.16	gold quality
coronary artery	UBERON:0001621	83.01	gold quality
left coronary artery	UBERON:0001626	82.99	gold quality
middle temporal gyrus	UBERON:0002771	82.98	gold quality
deltoid	UBERON:0001476	82.92	gold quality
sural nerve	UBERON:0015488	82.89	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	82.70	gold quality
gingival epithelium	UBERON:0001949	82.65	gold quality
trabecular bone tissue	UBERON:0002483	82.59	gold quality
hindlimb stylopod muscle	UBERON:0004252	82.59	gold quality
cervix epithelium	UBERON:0004801	82.57	gold quality
right coronary artery	UBERON:0001625	82.52	gold quality
lung	UBERON:0002048	82.47	gold quality
gingiva	UBERON:0001828	82.33	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	82.10	gold quality
bone marrow cell	CL:0002092	82.05	gold quality
ascending aorta	UBERON:0001496	81.91	gold quality
subcutaneous adipose tissue	UBERON:0002190	81.88	gold quality
thoracic aorta	UBERON:0001515	81.87	gold quality
urinary bladder	UBERON:0001255	81.85	gold quality
uterine cervix	UBERON:0000002	81.67	gold quality
lower esophagus muscularis layer	UBERON:0035833	81.66	gold quality
lower esophagus	UBERON:0013473	81.63	gold quality
fallopian tube	UBERON:0003889	81.50	gold quality
cardia of stomach	UBERON:0001162	81.48	gold quality
mammalian vulva	UBERON:0000997	81.43	gold quality
descending thoracic aorta	UBERON:0002345	81.33	gold quality
ectocervix	UBERON:0012249	81.25	gold quality
jejunum	UBERON:0002115	81.24	gold quality
germinal epithelium of ovary	UBERON:0001304	80.99	gold quality
thoracic mammary gland	UBERON:0005200	80.99	gold quality
mammary gland	UBERON:0001911	80.94	gold quality
adipose tissue of abdominal region	UBERON:0007808	80.87	gold quality
stromal cell of endometrium	CL:0002255	80.83	gold quality
rectum	UBERON:0001052	80.72	gold quality
epithelial cell of pancreas	CL:0000083	80.65	silver quality
pancreatic ductal cell	CL:0002079	80.49	gold quality

Single-cell (SCXA)

Detected in 6 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-HCAD-35	yes	33.48
E-HCAD-25	yes	15.59
E-MTAB-9388	yes	13.35
E-CURD-119	yes	10.73
E-ANND-3	yes	8.26
E-MTAB-6386	no	416.91

HPA expression

RNA tissue specificity: Low tissue specificity

showing 60 of 80 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Choroid plexus	tissue	42.3
Basal ganglia	tissue	39.0	medium
Hippocampal formation	tissue	37.0
Putamen	tissue	36.6
Entorhinal cortex	tissue	32.4
Cerebral cortex	tissue	32.3	low
Occipital cortex	tissue	32.3
Amygdala	tissue	31.7
Temporal cortex	tissue	31.0
Prefrontal cortex	tissue	30.2
Somatosensory cortex	tissue	30.2
Ventral forebrain	tissue	30.0
Motor cortex	tissue	29.6
Insular cortex	tissue	28.5
Retrosplenial and cingulate cortex	tissue	28.0
Cerebellum	tissue	27.3	low
Retrosplenial cortex	tissue	26.8
Septum	tissue	24.9
Thalamus	tissue	19.9
Substantia nigra	tissue	19.4
Nucleus accumbens	tissue	19.2
Superior colliculi	tissue	18.7
Midbrain	tissue	18.4
Hypothalamus	tissue	18.4
Periaqueductal gray	tissue	18.4
Pons	tissue	18.2
Olfactory bulb	tissue	17.8
Hippocampus	tissue	16.1	high
Bone marrow	tissue	16.0	medium
Corpus callosum	tissue	15.8
Spinal cord	tissue	15.7
Medulla oblongata	tissue	14.5
Caudate putamen	tissue	14.3
Placenta	tissue	11.1	medium
Liver	tissue	10.9	low
Adipose tissue	tissue	9.7	not detected
Vagina	tissue	9.0	low
Testis	tissue	8.5	high
Tongue	tissue	8.4
Skeletal muscle	tissue	7.8	low
Rectum	tissue	7.6	high
Colon	tissue	7.5	high
Lung	tissue	7.3	high
Seminal vesicle	tissue	6.8	medium
Esophagus	tissue	6.8	medium
Stomach 1	tissue	6.6	medium
Smooth muscle	tissue	6.5	low
Frontal cortex	tissue	6.5
Parathyroid gland	tissue	6.1	low
Postcentral gyrus	tissue	6.1
Urinary bladder	tissue	5.9	medium
Cervix	tissue	5.8	medium
Salivary gland	tissue	5.8	high
Ovary	tissue	5.7	high
Appendix	tissue	5.7	high
Fallopian tube	tissue	5.6	high
Locus coeruleus	tissue	5.5
Prostate	tissue	5.4	medium
Thymus	tissue	5.2
Gallbladder	tissue	5.1	medium

Brain sub-regions (HPA Brain Atlas): detected in 192; highest nTPM — Dorsal hippocampus (37.0), Subiculum (31.4), Ventral hippocampus (29.1), Caudate nucleus (19.9), Hippocampus, CA3 (19.8).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): NR5A2

miRNA regulators (miRDB)

Targeting DIAPH2 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 108 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-3658	99.96	73.87	4379
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

Functional genomics

Regional missense constraint (gnomAD)

ENST00000324765 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
X:96,685,059–96,881,665	131 / 145.6	0.90	no
X:96,881,666–96,916,568	34 / 74.7	0.46	no
X:96,916,569–97,599,314	536 / 599.3	0.89	no

Literature-anchored findings (GeneRIF, showing 13)

• Dia2 plays an important role in formation of lamellipodia. (PMID:18044991)
• Our results indicated that DIAPH2 may be a polygenic pleiotropy for premature ovarian failure (POF) and AMD. (PMID:21386871)
• Long HIV filopodial formation in infected dendritic cells was dependent on the formin diaphanous 2 (Diaph2) (PMID:22685410)
• Dia2 and DIP co-tether to nascent blebs and this linkage is required for bleb formation. (PMID:23024796)
• In podocytes, INF2 appears to be an important modulator of actin-dependent behaviors that are under the control of Rho/mDia signaling. (PMID:23620398)
• DIAPH2 has been associated with premature ovarian insufficiency, an aging phenotype in humans. (PMID:24037343)
• Dia1, Dia2, and Dia3 are involved in ErbB2-dependent capture of microtubules at the cell leading edge and ErbB2-driven guided migration. (PMID:24403606)
• Data show that diaphanous related formin 1 protein (Dia1) and diaphanous related formin 2 protein (Dia2) facilitated HIV-1-induced microtubule (MT) stabilization and the intracellular motility of virus particles. (PMID:28760985)
• Low DIA2 expression is associated with breast cancer. (PMID:29596520)
• DIAPH2 gene expression was an independent prognostic factors of clinical pregnancy rate and live birth in ICSI pregnancies. (PMID:30593440)
• Low DIAPH2 expression is associated with metastasis of laryngeal squamous cell carcinoma. (PMID:30793164)
• DIAPH2, PTPRD and HIC1 Gene Polymorphisms and Laryngeal Cancer Risk. (PMID:34299935)
• DIAPH2 gene polymorphisms and laryngeal cancer risk in men. (PMID:38844723)

Cross-species orthologs

9 orthologs

Organism	Symbol	Gene ID
danio_rerio	diaph2	ENSDARG00000076060
mus_musculus	Diaph2	ENSMUSG00000034480
rattus_norvegicus	Diaph2	ENSRNOG00000057826
drosophila_melanogaster	dia	FBGN0011202
drosophila_melanogaster	Frl	FBGN0267795
caenorhabditis_elegans		WBGENE00018976
caenorhabditis_elegans		WBGENE00019030
caenorhabditis_elegans	sydn-1	WBGENE00021473
caenorhabditis_elegans		WBGENE00021698

Paralogs (18): DAAM1 (ENSG00000100592), FNBP4 (ENSG00000109920), DIAPH1 (ENSG00000131504), FHOD3 (ENSG00000134775), FHOD1 (ENSG00000135723), FHDC1 (ENSG00000137460), DIAPH3 (ENSG00000139734), DAAM2 (ENSG00000146122), 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:1858500) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 5 distinct phenotype terms.

Mouse phenotype (MP)	Records
abnormal heart morphology	1
increased circulating phosphate level	1
hemorrhage	1
abnormal brain morphology	1
hearing/vestibular/ear phenotype	1

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
Oryza sativa Japonica Group	Q6MWG9	64.6%	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
RPA4	protein-coding	29935
ERVFC1	protein-coding	105373297
DIAPH2-AS1	ncRNA	10824

Protein

Protein identifiers

Protein diaphanous homolog 2 — O60879 (reviewed: O60879)

Alternative names: Diaphanous-related formin-2

All UniProt accessions (1): O60879

UniProt curated annotations — full annotation on UniProt →

Function. Could be involved in oogenesis. Involved in the regulation of endosome dynamics. Implicated in a novel signal transduction pathway, in which isoform 3 and CSK are sequentially activated by RHOD to regulate the motility of early endosomes through interactions with the actin cytoskeleton.

Subunit / interactions. Isoform 3 interacts with RHOD in the GTP-bound form.

Subcellular location. Cytoplasm. Cytosol. Early endosome.

Tissue specificity. Expressed in testis, ovary, small intestine, prostate, lung, liver, kidney and leukocytes.

Disease relevance. Premature ovarian failure 2A (POF2A) [MIM:300511] An ovarian disorder defined as the cessation of ovarian function under the age of 40 years. It is characterized by oligomenorrhea or amenorrhea, in the presence of elevated levels of serum gonadotropins and low estradiol. 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?
O60879-1	1, DIA-156	yes
O60879-2	2, DIA-12C, DIA2B
O60879-3	3, DIA2C

RefSeq proteins (2): NP_006720, NP_009293 (=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

Pfam: PF02181, PF06367, PF06371

UniProt features (23 total): compositionally biased region 5, domain 4, region of interest 4, coiled-coil region 3, splice variant 3, sequence variant 2, chain 1, modified residue 1

Structure

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O60879-F1	76.09	0.35

Human Protein Atlas

Protein class: Predicted intracellular proteins, Plasma proteins, Disease related genes, Human disease related genes

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): endoplasmic reticulum; vesicles; nucleoli

Antibody reliability (HPA): IH enhanced · IF supported

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 (1)

Type	Positions
N-acetylmethionine	1

Function

Pathways and Gene Ontology

Reactome pathways

3 curated (TAS) of 7; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

7 pathways:

ID	Pathway	Evidence
R-HSA-5663220	RHO GTPases Activate Formins	curated
R-HSA-9013405	RHOD GTPase cycle	curated
R-HSA-9035034	RHOF GTPase cycle	curated
R-HSA-9012999	RHO GTPase cycle	—
R-HSA-162582	Signal Transduction	—
R-HSA-194315	Signaling by Rho GTPases	—
R-HSA-9716542	Signaling by Rho GTPases, Miro GTPases and RHOBTB3	—

MSigDB gene sets: 213 (showing top): TGGTGCT_MIR29A_MIR29B_MIR29C, GOBP_OOGENESIS, GOMF_GTPASE_BINDING, ONKEN_UVEAL_MELANOMA_UP, BLALOCK_ALZHEIMERS_DISEASE_UP, GOBP_ACTIN_FILAMENT_ORGANIZATION, BROWNE_HCMV_INFECTION_14HR_DN, GOBP_CELLULAR_PROCESS_INVOLVED_IN_REPRODUCTION_IN_MULTICELLULAR_ORGANISM, BROWNE_HCMV_INFECTION_24HR_DN, SCHLOSSER_SERUM_RESPONSE_DN, GUO_HEX_TARGETS_UP, GOMF_ACTIN_BINDING, GOBP_FEMALE_GAMETE_GENERATION, GOBP_DEVELOPMENTAL_PROCESS_INVOLVED_IN_REPRODUCTION, FUJII_YBX1_TARGETS_UP

GO Biological Process (6): female gamete generation (GO:0007292), actin filament polymerization (GO:0030041), oogenesis (GO:0048477), cellular component organization (GO:0016043), actin cytoskeleton organization (GO:0030036), cell differentiation (GO:0030154)

GO Molecular Function (3): actin binding (GO:0003779), signaling receptor binding (GO:0005102), small GTPase binding (GO:0031267)

GO Cellular Component (3): early endosome (GO:0005769), cytosol (GO:0005829), actin filament (GO:0005884)

Reactome top-level categories

5 top-level categories:

Category	Pathways
RHO GTPase cycle	2
RHO GTPase Effectors	1
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1
Signaling by Rho GTPases	1
Signal Transduction	1

GO top-level categories

17 GO namespaces:

Category	Terms
gamete generation	1
actin polymerization or depolymerization	1
protein polymerization	1
germ cell development	1
female gamete generation	1
cellular component organization or biogenesis	1
cytoskeleton organization	1
actin filament-based process	1
cellular developmental process	1
cytoskeletal protein binding	1
protein binding	1
GTPase binding	1
endosome	1
cytoplasm	1
cellular anatomical structure	1
actin cytoskeleton	1
polymeric cytoskeletal fiber	1

Protein interactions and networks

STRING

showing 15 of 1,199 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DIAPH2	POF1B	Q8WVV4	873
DIAPH2	RHOD	O00212	866
DIAPH2	BMP15	O95972	768
DIAPH2	FIGLA	Q6QHK4	711
DIAPH2	FMR1	Q06787	702
DIAPH2	FOXL2	P58012	692
DIAPH2	NOBOX	O60393	684
DIAPH2	CDC34	P49427	683
DIAPH2	HEY1	Q9Y5J3	646
DIAPH2	FBXW7	Q969H0	644
DIAPH2	IDS	P22304	631
DIAPH2	TRIM3	O75382	630
DIAPH2	CDC42	P21181	602
DIAPH2	BLVRA	P53004	551
DIAPH2	BLVRB	P30043	535

IntAct

Human interaction partners of DIAPH2 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

2 partners by confidence:

Partner	Interaction type	MIscore	Records
PRMT2	association	0.350	1
CDC42	physical association	0.000	1

BioGRID (78 interactions; top human partners by supporting records): CDC42 (Affinity Capture-MS; 3 records), RHOD (Affinity Capture-Western; 3 records), PFN1 (Proximity Label-MS; 2 records), RAB11A (Proximity Label-MS; 2 records), RAC1 (Affinity Capture-MS; 2 records), RHOA (Affinity Capture-MS; 2 records), RHOB (Proximity Label-MS; 2 records), ALDH9A1 (Co-fractionation), AMBRA1 (Affinity Capture-MS), ANAPC2 (Proximity Label-MS), APBB1 (Reconstituted Complex), ATG16L1 (Proximity Label-MS), CNPY3 (Proximity Label-MS), CTDP1 (Affinity Capture-MS), DCAF8L2 (Proximity Label-MS)

SIGNOR signaling

1 signaling interactions:

A	Effect	B	Mechanism
AURKB	up-regulates	DIAPH2	phosphorylation

Disease & clinical

Genetic variants

Variant evidence for DIAPH2: 356 ClinVar records (6 pathogenic / likely pathogenic). Per-variant detail is on Sugi Variant.

ClinVar

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

Classification	Count (floor)
Pathogenic	5
Likely pathogenic	1
Uncertain significance	141
Likely benign	38
Benign	8

Top pathogenic / likely-pathogenic (6)

Showing all 6 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
1330214	Single allele	Pathogenic	criteria provided, single submitter	1
4974534	NC_000023.11:g.(?91518032)(100278639_?)del	Pathogenic	criteria provided, single submitter	1
549659	NC_000023.11:g.97519547_97572671dup	Likely pathogenic	criteria provided, single submitter	1
11622	t(X;12)(q21;p13)	Pathogenic	no assertion criteria provided	1
686268	GRCh37/hg19 Xq21.32-22.1(chrX:92939446-99556731)x1	Pathogenic	no assertion criteria provided	1
1708202	GRCh37/hg19 Xq21.31-22.1(chrX:90868186-99828437)x1	Pathogenic	no assertion criteria provided	1

Per-variant reference — Sugi Variant

Explore DIAPH2’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; 26 predictions of 4,747):

Position(s)	Effect	Δscore	Sites
X:96685191–96685192	donor_loss	1.0000	3
X:96712665	donor_gain	1.0000
X:96738577	acceptor_gain	1.0000
X:96738584–96738585	acceptor_loss	1.0000	3
X:96738733	donor_gain	1.0000
X:96738763–96738764	donor_loss	1.0000	5
X:96758259–96758260	donor_loss	1.0000	5
X:96763065–96763067	acceptor_gain	1.0000	2
X:96881576–96881578	acceptor_gain	1.0000	2
X:96881577–96881578	acceptor_loss	1.0000	3

AlphaMissense

2,314 missense substitutions predicted likely pathogenic (of 7,296 scored), across 621 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
M113	9	0.945	0.998
M138	9	0.936	0.997
M117	9	0.901	0.995
M272	9	0.869	0.969
M1056	9	0.858	0.991
F1069	8	0.993	1.000
D387	8	0.991	0.998
N845	8	0.989	0.999
D1057	8	0.986	0.998
D116	8	0.985	0.997
N242	8	0.978	0.997
F201	8	0.972	0.996
N842	8	0.972	0.998
F780	8	0.969	0.997
D54	8	0.966	0.985
N334	8	0.954	0.999
F110	8	0.952	0.991
F380	8	0.946	0.994
F678	8	0.934	0.995
D464	8	0.932	0.973

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

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

2 prognostic cancer types:

Cancer	Prognostic	p-value
Kidney Renal Clear Cell Carcinoma (TCGA)	favorable	0.00014
Thyroid Carcinoma (TCGA)	unfavorable	0.000389

Disease associations

OMIM: gene MIM:300108 | disease phenotypes: MIM:300511, MIM:300088

GenCC curated gene-disease

1 curated gene-disease records:

Disease	Classification	Inheritance	Records
premature ovarian failure 2A	Limited	Unknown

Mondo (3): premature ovarian failure 2A (MONDO:0010350), developmental and epileptic encephalopathy, 9 (MONDO:0010246), primary amenorrhea (MONDO:1060208)

Orphanet (2): Female restricted epilepsy with intellectual disability (Orphanet:101039), X-linked intellectual disability-epilepsy syndrome (Orphanet:2076)

HPO phenotypes

6 phenotypes (HPO-id order):

HPO	Term
HP:0000869	Secondary amenorrhea
HP:0001423	X-linked dominant inheritance
HP:0008209	Premature ovarian insufficiency
HP:0008232	Elevated circulating follicle stimulating hormone level
HP:0011462	Young adult onset
HP:0011969	Elevated circulating luteinizing hormone level

MeSH disease descriptors

2 disease descriptors:

Descriptor	Name	Tree numbers
C564715	Epilepsy, Female-Restricted, with Mental Retardation *(supp.)*
C564498	Premature Ovarian Failure 2a *(supp.)*

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (CPIC guideline: no)

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects expression, affects methylation, decreases expression, increases methylation, increases mutagenesis	8
Cisplatin	decreases expression, affects expression, affects cotreatment	4
Valproic Acid	affects expression, increases expression	3
Aflatoxin B1	affects expression, decreases expression, decreases methylation	3
entinostat	increases expression, affects cotreatment	2
belinostat	increases expression, affects cotreatment	2
Panobinostat	affects cotreatment, increases expression	2
Acetaminophen	decreases expression	2
Tobacco Smoke Pollution	decreases expression, increases methylation	2
aristolochic acid I	decreases expression	1
bisphenol F	increases methylation	1
2,4,6-tribromophenol	increases expression	1
testosterone enanthate	affects expression	1
methyleugenol	decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	decreases expression	1
decabromobiphenyl ether	increases expression	1
arsenite	affects binding, decreases reaction	1
sodium bichromate	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
sodium arsenite	decreases expression	1
tetrabromobisphenol A	increases expression	1
zinc chromate	decreases expression, increases abundance	1
tobacco tar	decreases expression	1
benzo(e)pyrene	decreases methylation, increases methylation	1
potassium chromate(VI)	decreases expression	1
aflatoxin B2	affects methylation	1
nickel sulfate	decreases expression	1
evodiamine	decreases expression	1
di-n-butylphosphoric acid	affects expression	1

Clinical trials (associated diseases)

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

3 trials:

NCT	Phase	Status	Title
NCT03178695	Phase 1	COMPLETED	Inovium Ovarian Rejuvenation Trials
NCT04009473	Phase 1/2	UNKNOWN	Stem Cell Therapy and Growth Factor Ovarian in Vitro Activation
NCT07164248	Not specified	COMPLETED	Evaluation of Bone Mineral Density Indications and Outcomes in Female Adolescents: Implications for Early Detection of Osteopenia/Osteoporosis and Gynecologic Practice