POU3F4

Summary

POU3F4 (POU class 3 homeobox 4, HGNC:9217) is a protein-coding gene on chromosome Xq21.1, encoding POU domain, class 3, transcription factor 4 (P49335). Probable transcription factor which exert its primary action widely during early neural development and in a very limited set of neurons in the mature brain. It is haploinsufficient (ClinGen: sufficient evidence).

This gene encodes a member of the POU-III class of neural transcription factors. This family member plays a role in inner ear development. The protein is thought to be involved in the mediation of epigenetic signals which induce striatal neuron-precursor differentiation. Mutations in this gene are associated with X chromosome-linked nonsyndromic mixed deafness.

Source: NCBI Gene 5456 — RefSeq curated summary.

At a glance

• Gene–disease (curated): nonsyndromic genetic hearing loss (Definitive, ClinGen) — +3 more curated relationships
• GWAS associations: 2
• Clinical variants (ClinVar): 220 total — 75 pathogenic, 34 likely-pathogenic
• Phenotypes (HPO): 43
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_000307

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9217
Approved symbol	POU3F4
Name	POU class 3 homeobox 4
Location	Xq21.1
Locus type	gene with protein product
Status	Approved
Aliases	BRN4, OTF9, DFNX2
Ensembl gene	ENSG00000196767
Ensembl biotype	protein_coding
OMIM	300039
Entrez	5456

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000644024

RefSeq mRNA: 1 — MANE Select: NM_000307 NM_000307

CCDS: CCDS14450

Canonical transcript exons

ENST00000644024 — 1 exons

Exon	Start	End
ENSE00003818932	83508290	83512127

Expression profiles

Bgee: expression breadth broad, 54 present calls, max score 87.83.

FANTOM5 (CAGE): breadth broad, TPM avg 3.2754 / max 153.1345, expressed in 193 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
196828	2.4649	189
196827	0.4347	134
196829	0.3357	113
196826	0.0400	18

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
ganglionic eminence	UBERON:0004023	87.83	gold quality
ventricular zone	UBERON:0003053	87.44	gold quality
nucleus accumbens	UBERON:0001882	82.15	gold quality
caudate nucleus	UBERON:0001873	77.91	gold quality
putamen	UBERON:0001874	77.82	gold quality
cortical plate	UBERON:0005343	70.77	gold quality
amygdala	UBERON:0001876	63.82	gold quality
myocardium	UBERON:0002349	63.82	gold quality
anterior cingulate cortex	UBERON:0009835	63.49	gold quality
prefrontal cortex	UBERON:0000451	63.10	gold quality
hypothalamus	UBERON:0001898	62.32	gold quality
Brodmann (1909) area 9	UBERON:0013540	61.98	gold quality
right frontal lobe	UBERON:0002810	61.31	gold quality
frontal pole	UBERON:0002795	60.90	gold quality
middle frontal gyrus	UBERON:0002702	60.84	gold quality
paraflocculus	UBERON:0005351	60.42	gold quality
substantia nigra	UBERON:0002038	59.94	gold quality
neocortex	UBERON:0001950	59.85	gold quality
metanephros cortex	UBERON:0010533	59.28	gold quality
right hemisphere of cerebellum	UBERON:0014890	59.24	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	58.66	gold quality
frontal cortex	UBERON:0001870	58.52	gold quality
forebrain	UBERON:0001890	58.52	gold quality
endometrium epithelium	UBERON:0004811	58.50	gold quality
brain	UBERON:0000955	57.99	gold quality
central nervous system	UBERON:0001017	57.83	gold quality
midbrain	UBERON:0001891	57.55	gold quality
tendon of biceps brachii	UBERON:0008188	57.22	gold quality
cerebral cortex	UBERON:0000956	56.69	gold quality
cerebellar vermis	UBERON:0004720	56.69	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	2.47

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

5 targets.

Target	Regulation
DRD1
GCG	Unknown
OXT
POU3F4
POU5F1	Repression

JASPAR motifs

Motif	Name	Family
MA0789.1	POU3F4	POU domain factors

Upstream regulators (CollecTRI, top): POU3F4

miRNA regulators (miRDB)

36 targeting POU3F4, 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-5692A	100.00	74.40	6850
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-10527-5P	99.91	72.28	3754
HSA-MIR-4779	99.86	66.50	1583
HSA-MIR-6739-5P	99.80	67.87	2806
HSA-MIR-4668-5P	99.79	70.58	3782
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
HSA-MIR-548X-5P	99.78	71.12	3085
HSA-MIR-6733-5P	99.74	67.94	2759
HSA-MIR-3202	99.66	67.70	2737
HSA-MIR-488-3P	99.61	68.79	1731
HSA-MIR-1249-5P	99.61	66.55	2049
HSA-MIR-6797-5P	99.61	66.55	2084
HSA-MIR-3153	99.55	67.59	2337
HSA-MIR-5584-5P	99.49	68.22	2814
HSA-MIR-6507-5P	99.36	70.46	2524
HSA-MIR-7515	99.31	68.22	1795
HSA-MIR-505-3P	99.19	69.71	896
HSA-MIR-3154	98.94	66.55	1455
HSA-MIR-421	98.90	67.04	1883

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 34)

• This publication describes mutations in a similar mouse gene. (PMID:12062767)
• model of DFN3 non-syndromic deafness (PMID:12062767)
• POU3F4 did not contribute to Y linked familial deafness in a Chinese pedigree. (PMID:16229168)
• two novel mutations of the POU3F4 gene in X-linked deafness type 3 patients in the Korean population (PMID:19438930)
• Results strongly suggest that the deafness in DFN3 patients is largely due to the null function of POU3F4. (PMID:19671658)
• The phenotype of eight independent females carrying POU3F4 anomalies is defined, and a late-onset hearing loss is found in three patients. (PMID:19930154)
• evaluation of DFN3 patients with deletions in the POU3F4 locus and detection of carrier female using MLPA. (PMID:20412083)
• Data suggest that multiple enhancers control the expression of Pou3f4 in the inner ear and these may contribute to the phenotype observed in DFN3 patients. (PMID:20668882)
• DNA sequencing of the POU3F4 gene revealed a novel nucleotide variation, c.647G to A. The additional mutation confirms the crucial role of POU3F4 in auditory function. (PMID:21193157)
• pou3f4 expression in inner ear might be under the control of distinct regulatory elements that fine-tune the spatio-temporal activity of this gene (PMID:21209840)
• novel mutations in the POU3F4 gene resulting in congenital X-linked deafness DFN3. (PMID:21250553)
• Study found no mutations in GJB6 or POU3F4 in nonsyndromic Tibetan Chinese patients with hearing impairment. (PMID:22389666)
• Frameshift truncation and extension mutations in the C-terminus of POU3F4 lead to cytoplasmic localization and subsequent proteosomal degradation due to structural aberrations, which cause transcriptional inactivity and thus nonsyndromic hearing loss. (PMID:23076972)
• We concluded that the probable presence of the third window effect is not limited to the particular type of POU3F4 mutation. (PMID:23400403)
• Results show three novel mutations in the POU3F4 gene resulting in profound hearing loss in both humans and mice. (PMID:23606368)
• Our data suggest that different POU3F4 mutations might show different recurrence rate in siblings of the incomplete partition type III anomaly especially in East Asian population (PMID:24608376)
• Audiological, medical, and family histories were collected and family members interviewed to compare hearing thresholds and case histories between cases with mutations in SMPX versus POU3F4. (PMID:24687041)
• POU3F4 mutations are associated with X-linked deafness (PMID:25928534)
• findings may greatly contribute to the elucidation of the roles of the Oct and Myc proteins in osteoblast direct reprogramming. The results may also lead to establishment of novel regenerative therapy for various bone resorption diseases (PMID:26499074)
• POU3F4 mutation in profoundly deaf patients may have poorer prognosis after cochlear implantation, than other types. (PMID:26600195)
• POU3F4 mutations can be predicted by incomplete partition type III anomaly by radiological examination of the inner ear. All six of the patients showed mixed hearing loss, but none showed fluctuations in hearing, which may be related to the lack of vestibular aqueduct enlargement at the operculum. (PMID:27577114)
• Sequencing of the entire POU3F4 gene is recommended in patients with characteristic temporal bone malformations. Results of POU3F4 mutation testing are important not only for a proper genetic counseling, but also for adequate preparation and conduction of a surgical procedure. (PMID:27941975)
• A nonsense mutation is identified in a family displaying the pedigree consistent with X-linked recessive pattern in POU3F4 gene. (PMID:28051029)
• POU3F4 gene mutation analysis will increase the success rate of stapes operations and cochlear implantations. (PMID:30176854)
• BRN4 Is a Novel Driver of Neuroendocrine Differentiation in Castration-Resistant Prostate Cancer and Is Selectively Released in Extracellular Vesicles with BRN2. (PMID:31371344)
• In this study, we identified a novel hemizygous variant, c.870G > T in the POU3F4 gene, leading to a substitution of a Lysine with an Asparagine in position 290, in two brothers from one Italian family with identical inner ear abnormalities specific to the X-linked deafness-2 (DFNX2, MIM 304400). (PMID:31786483)
• Research progress of the transcription factor Brn4 (Review). (PMID:33398372)
• Study of complex structural variations of X-linked deafness-2 based on single-molecule sequencing. (PMID:33860785)
• Next-Generation Sequencing Identifies Pathogenic Variants in HGF, POU3F4, TECTA, and MYO7A in Consanguineous Pakistani Deaf Families. (PMID:33976695)
• X-linked Malformation Deafness: Neurodevelopmental Symptoms Are Common in Children With IP3 Malformation and Mutation in POU3F4. (PMID:34133399)
• REST Inactivation and Coexpression of ASCL1 and POU3F4 Are Necessary for the Complete Transformation of RB1/TP53-Inactivated Lung Adenocarcinoma into Neuroendocrine Carcinoma. (PMID:35367201)
• Genome sequencing detects a balanced pericentric inversion with breakpoints that impact the DMD and upstream region of POU3F4 genes. (PMID:37929330)
• This publication describes mutations in a similar mouse gene. (PMID:9667433)
• This publication describes mutations in a similar mouse gene. (PMID:9889200)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
mus_musculus	Pou3f4	ENSMUSG00000056854
rattus_norvegicus	Pou3f4	ENSRNOG00000002784
drosophila_melanogaster	acj6	FBGN0000028
drosophila_melanogaster	vvl	FBGN0086680
caenorhabditis_elegans		WBGENE00000441
caenorhabditis_elegans		WBGENE00006818

Paralogs (17): POU2F2 (ENSG00000028277), POU1F1 (ENSG00000064835), POU4F3 (ENSG00000091010), POU6F2 (ENSG00000106536), POU2F3 (ENSG00000137709), POU2F1 (ENSG00000143190), POU4F2 (ENSG00000151615), POU4F1 (ENSG00000152192), HDX (ENSG00000165259), POU6F1 (ENSG00000184271), POU3F2 (ENSG00000184486), POU3F1 (ENSG00000185668), POU3F3 (ENSG00000198914), CCDC160 (ENSG00000203952), POU5F1 (ENSG00000204531), POU5F1B (ENSG00000212993), POU5F2 (ENSG00000248483)

Protein

Protein identifiers

POU domain, class 3, transcription factor 4 — P49335 (reviewed: P49335)

Alternative names: Brain-specific homeobox/POU domain protein 4, Octamer-binding protein 9, Octamer-binding transcription factor 9

All UniProt accessions (1): A0A2R8Y739

UniProt curated annotations — full annotation on UniProt →

Function. Probable transcription factor which exert its primary action widely during early neural development and in a very limited set of neurons in the mature brain.

Subunit / interactions. Interacts with HNRNPU.

Subcellular location. Nucleus.

Tissue specificity. Brain specific.

Disease relevance. Deafness, X-linked, 2 (DFNX2) [MIM:304400] A form of deafness characterized by both conductive hearing loss resulting from stapes (perilymphatic gusher) fixation, and progressive sensorineural deafness. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the POU transcription factor family. Class-3 subfamily.

RefSeq proteins (1): NP_000298* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000327	POU_dom	Domain
IPR001356	HD	Domain
IPR009057	Homeodomain-like_sf	Homologous_superfamily
IPR010982	Lambda_DNA-bd_dom_sf	Homologous_superfamily
IPR013847	POU	Domain
IPR016362	TF_POU_3	Family
IPR017970	Homeobox_CS	Conserved_site
IPR050255	POU_domain_TF	Family

Pfam: PF00046, PF00157

UniProt features (15 total): sequence variant 7, region of interest 2, compositionally biased region 2, chain 1, domain 1, DNA-binding region 1, modified residue 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P49335-F1	64.25	0.32

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): 265

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 255 (showing top): AGGAAGC_MIR5163P, FREAC2_01, BENPORATH_ES_WITH_H3K27ME3, WWTAAGGC_UNKNOWN, GOBP_SENSORY_PERCEPTION_OF_MECHANICAL_STIMULUS, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_UP, GRAESSMANN_RESPONSE_TO_MC_AND_SERUM_DEPRIVATION_UP, FOXO1_01, GGGTGGRR_PAX4_03, NKX61_01, MARTORIATI_MDM4_TARGETS_NEUROEPITHELIUM_DN, GOBP_ANIMAL_ORGAN_MORPHOGENESIS, SRF_C, GOBP_EAR_DEVELOPMENT, KOYAMA_SEMA3B_TARGETS_UP

GO Biological Process (8): regulation of transcription by RNA polymerase II (GO:0006357), brain development (GO:0007420), sensory perception of sound (GO:0007605), cochlea morphogenesis (GO:0090103), negative regulation of mesenchymal cell apoptotic process (GO:2001054), regulation of DNA-templated transcription (GO:0006355), forebrain neuron differentiation (GO:0021879), inner ear development (GO:0048839)

GO Molecular Function (7): RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), DNA-binding transcription factor activity (GO:0003700), sequence-specific double-stranded DNA binding (GO:1990837), RNA polymerase II transcription regulatory region sequence-specific DNA binding (GO:0000977), DNA binding (GO:0003677), sequence-specific DNA binding (GO:0043565)

GO Cellular Component (3): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regulation of DNA-templated transcription	2
RNA polymerase II transcription regulatory region sequence-specific DNA binding	2
transcription cis-regulatory region binding	2
cellular anatomical structure	2
transcription by RNA polymerase II	1
central nervous system development	1
animal organ development	1
head development	1
sensory perception of mechanical stimulus	1
inner ear morphogenesis	1
embryonic morphogenesis	1
cochlea development	1
negative regulation of apoptotic process	1
mesenchymal cell apoptotic process	1
regulation of mesenchymal cell apoptotic process	1
DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
forebrain generation of neurons	1
central nervous system neuron differentiation	1
ear development	1
anatomical structure development	1
cis-regulatory region sequence-specific DNA binding	1
chromatin	1
DNA-binding transcription factor activity	1
regulation of transcription by RNA polymerase II	1
transcription regulator activity	1
double-stranded DNA binding	1
sequence-specific DNA binding	1
nucleic acid binding	1
DNA binding	1
chromosome	1
intracellular membrane-bounded organelle	1
nuclear lumen	1

Protein interactions and networks

STRING

1132 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
POU3F4	PRPS1	P09329	717
POU3F4	PRPS1L1	P21108	692
POU3F4	SOX2	P48431	644
POU3F4	SMPX	Q9UHP9	642
POU3F4	GJB2	P29033	624
POU3F4	SLC26A4	O43511	621
POU3F4	PGK1	P00558	615
POU3F4	RFXAP	O00287	587
POU3F4	KLF4	P78338	582
POU3F4	MYO15A	Q9UKN7	578
POU3F4	RET	P07949	572
POU3F4	STRC	Q7RTU9	570
POU3F4	RFX5	P48382	562
POU3F4	RFX2	P48378	558
POU3F4	RFXANK	O14593	551

IntAct

0 interactions, top by confidence:

ESM2 similar proteins: A0A1L8FFY5, A1L0Z1, A1L1N5, A4IFD2, A8XJD0, B3DM25, B7ZQA9, D3ZTL1, P10037, P20268, P20912, P23899, P24350, P27889, P31362, P31363, P31364, P31365, P31369, P35680, P42571, P49335, P56224, P62515, P62516, P70030, P79364, P79745, P79746, Q00196, Q03365, Q05041, Q08478, Q15319, Q2LE08, Q4QQQ7, Q561L5, Q5RER5, Q5W1J5, Q6DJN3

Diamond homologs: A0A1L8FFY5, A1L0Z1, A7Y7W2, B3DM23, B3DM25, B7ZQA9, D3ZTL1, G3V7L5, O97552, P09086, P10036, P10037, P13528, P14859, P15143, P16143, P16241, P17208, P20263, P20264, P20265, P20266, P20267, P20268, P20912, P20913, P20914, P21952, P24350, P25425, P28069, P31360, P31361, P31362, P31363, P31364, P31365, P31367, P31368, P31369

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
POU3F4	“up-regulates activity”	POU3F2	binding
POU3F4	“up-regulates activity”	POU3F3	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	75
Likely pathogenic	34
Uncertain significance	66
Likely benign	20
Benign	10

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
11677	NM_000307.5(POU3F4):c.648del (p.Leu217fs)	Pathogenic
11678	NM_000307.5(POU3F4):c.604A>T (p.Lys202Ter)	Pathogenic
11679	NM_000307.5(POU3F4):c.950T>G (p.Leu317Trp)	Pathogenic
11681	NM_000307.5(POU3F4):c.862_865del (p.Val289fs)	Pathogenic
11682	NM_000307.5(POU3F4):c.935C>T (p.Ala312Val)	Pathogenic
11683	NM_000307.5(POU3F4):c.990A>T (p.Arg330Ser)	Pathogenic
11684	NM_000307.5(POU3F4):c.967C>G (p.Arg323Gly)	Pathogenic
1185600	NM_000307.5(POU3F4):c.65_66del (p.Ser22fs)	Pathogenic
1185618	NM_000307.5(POU3F4):c.669T>A (p.Tyr223Ter)	Pathogenic
1185660	NM_000307.5(POU3F4):c.609_610del (p.Arg204fs)	Pathogenic
1418463	NM_000307.5(POU3F4):c.172del (p.Trp57_Val58insTer)	Pathogenic
156303	NM_000307.5(POU3F4):c.896del (p.Lys299fs)	Pathogenic
1687028	NM_000307.5(POU3F4):c.340dup (p.Trp114fs)	Pathogenic
1799532	NM_000307.5(POU3F4):c.916C>T (p.Gln306Ter)	Pathogenic
2005526	NM_000307.5(POU3F4):c.509del (p.Pro170fs)	Pathogenic
228391	NM_000307.5(POU3F4):c.607_610del (p.Gln203fs)	Pathogenic
236062	NM_000307.5(POU3F4):c.235C>T (p.Gln79Ter)	Pathogenic
2422849	NC_000023.10:g.(?82763333)(82764418_?)del	Pathogenic
2445677	NM_000307.5(POU3F4):c.300dup (p.Val101fs)	Pathogenic
2505306	NM_000307.5(POU3F4):c.607_610dup (p.Arg204fs)	Pathogenic
2582792	NM_000307.5(POU3F4):c.80dup (p.Ser29fs)	Pathogenic
2582793	NM_000307.5(POU3F4):c.985C>T (p.Arg329Ter)	Pathogenic
2771380	NM_000307.5(POU3F4):c.391del (p.Leu131fs)	Pathogenic
3387797	NM_000307.5(POU3F4):c.782C>A (p.Ser261Ter)	Pathogenic
3601640	NM_000307.5(POU3F4):c.823_824del (p.Gln275fs)	Pathogenic
3601642	NM_000307.5(POU3F4):c.101del (p.Pro34fs)	Pathogenic
3601643	NM_000307.5(POU3F4):c.1075del (p.His359fs)	Pathogenic
3601644	NM_000307.5(POU3F4):c.1085G>C (p.Ter362Ser)	Pathogenic
3601645	NM_000307.5(POU3F4):c.126C>G (p.Tyr42Ter)	Pathogenic
3601648	NM_000307.5(POU3F4):c.207del (p.Thr70fs)	Pathogenic

SpliceAI

73 predictions. Top by Δscore:

Variant	Effect	Δscore
X:83510477:T:TA	acceptor_gain	0.6500
X:83510719:G:C	acceptor_gain	0.4800
X:83510377:G:A	acceptor_gain	0.4600
X:83509204:GA:G	donor_gain	0.3900
X:83510717:T:A	acceptor_gain	0.3900
X:83509282:G:GT	donor_gain	0.3700
X:83510798:G:GG	donor_gain	0.3600
X:83509218:C:CT	donor_gain	0.3500
X:83509202:T:TG	donor_gain	0.3400
X:83509203:G:GG	donor_gain	0.3400
X:83509219:A:AT	donor_gain	0.3400
X:83509217:TC:T	donor_gain	0.3300
X:83509417:G:GT	donor_gain	0.3300
X:83510376:C:CA	acceptor_gain	0.3300
X:83509196:GC:G	donor_gain	0.3200
X:83509198:GTACT:G	donor_gain	0.3200
X:83509205:AG:A	donor_gain	0.3200
X:83508935:G:GT	donor_gain	0.3100
X:83509188:T:TA	donor_gain	0.3100
X:83509227:C:CT	donor_gain	0.3100
X:83509191:CA:C	donor_gain	0.3000
X:83509192:AA:A	donor_gain	0.3000
X:83509206:G:GT	donor_gain	0.3000
X:83509214:T:TC	donor_gain	0.3000
X:83509215:C:CC	donor_gain	0.3000
X:83509216:C:CC	donor_gain	0.3000
X:83509222:T:TA	donor_gain	0.3000
X:83510797:A:AG	donor_gain	0.3000
X:83509210:C:CT	donor_gain	0.2900
X:83509220:A:AA	donor_gain	0.2900

AlphaMissense

2371 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:83508905:T:C	L194S	1.000
X:83508913:T:C	F197L	1.000
X:83508914:T:C	F197S	1.000
X:83508914:T:G	F197C	1.000
X:83508915:C:A	F197L	1.000
X:83508915:C:G	F197L	1.000
X:83508917:C:A	A198D	1.000
X:83508926:T:C	F201S	1.000
X:83508928:A:G	K202E	1.000
X:83508929:A:T	K202I	1.000
X:83508930:A:C	K202N	1.000
X:83508930:A:T	K202N	1.000
X:83508938:G:C	R205T	1.000
X:83508938:G:T	R205I	1.000
X:83508939:A:C	R205S	1.000
X:83508939:A:T	R205S	1.000
X:83508941:T:A	I206N	1.000
X:83508941:T:C	I206T	1.000
X:83508941:T:G	I206S	1.000
X:83508949:G:C	G209R	1.000
X:83508950:G:A	G209D	1.000
X:83508950:G:T	G209V	1.000
X:83508952:T:C	F210L	1.000
X:83508953:T:C	F210S	1.000
X:83508954:C:A	F210L	1.000
X:83508954:C:G	F210L	1.000
X:83508956:C:T	T211M	1.000
X:83508960:G:C	Q212H	1.000
X:83508960:G:T	Q212H	1.000
X:83508970:G:A	G216R	1.000

dbSNP variants (sampled 300 via entrez): RS1000171723 (X:83511670 A>C), RS1000504234 (X:83510129 T>C), RS1001118819 (X:83509769 C>G), RS1001450891 (X:83507604 A>T), RS1002171800 (X:83507812 G>A,T), RS1002590916 (X:83510288 A>C,G), RS1003167245 (X:83512118 CAA>C,CA,CAAA), RS1003282266 (X:83511573 TC>T), RS1006178796 (X:83508213 T>C), RS1006982724 (X:83511335 G>C), RS1007314609 (X:83509646 C>T), RS1007776453 (X:83507287 G>A,C,T), RS1008983087 (X:83507199 T>C), RS1009315477 (X:83510013 T>C), RS1009356259 (X:83512574 A>C,G)

Disease associations

OMIM: gene MIM:300039 | disease phenotypes: MIM:304400, MIM:128600

GenCC curated gene-disease

Disease	Classification	Inheritance
nonsyndromic genetic hearing loss	Definitive	X-linked
X-linked mixed hearing loss with perilymphatic gusher	Strong	X-linked
choroideremia-deafness-obesity syndrome	Supportive	X-linked
mitochondrial non-syndromic sensorineural hearing loss	Supportive	Mitochondrial

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
nonsyndromic genetic hearing loss	Definitive	XL

Mondo (8): X-linked mixed hearing loss with perilymphatic gusher (MONDO:0010576), ear malformation (MONDO:0007500), X-linked nonsyndromic hearing loss (MONDO:0019586), nonsyndromic genetic hearing loss (MONDO:0019497), hearing loss disorder (MONDO:0005365), ependymoma (MONDO:0016698), choroideremia-deafness-obesity syndrome (MONDO:0010558), mitochondrial non-syndromic sensorineural hearing loss (MONDO:0010779)

Orphanet (5): X-linked mixed deafness with perilymphatic gusher (Orphanet:383), Rare genetic deafness (Orphanet:96210), Rare X-linked non-syndromic sensorineural deafness type DFN (Orphanet:90625), Rare non-syndromic genetic deafness (Orphanet:87884), Ependymoma (Orphanet:251636)

HPO phenotypes

43 total (30 of 43 shown, HPO-id order):

HPO	Term
HP:0000375	Abnormal cochlea morphology
HP:0000381	Stapes ankylosis
HP:0000405	Conductive hearing impairment
HP:0000407	Sensorineural hearing impairment
HP:0000408	Progressive sensorineural hearing impairment
HP:0000410	Mixed hearing impairment
HP:0000486	Strabismus
HP:0000532	Abnormal chorioretinal morphology
HP:0000533	Chorioretinal atrophy
HP:0000639	Nystagmus
HP:0000648	Optic atrophy
HP:0000822	Hypertension
HP:0000824	Decreased response to growth hormone stimulation test
HP:0000830	Anterior hypopituitarism
HP:0000863	Central diabetes insipidus
HP:0001139	Chorioretinal scalloped atrophy
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001256	Mild intellectual disability
HP:0001263	Global developmental delay
HP:0001347	Hyperreflexia
HP:0001419	X-linked recessive inheritance
HP:0001510	Growth delay
HP:0001513	Obesity
HP:0001920	Renal artery stenosis
HP:0002066	Gait ataxia
HP:0002075	Dysdiadochokinesis
HP:0002750	Delayed skeletal maturation
HP:0003484	Upper limb muscle weakness
HP:0004458	Dilatated internal auditory canal

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST002579_2	Heschl’s gyrus morphology	2.000000e-06
GCST007576_27	Chronotype	5.000000e-12

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0008328	chronotype measurement

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D004806	Ependymoma	C04.557.465.625.600.380.290; C04.557.470.670.380.290; C04.557.580.625.600.380.290
D034381	Hearing Loss	C09.218.458.341; C10.597.751.418.341; C23.888.592.763.393.341
C537793	Ayazi syndrome (supp.)
C580334	Nonsyndromic Deafness (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

5 total (human), top 5 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
arsenite	increases methylation	1
CGP 52608	affects binding, increases reaction	1
Benzo(a)pyrene	affects methylation, decreases methylation, increases methylation	1
Pantothenic Acid	increases expression	1
Rotenone	decreases expression	1

Cellosaurus cell lines

3 cell lines: 3 embryonic stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_A5M2	SEES3-1V human POU3F4, clone1	Embryonic stem cell	Male
CVCL_A5M3	SEES3-1V human POU3F4, clone2	Embryonic stem cell	Male
CVCL_A5M4	SEES3-1V human POU3F4, clone3	Embryonic stem cell	Male

Clinical trials (associated diseases)

298 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
NCT01655212	PHASE3	TERMINATED	Congenital Cytomegalovirus: Efficacy of Antiviral Treatment in a Randomized Controlled Trial
NCT02005822	PHASE3	COMPLETED	Congenital Cytomegalovirus: Efficacy of Antiviral Treatment
NCT03374514	PHASE3	UNKNOWN	Cochlear Electrical Impedance and the Effect of Topical Dexamethasone on Cochlear Implant Surgery
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
NCT02497690	PHASE2	COMPLETED	Effectiveness of Therapy Via Telemedicine Following Cochlear Implants
NCT03107871	PHASE2	ACTIVE_NOT_RECRUITING	Randomized Controlled Trial of Valganciclovir for Cytomegalovirus Infected Hearing Impaired Infants
NCT04120116	PHASE2	COMPLETED	FX-322 in Adults With Stable Sensorineural Hearing Loss
NCT05061758	PHASE2	WITHDRAWN	A Trial of LY3056480 in Patients With SNLH
NCT07364747	PHASE2	RECRUITING	Protective Effect of Acetylcysteine Against Cisplatinum-Induced Ototoxicity: A Randomized Controlled Trial
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
NCT02259595	PHASE1	COMPLETED	Study to Determine the Safety, Tolerability, and Pharmacokinetic Profile of HPN-07 and HPN-07 Plus NAC
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
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
NCT01802190	Not specified	TERMINATED	Prevalence of POU4F3 and SLC17A8 Mutations
NCT02693704	PHASE2/PHASE3	COMPLETED	Evaluation of a Binaural Spatialization Method for Hearing Aids