FOXI1

Summary

FOXI1 (forkhead box I1, HGNC:3815) is a protein-coding gene on chromosome 5q35.1, encoding Forkhead box protein I1 (Q12951). Transcriptional activator required for the development of normal hearing, sense of balance and kidney function.

This gene belongs to the forkhead family of transcription factors, which is characterized by a distinct forkhead domain. This gene may play an important role in the development of the cochlea and vestibulum, as well as in embryogenesis. The encoded protein has been found to be required for the transcription of four subunits of a proton pump found in the inner ear, the kidney, and the epididymis. Mutations in this gene have been associated with deafness, autosomal recessive 4.

Source: NCBI Gene 2299 — RefSeq curated summary.

At a glance

• Gene–disease (curated): autosomal recessive distal renal tubular acidosis (Strong, GenCC) — +4 more curated relationships
• GWAS associations: 2
• Clinical variants (ClinVar): 228 total — 1 pathogenic, 4 likely-pathogenic
• Phenotypes (HPO): 23
• Transcription factor: yes — 10 downstream targets (CollecTRI)
• MANE Select transcript: NM_012188

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3815
Approved symbol	FOXI1
Name	forkhead box I1
Location	5q35.1
Locus type	gene with protein product
Status	Approved
Aliases	FREAC6
Ensembl gene	ENSG00000168269
Ensembl biotype	protein_coding
OMIM	601093
Entrez	2299

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 2 protein_coding

ENST00000306268, ENST00000449804

RefSeq mRNA: 2 — MANE Select: NM_012188 NM_012188, NM_144769

CCDS: CCDS4372, CCDS47337

Canonical transcript exons

ENST00000306268 — 2 exons

Exon	Start	End
ENSE00001314154	170108049	170109734
ENSE00001811945	170105897	170106531

Expression profiles

Bgee: expression breadth broad, 46 present calls, max score 88.80.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.4385 / max 35.3450, expressed in 118 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
60104	0.4385	118

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
metanephros cortex	UBERON:0010533	88.80	gold quality
adult mammalian kidney	UBERON:0000082	83.60	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	71.65	gold quality
kidney	UBERON:0002113	70.94	gold quality
minor salivary gland	UBERON:0001830	66.82	gold quality
cortex of kidney	UBERON:0001225	65.90	gold quality
saliva-secreting gland	UBERON:0001044	65.80	gold quality
mouth mucosa	UBERON:0003729	63.35	gold quality
metanephros	UBERON:0000081	62.15	gold quality
skin of leg	UBERON:0001511	62.15	gold quality
endometrium epithelium	UBERON:0004811	61.69	gold quality
zone of skin	UBERON:0000014	57.98	gold quality
renal medulla	UBERON:0000362	57.92	silver quality
skin of abdomen	UBERON:0001416	57.55	gold quality
pancreatic ductal cell	CL:0002079	55.34	silver quality
nasal cavity mucosa	UBERON:0001826	55.23	gold quality
upper leg skin	UBERON:0004262	54.82	silver quality
skin of hip	UBERON:0001554	53.12	silver quality
parotid gland	UBERON:0001831	52.88	gold quality
cerebellar vermis	UBERON:0004720	52.38	gold quality
bone marrow cell	CL:0002092	50.90	gold quality
Brodmann (1909) area 10	UBERON:0013541	50.82	gold quality
thymus	UBERON:0002370	50.56	gold quality
quadriceps femoris	UBERON:0001377	50.54	gold quality
frontal pole	UBERON:0002795	50.41	gold quality
epithelial cell of pancreas	CL:0000083	50.39	gold quality
tonsil	UBERON:0002372	50.37	gold quality
middle frontal gyrus	UBERON:0002702	50.30	gold quality
mucosa of transverse colon	UBERON:0004991	50.26	gold quality
paraflocculus	UBERON:0005351	50.18	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-CURD-114	yes	11.63
E-ANND-3	no	1.13

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

10 targets.

Target	Regulation
APP
CDH1
CFTR	Repression
PAX2	Unknown
PAX8	Unknown
SIX1	Unknown
SLC26A4	Unknown
SLC4A9
TSC1
TSC22D1	Unknown

JASPAR motifs

Motif	Name	Family
MA0042.1	FOXI1	FOX
MA0042.2	FOXI1	FOX
MA1935.1	ERF::FOXI1	Ets-related::FOX
MA1935.2	ERF::FOXI1	Ets-related::FOX
MA1942.1	ETV2::FOXI1	Ets-related::FOX
MA1942.2	ETV2::FOXI1	Ets-related::FOX
MA1946.1	ETV5::FOXI1	Ets-related::FOX
MA1946.2	ETV5::FOXI1	Ets-related::FOX

JASPAR matrix evidence (PMIDs): PMID:9153225, PMID:23836653, PMID:31913281, PMID:19070576

miRNA regulators (miRDB)

67 targeting FOXI1, 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-6833-3P	100.00	70.63	3197
HSA-MIR-518D-5P	100.00	67.51	979
HSA-MIR-518E-5P	100.00	67.66	954
HSA-MIR-518F-5P	100.00	67.51	979
HSA-MIR-519A-5P	100.00	67.66	954
HSA-MIR-519B-5P	100.00	67.66	954
HSA-MIR-519C-5P	100.00	67.66	954
HSA-MIR-520C-5P	100.00	67.51	979
HSA-MIR-522-5P	100.00	67.66	954
HSA-MIR-523-5P	100.00	67.66	954
HSA-MIR-526A-5P	100.00	67.51	979
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-1184	99.99	68.19	1458
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-7152-3P	99.97	67.47	849
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-6508-5P	99.92	70.67	2465
HSA-MIR-6809-3P	99.91	71.45	3814
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-8067	99.86	69.59	2260
HSA-MIR-4306	99.72	70.50	3630
HSA-MIR-378G	99.71	64.90	1106
HSA-MIR-518A-5P	99.70	69.01	2209
HSA-MIR-527	99.70	69.01	2209

Literature-anchored findings (GeneRIF, showing 20)

• We report here that tropomyosins are post-translationally modified by several phosphorylations in their C-termini in mature flies, but not in recently emerged flies that are incapable of flight. (PMID:16752200)
• analysis of arrhythmia caused by a Drosophila tropomyosin mutation using optical coherence tomography (PMID:21179409)
• Tm1C-Khc interaction is specific for the osk localization pathway. (PMID:27802167)
• The authors demonstrate that kinesin-1 recruitment requires the DmTropomyosin1-I/C isoform, an atypical RNA-binding tropomyosin that binds directly to dimerizing oskar 3’UTRs. (PMID:28028052)
• C/EBP alpha and HNF-3 gamma cooperatively regulate CYP3A4 expression in hepatic cells by a mechanism that probably involves chromatin remodeling. (PMID:12695546)
• Data suggestthat Foxi1 is necessary for expression of at least four subunits in three different epithelia and most likely is a major determinant for proper assembly of a functional vacuolar H(+)-ATPase complex at these locations. (PMID:19214237)
• SLC26A4, FOXI1 and KCNJ10 are not major determinants in unilateral deafness and enlarged vestibular aqueduct (PMID:20621367)
• No FOXI1 mutations were present in bilateral deafness patients with inner ear malformation. (PMID:22412181)
• We found no evidence for a significant association between mutations of KCNJ10 and FOXI1 with SLC26A4 in Pendred syndrome/enlarged vestibular aqueducts. (PMID:23965030)
• study reveals that Foxi1/miR-491-5p/Wnt3a/beta-catenin signaling is critical in the progression of GC. Targeting the pathway described in this study may open up new prospects to restrict the progression of gastric cancer (PMID:28358374)
• A substantial proportion of patients with a clinical diagnosis of inherited distal renal tubular acidosis has no identified causative mutations in currently known disease genes. Our data suggest that recessive mutations in FOXI1 can explain the disease in a subset of these patients. (PMID:29242249)
• Study found positive nuclear FOXI1 staining in 96% of renal oncocytoma (RO) and only 3% of chromophobe renal cell carcinoma (chRCC) and none of other types of renal cell tumor, including ‘oncocytic’ cellular variants. These findings suggest that FOXI1 immunohistochemistry is useful in differential diagnosis of RO from chRCC with overlapping histology. (PMID:31177114)
• These data suggest that individuals with an SLC26A4 single-allele mutation, combined with FOXI1 or KCNJ10 gene mutations, do not suffer hearing loss during infancy (PMID:31243244)
• Next-generation sequencing-based mutation analysis of genes associated with enlarged vestibular aqueduct in Chinese families. (PMID:32447495)
• FOXI1 expression in chromophobe renal cell carcinoma and renal oncocytoma: a study of The Cancer Genome Atlas transcriptome-based outlier mining and immunohistochemistry. (PMID:32812119)
• FOXI1 inhibits gastric cancer cell proliferation by activating miR-590/ATF3 axis via integrating ChIP-seq and RNA-seq data. (PMID:33610681)
• [Diagnosis of a Chinese pedigree affected with autosomal recessive deafness 4 with enlarged vestibular aqueduct due to compound heterozygous variants of FOXI1 gene]. (PMID:36184087)
• Analysis of SLC26A4, FOXI1, and KCNJ10 Gene Variants in Patients with Incomplete Partition of the Cochlea and Enlarged Vestibular Aqueduct (EVA) Anomalies. (PMID:36499699)
• [Analysis of genotypes on 850 newborns with SLC26A4 single-allele mutation and the phenotypes of those with second variant]. (PMID:36748152)
• Homozygous Missense Variants in FOXI1 and TMPRSS3 Genes Associated with Non-syndromic Deafness in Moroccan Families. (PMID:37777971)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	foxp1a	ENSDARG00000004843
danio_rerio	foxp1b	ENSDARG00000014181
mus_musculus	Foxi1	ENSMUSG00000047861
rattus_norvegicus	Foxi1	ENSRNOG00000006293

Paralogs (4): FOXP2 (ENSG00000128573), FOXP4 (ENSG00000137166), FOXF2 (ENSG00000137273), FOXG1 (ENSG00000176165)

Protein

Protein identifiers

Forkhead box protein I1 — Q12951 (reviewed: Q12951)

Alternative names: Forkhead-related protein FKHL10, Forkhead-related transcription factor 6, Hepatocyte nuclear factor 3 forkhead homolog 3

All UniProt accessions (2): E0XEN6, Q12951

UniProt curated annotations — full annotation on UniProt →

Function. Transcriptional activator required for the development of normal hearing, sense of balance and kidney function. Required for the expression of SLC26A4/PDS, JAG1 and COCH in a subset of epithelial cells and the development of the endolymphatic system in the inner ear. Also required for the expression of SLC4A1/AE1, SLC4A9/AE4, ATP6V1B1 and the differentiation of intercalated cells in the epithelium of distal renal tubules.

Subcellular location. Nucleus.

Tissue specificity. Expressed in kidney.

Isoforms (2)

UniProt ID	Names	Canonical?
Q12951-1	1	yes
Q12951-2	2

RefSeq proteins (2): NP_036320, NP_658982 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001766	Fork_head_dom	Domain
IPR018122	TF_fork_head_CS_1	Conserved_site
IPR030456	TF_fork_head_CS_2	Conserved_site
IPR036388	WH-like_DNA-bd_sf	Homologous_superfamily
IPR036390	WH_DNA-bd_sf	Homologous_superfamily
IPR050211	FOX_domain-containing	Family

Pfam: PF00250

UniProt features (9 total): region of interest 2, sequence variant 2, chain 1, DNA-binding region 1, compositionally biased region 1, splice variant 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q12951-F1	60.03	0.18

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 153 (showing top): SHEPARD_BMYB_MORPHOLINO_UP, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GGGTGGRR_PAX4_03, BROWNE_HCMV_INFECTION_48HR_DN, GOBP_ANIMAL_ORGAN_MORPHOGENESIS, GOBP_EAR_DEVELOPMENT, GOBP_EMBRYONIC_ORGAN_MORPHOGENESIS, TGIF_01, MYOD_Q6, GOBP_EAR_MORPHOGENESIS, GOBP_EMBRYO_DEVELOPMENT, E12_Q6, GOBP_SENSORY_ORGAN_DEVELOPMENT, GOBP_SENSORY_ORGAN_MORPHOGENESIS, GOBP_EMBRYONIC_ORGAN_DEVELOPMENT

GO Biological Process (8): regulation of transcription by RNA polymerase II (GO:0006357), anatomical structure morphogenesis (GO:0009653), embryo development ending in birth or egg hatching (GO:0009792), cell differentiation (GO:0030154), inner ear morphogenesis (GO:0042472), positive regulation of transcription by RNA polymerase II (GO:0045944), regulation of DNA-templated transcription (GO:0006355), positive regulation of DNA-templated transcription (GO:0045893)

GO Molecular Function (10): transcription cis-regulatory region binding (GO:0000976), 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 activator activity, RNA polymerase II-specific (GO:0001228), DNA-binding transcription factor activity (GO:0003700), DNA binding, bending (GO:0008301), sequence-specific DNA binding (GO:0043565), sequence-specific double-stranded DNA binding (GO:1990837), DNA binding (GO:0003677), protein binding (GO:0005515)

GO Cellular Component (3): chromatin (GO:0000785), nucleus (GO:0005634), nucleolus (GO:0005730)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regulation of DNA-templated transcription	3
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
transcription by RNA polymerase II	2
regulation of transcription by RNA polymerase II	2
DNA-templated transcription	2
DNA binding	2
developmental process	1
anatomical structure development	1
embryo development	1
cellular developmental process	1
ear morphogenesis	1
embryonic morphogenesis	1
inner ear development	1
positive regulation of DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
positive regulation of RNA biosynthetic process	1
transcription regulatory region nucleic acid binding	1
sequence-specific double-stranded DNA binding	1
cis-regulatory region sequence-specific DNA binding	1
chromatin	1
DNA-binding transcription factor activity	1
DNA-binding transcription factor activity, RNA polymerase II-specific	1
DNA-binding transcription activator activity	1
positive regulation of transcription by RNA polymerase II	1
transcription cis-regulatory region binding	1
transcription regulator activity	1
double-stranded DNA binding	1
sequence-specific DNA binding	1
nucleic acid binding	1
binding	1
chromosome	1
cellular anatomical structure	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
intracellular membraneless organelle	1

Protein interactions and networks

STRING

1316 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FOXI1	SLC26A4	O43511	944
FOXI1	KCNJ10	P78508	847
FOXI1	GJB2	P29033	742
FOXI1	FBXO6	Q9NRD1	666
FOXI1	ATP6V1B1	P15313	653
FOXI1	ATP6V0A4	Q9HBG4	626
FOXI1	SOSTDC1	Q6X4U4	584
FOXI1	DKK4	Q9UBT3	557
FOXI1	SLC4A1	P02730	540
FOXI1	DRC12	Q494R4	519
FOXI1	EDA	Q92838	490
FOXI1	ASCL3	Q9NQ33	482
FOXI1	EYA1	Q99502	481
FOXI1	POU4F3	Q15319	479
FOXI1	HINFP	Q9BQA5	478

IntAct

115 interactions, top by confidence:

A	B	Type	Score
NFIA	FOXI1	psi-mi:“MI:0915”(physical association)	0.470
YAP1	FOXI1	psi-mi:“MI:0407”(direct interaction)	0.440
FOXI1	MAST2	psi-mi:“MI:0407”(direct interaction)	0.440
FOXI1	SYNJ2BP	psi-mi:“MI:0407”(direct interaction)	0.440
FOXI1	MAGI2	psi-mi:“MI:0407”(direct interaction)	0.440
FOXI1	PDZD2	psi-mi:“MI:0407”(direct interaction)	0.440
FOXI1	DLG1	psi-mi:“MI:0407”(direct interaction)	0.440
FOXI1	PTPN3	psi-mi:“MI:0407”(direct interaction)	0.440
FOXI1	MAST1	psi-mi:“MI:0407”(direct interaction)	0.440
FOXI1	HTRA1	psi-mi:“MI:0407”(direct interaction)	0.440
FOXI1	DLG4	psi-mi:“MI:0407”(direct interaction)	0.440
FOXI1	DLG3	psi-mi:“MI:0407”(direct interaction)	0.440
ARHGEF11	FOXI1	psi-mi:“MI:0407”(direct interaction)	0.440
FOXI1	MAGI3	psi-mi:“MI:0407”(direct interaction)	0.440
FOXI1	APBA1	psi-mi:“MI:0407”(direct interaction)	0.440
FOXI1	PDZRN3	psi-mi:“MI:0407”(direct interaction)	0.440
FOXI1	DLG2	psi-mi:“MI:0407”(direct interaction)	0.440
FOXI1	SCRIB	psi-mi:“MI:0407”(direct interaction)	0.440
FOXI1	SNX27	psi-mi:“MI:0407”(direct interaction)	0.440
TAMALIN	FOXI1	psi-mi:“MI:0407”(direct interaction)	0.440
FOXI1	HTRA4	psi-mi:“MI:0407”(direct interaction)	0.440
LIN7C	FOXI1	psi-mi:“MI:0407”(direct interaction)	0.440
FOXI1	PDZRN4	psi-mi:“MI:0407”(direct interaction)	0.440
FOXI1	LNX2	psi-mi:“MI:0407”(direct interaction)	0.440
FOXI1	PICK1	psi-mi:“MI:0407”(direct interaction)	0.440
FOXI1	LNX1	psi-mi:“MI:0407”(direct interaction)	0.440
SCRIB	FOXI1	psi-mi:“MI:0407”(direct interaction)	0.440

BioGRID (92): SMPD4 (Affinity Capture-MS), TRIM24 (Affinity Capture-MS), TRIM33 (Affinity Capture-MS), DDX39A (Affinity Capture-MS), HEATR1 (Affinity Capture-MS), PDS5A (Affinity Capture-MS), TOMM40 (Affinity Capture-MS), VARS (Affinity Capture-MS), FASN (Affinity Capture-MS), FOXI1 (Affinity Capture-MS), FOXI1 (Two-hybrid), FOXI1 (Two-hybrid), FOXI1 (Two-hybrid), FOXI1 (Two-hybrid), FOXI1 (Two-hybrid)

ESM2 similar proteins: A0A8V0YY16, A0JPN1, A1YG01, A2D4R4, A2D649, A2T6H5, A2T6Z0, A2T7J2, A3KNJ3, A7MB54, A8MTJ6, B5RHS5, D3Z120, O54743, P09027, P14653, P17919, P31249, P32183, P35584, P55316, P55318, P56260, Q00939, Q12946, Q12947, Q12948, Q12951, Q1A1A1, Q1A1A2, Q1A1A3, Q1A1A4, Q1A1A5, Q1A1A6, Q28D67, Q28HT3, Q3I5G5, Q3Y598, Q60987, Q61080

Diamond homologs: A0A078BQN7, A0A1W2PRP0, A0A8V0YY16, A1L1S5, A3KNJ3, A8MTJ6, A8XJN7, B5RHS5, D3Z120, F1R8Z9, O00358, O17617, O43638, O54743, O60129, O88470, P32027, P32028, P32030, P32315, P42128, P55316, P56260, P58012, P79772, P85037, P91278, Q00939, Q01167, Q02360, Q12946, Q12947, Q12948, Q12950, Q12951, Q12952, Q13461, Q19802, Q1A1A1, Q1A1A2

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
FOXI1	“up-regulates quantity by expression”	CFTR	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 82 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
Dopamine Neurotransmitter Release Cycle	5	42.8×	5e-06
Assembly and cell surface presentation of NMDA receptors	9	39.4×	1e-10
Neurexins and neuroligins	10	34.0×	5e-11
Protein-protein interactions at synapses	6	27.5×	5e-06
RHOA GTPase cycle	5	6.4×	9e-03
Signaling by Rho GTPases	8	4.7×	3e-03
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	8	4.6×	3e-03

GO biological processes:

GO term	Partners	Fold	FDR
establishment or maintenance of epithelial cell apical/basal polarity	9	65.4×	4e-12
protein localization to synapse	5	47.9×	5e-06
receptor clustering	6	46.8×	5e-07
regulation of postsynaptic membrane neurotransmitter receptor levels	6	37.2×	2e-06
protein-containing complex assembly	8	11.4×	4e-05
cell-cell adhesion	8	10.2×	9e-05
regulation of small GTPase mediated signal transduction	5	9.0×	5e-03
chemical synaptic transmission	7	6.8×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	4
Uncertain significance	143
Likely benign	48
Benign	11

Top pathogenic / likely-pathogenic (5)

Variant ID	HGVS	Classification
3775116	NM_012188.5(FOXI1):c.748dup (p.Asp250fs)	Pathogenic
1064953	NM_012188.5(FOXI1):c.92A>G (p.Tyr31Cys)	Likely pathogenic
3777221	NM_012188.5(FOXI1):c.879C>A (p.Ser293Arg)	Likely pathogenic
4526494	NM_012188.5(FOXI1):c.376T>A (p.Tyr126Asn)	Likely pathogenic
4532242	NM_012188.5(FOXI1):c.638G>T (p.Arg213Leu)	Likely pathogenic

SpliceAI

320 predictions. Top by Δscore:

Variant	Effect	Δscore
5:170106527:CCCGG:C	donor_gain	1.0000
5:170106528:CCGG:C	donor_gain	1.0000
5:170106529:CGG:C	donor_gain	1.0000
5:170106530:GG:G	donor_gain	1.0000
5:170106530:GGG:G	donor_gain	1.0000
5:170106531:GG:G	donor_gain	1.0000
5:170106531:GGT:G	donor_loss	1.0000
5:170106532:G:GG	donor_gain	1.0000
5:170106532:GT:G	donor_loss	1.0000
5:170106540:GCTT:G	donor_gain	1.0000
5:170106522:G:GT	donor_gain	0.9900
5:170106533:T:A	donor_loss	0.9900
5:170108047:A:AG	acceptor_gain	0.9700
5:170108048:G:GG	acceptor_gain	0.9700
5:170108247:G:GT	donor_gain	0.9700
5:170106537:G:GT	donor_gain	0.9600
5:170108045:T:G	acceptor_gain	0.9600
5:170108046:CAGG:C	acceptor_gain	0.9600
5:170107468:G:GT	donor_gain	0.9500
5:170106531:GGTAA:G	donor_gain	0.9400
5:170106532:GTAAG:G	donor_gain	0.9400
5:170107415:C:T	donor_gain	0.9300
5:170107450:GC:G	donor_gain	0.9200
5:170107492:A:T	donor_gain	0.9200
5:170108036:A:AG	acceptor_gain	0.9200
5:170108045:TCAG:T	acceptor_loss	0.9200
5:170108046:CAGGC:C	acceptor_loss	0.9200
5:170108047:AGGC:A	acceptor_gain	0.9200
5:170108048:GGCA:G	acceptor_gain	0.9200
5:170108048:GGCAA:G	acceptor_gain	0.9200

AlphaMissense

2493 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:170106324:C:G	R123G	1.000
5:170106327:C:A	P124T	1.000
5:170106327:C:T	P124S	1.000
5:170106328:C:A	P124Q	1.000
5:170106328:C:G	P124R	1.000
5:170106333:T:G	Y126D	1.000
5:170106337:C:T	S127F	1.000
5:170106339:T:C	Y128H	1.000
5:170106340:A:G	Y128C	1.000
5:170106346:C:A	A130D	1.000
5:170106349:T:A	L131H	1.000
5:170106349:T:C	L131P	1.000
5:170106349:T:G	L131R	1.000
5:170106351:A:T	I132F	1.000
5:170106352:T:A	I132N	1.000
5:170106352:T:G	I132S	1.000
5:170106354:G:C	A133P	1.000
5:170106355:C:A	A133D	1.000
5:170106359:G:A	M134I	1.000
5:170106359:G:C	M134I	1.000
5:170106359:G:T	M134I	1.000
5:170106360:G:C	A135P	1.000
5:170106361:C:A	A135D	1.000
5:170106364:T:A	I136N	1.000
5:170106364:T:C	I136T	1.000
5:170106364:T:G	I136S	1.000
5:170106385:G:C	R143P	1.000
5:170106388:T:C	L144P	1.000
5:170106391:C:T	T145I	1.000
5:170106393:C:T	L146F	1.000

dbSNP variants (sampled 300 via entrez): RS1000172685 (5:170106924 C>G), RS1000827520 (5:170107428 C>G,T), RS1001124969 (5:170107495 G>T), RS1001262334 (5:170106585 T>C), RS1001588964 (5:170106950 T>A,C), RS1002312868 (5:170107830 C>A,T), RS1002823952 (5:170104607 C>T), RS1003236993 (5:170109174 G>A,C,T), RS1003288855 (5:170108878 T>C), RS1003437082 (5:170103979 T>C), RS1003556525 (5:170105392 A>G), RS1003724719 (5:170109002 G>A), RS1004688536 (5:170109434 C>T), RS1004937899 (5:170104578 C>T), RS1005032697 (5:170109526 T>C)

Disease associations

OMIM: gene MIM:601093 | disease phenotypes: MIM:274600, MIM:600791

GenCC curated gene-disease

Disease	Classification	Inheritance
autosomal recessive distal renal tubular acidosis	Strong	Autosomal recessive
Pendred syndrome	Supportive	Autosomal recessive
autosomal recessive nonsyndromic hearing loss 4	Limited	Autosomal recessive
hearing loss disorder	Limited	Autosomal recessive
enlarged vestibular aqueduct syndrome	Disputed Evidence	Autosomal recessive

ClinGen Gene-Disease Validity (2)

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

Disease	Classification	Inheritance
hearing loss disorder	Limited	AR
enlarged vestibular aqueduct syndrome	Disputed	AR

Mondo (6): hearing loss disorder (MONDO:0005365), Pendred syndrome (MONDO:0010134), autosomal recessive nonsyndromic hearing loss 4 (MONDO:0010933), sensorineural hearing loss disorder (MONDO:0020678), enlarged vestibular aqueduct syndrome (MONDO:0023069), autosomal recessive distal renal tubular acidosis (MONDO:0018440)

Orphanet (2): Pendred syndrome (Orphanet:705), Rare autosomal recessive non-syndromic sensorineural deafness type DFNB (Orphanet:90636)

HPO phenotypes

23 total (23 of 23 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000112	Nephropathy
HP:0000359	Abnormality of the inner ear
HP:0000376	Incomplete partition of the cochlea type II
HP:0000407	Sensorineural hearing impairment
HP:0000821	Hypothyroidism
HP:0000843	Hyperparathyroidism
HP:0000853	Goiter
HP:0001249	Intellectual disability
HP:0001251	Ataxia
HP:0001751	Abnormal vestibular function
HP:0002093	Respiratory insufficiency
HP:0002167	Abnormal speech pattern
HP:0002321	Vertigo
HP:0002777	Tracheal stenosis
HP:0002890	Thyroid carcinoma
HP:0003577	Congenital onset
HP:0008223	Compensated hypothyroidism
HP:0008527	Congenital sensorineural hearing impairment
HP:0008554	Cochlear malformation
HP:0008586	Hypoplasia of the cochlea
HP:0011387	Enlarged vestibular aqueduct
HP:0025484	Increased circulating thyroglobulin concentration

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST001998_5	Adverse response to chemotherapy (neutropenia/leucopenia) (all platinum-based drugs)	7.000000e-06
GCST002481_3	Acne (severe)	3.000000e-06

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D034381	Hearing Loss	C09.218.458.341; C10.597.751.418.341; C23.888.592.763.393.341
C566366	Deafness, Autosomal Recessive 4 (supp.)
C536648	Pendred syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

16 total (human), top 16 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases methylation, increases methylation	2
lasiocarpine	decreases expression	1
pirinixic acid	affects binding, decreases expression, increases activity	1
aflatoxin B2	increases methylation	1
perfluorooctane sulfonic acid	decreases expression	1
CGP 52608	affects binding, increases reaction	1
Resveratrol	decreases expression, affects cotreatment	1
Glyphosate	increases expression	1
Diazinon	increases methylation	1
Mercury	decreases expression	1
Nickel	decreases expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Valproic Acid	increases expression	1
Asbestos, Crocidolite	decreases methylation	1
Asbestos, Amosite	decreases methylation	1
Permethrin	increases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00205881	PHASE4	COMPLETED	Bilateral Benefit in Adult Users of the HiRes 90K Bionic Ear System
NCT00331539	PHASE4	UNKNOWN	Relationship Between Auto NRT and Behavioural T & C Levels With the Nucleus Freedom Cochlear Implant
NCT00424307	PHASE4	UNKNOWN	Bilateral Cochlear Implant Benefit in Young Children
NCT00765635	PHASE4	COMPLETED	Chlorobutanol, Potassium Carbonate, and Irrigation in Cerumen Removal
NCT03321006	PHASE4	COMPLETED	Treating Hearing Loss to Improve Mood and Cognition in Older Adults
NCT01499901	PHASE3	WITHDRAWN	Comparison of the Bilateral Sequential and Simultaneous Cochlear Implantation in the Deaf Children
NCT02561091	PHASE3	COMPLETED	AM-111 in the Treatment of Acute Inner Ear Hearing Loss
NCT03331627	PHASE3	COMPLETED	Safety and Efficacy of STR001-IT and STR001-ER in Patients With SSHL
NCT05532657	PHASE3	ACTIVE_NOT_RECRUITING	ACHIEVE Brain Health Follow-Up Study
NCT00013455	PHASE2	COMPLETED	Quantifying Auditory Perceptual Learning Following Hearing Aid Fitting
NCT00323427	PHASE2	COMPLETED	Clinical Trial of the Living Well With Hearing Loss Workshop
NCT00552786	PHASE2	COMPLETED	Antioxidation Medication for Noise-induced Hearing Loss
NCT00802425	PHASE2	COMPLETED	Efficacy of AM-111 in Patients With Acute Sensorineural Hearing Loss
NCT01139281	PHASE2	COMPLETED	The Protective Effect of Ginkgo Biloba Extract on Cisplatin-induced Ototoxicity in Humans
NCT01451853	PHASE2	UNKNOWN	SPI-1005 for Prevention and Treatment of Chemotherapy Induced Hearing Loss
NCT01588925	PHASE2	COMPLETED	Hearing Preservation Using Dexamethasone and Hyaluronic Acid for Cochlear Implantation
NCT01773278	PHASE2	RECRUITING	Cholesterol and Antioxidant Treatment in Patients With Smith-Lemli-Opitz Syndrome (SLOS)
NCT02832128	PHASE2	COMPLETED	Evaluating Possible Improvement in Speech and Hearing Tests After 28 Days of Dosing of the Study Drug AUT00063 Compared to Placebo (QuicKfire)
NCT04915183	PHASE2	RECRUITING	Atorvastatin to Reduce Cisplatin-Induced Hearing Loss Among Individuals With Head and Neck Cancer
NCT05258773	PHASE2	COMPLETED	Evaluation of the Presence of SENS-401 in the Perilymph
NCT06340633	PHASE2	RECRUITING	SPI-1005 in Adults Receiving Cochlear Implant
NCT00582946	PHASE1	COMPLETED	Wide-Bandwidth Open Canal Hearing Aid For Better Multitalker Speech Understanding
NCT00584155	PHASE1	WITHDRAWN	Protection From Cisplatin Ototoxicity by Lactated Ringers
NCT01206829	PHASE1	UNKNOWN	Hearing Impairment, Cognitive Therapy and Coping
NCT01256229	PHASE1	COMPLETED	Outcomes In Children With Developmental Delay And Deafness
NCT01343394	PHASE1	WITHDRAWN	Safety of Autologous Human Umbilical Cord Blood Mononuclear Fraction to Treat Acquired Hearing Loss in Children
NCT01452607	PHASE1	COMPLETED	Study to Evaluate the Safety and Pharmacokinetics of SPI-1005
NCT02259595	PHASE1	COMPLETED	Study to Determine the Safety, Tolerability, and Pharmacokinetic Profile of HPN-07 and HPN-07 Plus NAC
NCT04041440	PHASE1	COMPLETED	Speech Recognition Training in Children With Hearing Loss
NCT07218913	PHASE1	RECRUITING	Testing the Addition of Pedmark to Cisplatin Chemotherapy for Reducing Drug-Induced Ear Damage in Men With Stage II-III Metastatic Testicular Germ Cell Tumors
NCT02798783	Not specified	COMPLETED	Enlarged Vestibular Aqueduct Registry
NCT04934605	Not specified	UNKNOWN	Genotype-phenotype Correlation of SLC26A4 in CI Patients With EVA
NCT00486577	PHASE2/PHASE3	COMPLETED	Chronic Electrical Stimulation of the Auditory Cortex for Intractable Tinnitus
NCT00789061	PHASE2/PHASE3	UNKNOWN	Applying Proton Pump Inhibitor to Prevent and Treat Acute Fluctuating Hearing Loss in Patients With SLC26A4 Mutation
NCT01423409	PHASE2/PHASE3	COMPLETED	Multicenter Trial Assessing an Innovative VAS of Pain Among Deaf People
NCT05786378	PHASE2/PHASE3	UNKNOWN	Assessment of The Efficacy of Intratympanic Platelet Rich Plasma for Treatment of Sensorineural Hearing Loss.
NCT01108601	PHASE1/PHASE2	UNKNOWN	Transtympanic Ringer’s Lactate for the Prevention of Cisplatin Ototoxicity
NCT01621256	PHASE1/PHASE2	COMPLETED	Efficacy, Safety, and Tolerability of Ancrod in Patients With Sudden Hearing Loss
NCT06370351	PHASE1/PHASE2	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	PHASE1/PHASE2	RECRUITING	Intracochlear Application of VSF1.01 for the Reduction of Cochlear Implant Surgery Related Trauma