SLC26A5

Summary

SLC26A5 (solute carrier family 26 member 5, HGNC:9359) is a protein-coding gene on chromosome 7q22.1, encoding Prestin (P58743). Voltage-sensitive motor protein that drives outer hair cell (OHC) electromotility (eM) and participates in sound amplification in the hearing organ.

This gene encodes a member of the SLC26A/SulP transporter family. The protein functions as a molecular motor in motile outer hair cells (OHCs) of the cochlea, inducing changes in cell length that act to amplify sound levels. The transmembrane protein is an incomplete anion transporter, and does not allow anions to cross the cell membrane but instead undergoes a conformational change in response to changes in intracellular Cl- levels that results in a change in cell length. The protein functions at microsecond rates, which is several orders of magnitude faster than conventional molecular motor proteins. Mutations in this gene are potential candidates for causing neurosensory deafness. Multiple transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 375611 — RefSeq curated summary.

At a glance

• Gene–disease (curated): autosomal recessive nonsyndromic hearing loss 61 (Strong, GenCC) — +2 more curated relationships
• GWAS associations: 4
• Clinical variants (ClinVar): 308 total — 14 pathogenic, 9 likely-pathogenic
• Phenotypes (HPO): 2
• MANE Select transcript: NM_198999

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9359
Approved symbol	SLC26A5
Name	solute carrier family 26 member 5
Location	7q22.1
Locus type	gene with protein product
Status	Approved
Aliases	DFNB61, PRESTIN
Ensembl gene	ENSG00000170615
Ensembl biotype	protein_coding
OMIM	604943
Entrez	375611

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 9 protein_coding, 4 nonsense_mediated_decay, 1 retained_intron

ENST00000306312, ENST00000339444, ENST00000356767, ENST00000393723, ENST00000393727, ENST00000393729, ENST00000393730, ENST00000393735, ENST00000423416, ENST00000432958, ENST00000445809, ENST00000454864, ENST00000456463, ENST00000487407

RefSeq mRNA: 6 — MANE Select: NM_198999 NM_001167962, NM_001321787, NM_198999, NM_206883, NM_206884, NM_206885

CCDS: CCDS43629, CCDS43630, CCDS55150, CCDS5732, CCDS5733

Canonical transcript exons

ENST00000306312 — 20 exons

Exon	Start	End
ENSE00001132499	103407851	103408003
ENSE00001352129	103443083	103443211
ENSE00003486426	103392919	103393066
ENSE00003487897	103389008	103389114
ENSE00003500868	103374207	103374592
ENSE00003518551	103410385	103410549
ENSE00003524121	103380480	103380549
ENSE00003546806	103379243	103379335
ENSE00003573513	103391622	103391735
ENSE00003583175	103421363	103421567
ENSE00003595732	103376808	103376862
ENSE00003606411	103389329	103389424
ENSE00003607475	103377599	103377799
ENSE00003610927	103397932	103398014
ENSE00003612148	103420738	103420877
ENSE00003630720	103411420	103411586
ENSE00003674395	103390429	103390506
ENSE00003711797	103378446	103378553
ENSE00003749568	103413002	103413112
ENSE00003893389	103446098	103446207

Expression profiles

Bgee: expression breadth broad, 81 present calls, max score 79.73.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.0882 / max 18.5754, expressed in 32 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
85377	0.0588	26
85378	0.0294	7

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	79.73	gold quality
cerebellar cortex	UBERON:0002129	63.39	gold quality
cerebellum	UBERON:0002037	63.32	gold quality
cerebellar hemisphere	UBERON:0002245	63.28	gold quality
right hemisphere of cerebellum	UBERON:0014890	62.59	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	60.96	gold quality
right lobe of thyroid gland	UBERON:0001119	56.71	gold quality
left lobe of thyroid gland	UBERON:0001120	56.55	gold quality
thyroid gland	UBERON:0002046	56.36	gold quality
thoracic mammary gland	UBERON:0005200	55.42	gold quality
zone of skin	UBERON:0000014	54.51	gold quality
skin of leg	UBERON:0001511	54.45	gold quality
skin of abdomen	UBERON:0001416	54.35	gold quality
body of stomach	UBERON:0001161	54.08	gold quality
prostate gland	UBERON:0002367	52.96	gold quality
stomach	UBERON:0000945	52.93	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	52.90	gold quality
urinary bladder	UBERON:0001255	52.83	gold quality
minor salivary gland	UBERON:0001830	52.70	gold quality
saliva-secreting gland	UBERON:0001044	51.97	gold quality
mucosa of stomach	UBERON:0001199	50.50	gold quality
liver	UBERON:0002107	49.70	silver quality
fundus of stomach	UBERON:0001160	49.36	gold quality
sural nerve	UBERON:0015488	48.51	gold quality
upper lobe of left lung	UBERON:0008952	48.23	gold quality
lung	UBERON:0002048	48.11	gold quality
right lobe of liver	UBERON:0001114	47.59	gold quality
right lung	UBERON:0002167	46.49	gold quality
lymph node	UBERON:0000029	46.25	gold quality
subcutaneous adipose tissue	UBERON:0002190	45.87	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	5.22

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): PROX1, SP1, THRB

miRNA regulators (miRDB)

8 targeting SLC26A5, 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-4801	98.96	69.42	2096
HSA-MIR-4731-3P	98.56	68.60	1860
HSA-MIR-3620-3P	97.78	64.88	772
HSA-MIR-6865-3P	97.54	64.67	684
HSA-MIR-6802-3P	97.29	65.42	613
HSA-MIR-424-3P	97.20	65.86	385
HSA-MIR-125B-2-3P	96.69	68.38	1210
HSA-MIR-3186-5P	87.11	67.29	51

Literature-anchored findings (GeneRIF, showing 34)

• an essential function of prestin in human auditory processing (PMID:12719379)
• KCNQ4 phosphorylation via PKA and coupling to a complex that may include prestin can lead to the negative activation and the negative resting potential found in adult outer hair cells. (PMID:15660259)
• Because mammals possess differentiated outer hair cells (OHC), they also benefit from a novel electromotile process, powered by the motor protein, prestin. (PMID:16873410)
• Packing of helices and interactions between residues surrounding the sulfate transporter motif is essential for normal prestin activity. (PMID:17151276)
• This is the first genetic and electrophysiological analysis of a human mutation in a coding exon of the pres gene by 47 patients with non-syndromic, sensorineural, mild-to-moderate hearing impairment. (PMID:17786286)
• Cholesterol levels modulate the distribution of prestin within plasma membrane microdomains and affect prestin self-association (PMID:17933870)
• results indicate that an evolutionarily conserved dimeric quaternary structure represents the native and functional state of SLC26 transporters (PMID:18073211)
• Results quantify the relation between membrane cholesterol concentration and prestin-associated charge movement and enhance our understanding of how membrane composition modulates prestin function. (PMID:18567583)
• heterozygosity for the mutation IVS2-2A>G in SLC26A5 gene may not, by itself, be sufficient to cause hearing loss. (PMID:19027966)
• analysis of novel DNA sequence variations in SLC26A5, encoding prestin (PMID:19492055)
• Results are consistent with significant movements in the COOH-terminal domain of prestin upon change in membrane potential, providing the first dynamic information on its molecular rearrangements. (PMID:19515900)
• This indicates that Met-225 in prestin somehow adjusts nonlinear capacitance and the motility of prestin-expressing cells. (PMID:19737539)
• Cysteine mutagenesis reveals transmembrane residues associated with charge translocation in prestin (PMID:19926791)
• These data reveal that the STAS (sulfate transporters and anti-sigma factor antagonist) domain starts immediately after the last transmembrane segment and lies beneath the lipid bilayer. (PMID:20471983)
• Four mutations (C124A, C192A, C260A, and C415A), all in nonconserved cysteinyl residues, significantly differed in their nonlinear capacitance properties compared with wild-type prestin. (PMID:21813750)
• This result implies that in cell membranes prestin oligomerizes to a tetramer. (PMID:21975444)
• prestin subunits are individually functional within a given multimer (PMID:23212912)
• The findings suggest that CASK and the truncated prestin splice isoform contribute to confinement of prestin to the basolateral region of the plasma membrane. (PMID:23542924)
• COCH and SLC26A5 mRNA are expressed in specific structures and cells of the inner ear in archival human temporal bone (PMID:23660400)
• The effects of fast temperature jumps induced by an infrared (IR) laser in control and prestin (SLC26a5)-transfected human embryonic kidney (HEK) cells, are reproted. (PMID:24138858)
• Calmodulin-prestin interaction may be involved in the medial olivocochlear-mediated modulation of cochlear amplification (PMID:24453323)
• I hypothesize that serum assays of OHC specific protein, prestin, will allow detection and quantification of OHC damage before audiometric testing can identify presence of hearing loss. (PMID:25920562)
• anion-pi interaction is the mechanism for the voltage-dependent response of prestin (PMID:26283790)
• Prestin expression imparts susceptibility to 2-hydroxypropyl-beta-cyclodextrin-induced hearing loss. (PMID:26903308)
• Our study thus provides experimental evidence that supports a causal relationship between the R130S mutation in the prestin gene and hearing loss found in patients with this missense mutation. (PMID:27041369)
• prestin itself is the main regulator of intracellular chloride concentration via a route distinct from its transporter pathway. (PMID:28422190)
• extracellular loop of pendrin and prestin modulates their voltage-sensing property (PMID:29777056)
• Deletion of exons 17 and 18 in prestin’s STAS domain results in loss of function. (PMID:31053797)
• Prestin and otolin-1 proteins in the hearing loss of adults chronically exposed to lead. (PMID:34273409)
• Molecular mechanism of prestin electromotive signal amplification. (PMID:34390643)
• Noise exposure levels predict blood levels of the inner ear protein prestin. (PMID:35064195)
• Evaluation of inner ear damage by mastoid drilling with measurement of serum prestin (SLC26A5) levels. (PMID:38237483)
• The pathogenic roles of the p.R130S prestin variant in DFNB61 hearing loss. (PMID:38431907)
• Functional Studies of Deafness-Associated Pendrin and Prestin Variants. (PMID:38474007)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	slc26a5	ENSDARG00000022424
mus_musculus	Slc26a5	ENSMUSG00000029015
rattus_norvegicus	Slc26a5	ENSRNOG00000011616

Paralogs (9): SLC26A4 (ENSG00000091137), SLC26A3 (ENSG00000091138), SLC26A8 (ENSG00000112053), SLC26A1 (ENSG00000145217), SLC26A7 (ENSG00000147606), SLC26A2 (ENSG00000155850), SLC26A9 (ENSG00000174502), SLC26A11 (ENSG00000181045), SLC26A6 (ENSG00000225697)

Protein

Protein identifiers

Prestin — P58743 (reviewed: P58743)

Alternative names: Solute carrier family 26 member 5

All UniProt accessions (7): P58743, E9PCM2, F8WD50, F8WDL4, Q496J0, Q496J3, Q7Z7F4

UniProt curated annotations — full annotation on UniProt →

Function. Voltage-sensitive motor protein that drives outer hair cell (OHC) electromotility (eM) and participates in sound amplification in the hearing organ. Converts changes in the transmembrane electric potential into mechanical displacements resulting in the coupling of its expansion to movement of a charged voltage sensor across the lipid membrane. The nature of the voltage sensor is not completely clear, and two models compete. In the first model, acts as an incomplete transporter where intracellular chloride anion acts as extrinsic voltage sensor that drives conformational change in the protein which is sufficient to produce a length change in the plane of the membrane and hence in the length of the OHC. The second model in which multiple charged amino acid residues are distributed at the intracellular and extracellular membrane interfaces that form an intrinsic voltage sensor, whose movement produces the non-linear capacitance (NLC). However, the effective voltage sensor may be the result of a hybrid voltage sensor, assembled from intrinsic charge (charged residues) and extrinsic charge (bound anion). Notably, binding of anions to the anion-binding pocket partially neutralizes the intrinsic positive charge rather than to form an electrically negative sensor, therefore remaining charge may serve as voltage sensor that, after depolarization, moves from down (expanded state) to up (contracted) conformation, which is accompanied by an eccentric contraction of the intermembrane cross-sectional area of the protein as well as a major increase in the hydrophobic thickness of the protein having as consequences the plasma membrane thickening and the cell contraction after membrane depolarization. The anion-binding pocket transits from the inward-open (Down) state, where it is exposed toward the intracellular solvent in the absence of anion, to the occluded (Up) state upon anion binding. Salicylate competes for the anion-binding site and inhibits the voltage-sensor movement, and therefore inhibits the charge transfer and electromotility by displacing Cl(-) from the anion-binding site and by preventing the structural transitions to the contracted state. In addition, can act as a weak Cl(-)/HCO3(-) antiporter across the cell membrane and so regulate the intracellular pH of the outer hair cells (OHCs), while firstly found as being unable to mediate electrogenic anion transport. Moreover, supports a role in cardiac mechanical amplification serving as an elastic element to enhance the actomyosin- based sarcomere contraction system.

Subunit / interactions. Homodimer. Interacts (via STAS domain) with CALM; this interaction is calcium-dependent and the STAS domain interacts with only one lobe of CALM which is an elongated conformation. Interacts with MYH1.

Subcellular location. Lateral cell membrane.

Disease relevance. Deafness, autosomal recessive, 61 (DFNB61) [MIM:613865] 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. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The STAS domain mediates dimerization, with both STAS domains latched onto each other in a domain-swapped manner. The N-terminus domain is involved in dimerization such that each N-terminus domain embraces both STAS domains. The STAS domain harbors a unique anion-binding site important for the fine regulation of the high-frequency electromotile properties. The transmembrane domain consists of 14 transmembrane segments organized in a 7(+)7 inverted repeat architecture that can be divided into two main helix bundles, the ‘‘core’’ domain and the ‘‘gate’’ domain. The transmembrane regions are domain-swapped with the STAS domain containing N- and C-terminal cytoplasmic domains. The STAS domain mediates CALM binding CALM.

Similarity. Belongs to the SLC26A/SulP transporter (TC 2.A.53) family.

Isoforms (6)

UniProt ID	Names	Canonical?
P58743-1	1, SLC26A5a	yes
P58743-2	2, SLC26A5b
P58743-3	3, SLC26A5c
P58743-4	4, SLC26A5d
P58743-5	5
P58743-6	6

RefSeq proteins (6): NP_001161434, NP_001308716, NP_945350, NP_996766, NP_996767, NP_996768 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001902	SLC26A/SulP_fam	Family
IPR002645	STAS_dom	Domain
IPR011547	SLC26A/SulP_dom	Domain
IPR018045	S04_transporter_CS	Conserved_site
IPR036513	STAS_dom_sf	Homologous_superfamily

Pfam: PF00916, PF01740

Catalyzed reactions (Rhea), 1 shown:

• 2 hydrogencarbonate(in) + chloride(out) = 2 hydrogencarbonate(out) + chloride(in) (RHEA:72207)

UniProt features (100 total): helix 36, topological domain 16, transmembrane region 14, strand 10, splice variant 8, turn 4, region of interest 2, site 2, glycosylation site 2, chain 1, intramembrane region 1, domain 1, short sequence motif 1, binding site 1, mutagenesis site 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
7LGU	ELECTRON MICROSCOPY	2.3
7LGW	ELECTRON MICROSCOPY	2.7
7LH2	ELECTRON MICROSCOPY	3.43
7LH3	ELECTRON MICROSCOPY	4.3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P58743-F1	83.86	0.54

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (2): 398 (controls the electromotile activity); 399 (contributes to anion binding)

Ligand- & substrate-binding residues (1): 398

Glycosylation sites (2): 163, 166

Mutagenesis-validated functional residues (1):

Position	Phenotype
101	decreases salicylate inhibition.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-9662361	Sensory processing of sound by outer hair cells of the cochlea
R-HSA-9659379	Sensory processing of sound
R-HSA-9709957	Sensory Perception

MSigDB gene sets: 107 (showing top): GOBP_NEGATIVE_REGULATION_OF_TRANSMEMBRANE_TRANSPORT, GOBP_CARBOHYDRATE_TRANSPORT, BENPORATH_ES_WITH_H3K27ME3, GOBP_REGULATION_OF_CELL_MORPHOGENESIS, GOBP_SENSORY_PERCEPTION_OF_MECHANICAL_STIMULUS, ROVERSI_GLIOMA_COPY_NUMBER_UP, GOBP_RESPONSE_TO_POTASSIUM_ION, GOBP_INORGANIC_ANION_TRANSPORT, GOBP_ORGANIC_ACID_TRANSPORT, GOBP_RESPONSE_TO_METAL_ION, GOBP_REGULATION_OF_ANATOMICAL_STRUCTURE_SIZE, GOBP_NEGATIVE_REGULATION_OF_TRANSPORT, GOBP_EAR_DEVELOPMENT, GOBP_CHLORIDE_TRANSPORT, GOBP_RESPONSE_TO_ISCHEMIA

GO Biological Process (23): response to ischemia (GO:0002931), chloride transport (GO:0006821), sensory perception of sound (GO:0007605), regulation of cell shape (GO:0008360), response to xenobiotic stimulus (GO:0009410), response to salicylic acid (GO:0009751), response to auditory stimulus (GO:0010996), bicarbonate transport (GO:0015701), fructose transmembrane transport (GO:0015755), oxalate transport (GO:0019532), negative regulation of monoatomic ion transmembrane transport (GO:0034766), response to potassium ion (GO:0035864), regulation of membrane potential (GO:0042391), positive regulation of cell size (GO:0045793), cochlea development (GO:0090102), response to thyroid hormone (GO:0097066), response to salt (GO:1902074), sulfate transmembrane transport (GO:1902358), chloride transmembrane transport (GO:1902476), positive regulation of cell motility (GO:2000147), monoatomic ion transmembrane transport (GO:0034220), transmembrane transport (GO:0055085), monoatomic anion transmembrane transport (GO:0098656)

GO Molecular Function (8): secondary active sulfate transmembrane transporter activity (GO:0008271), sulfate transmembrane transporter activity (GO:0015116), oxalate transmembrane transporter activity (GO:0019531), spectrin binding (GO:0030507), protein homodimerization activity (GO:0042803), chloride:bicarbonate antiporter activity (GO:0140900), protein binding (GO:0005515), identical protein binding (GO:0042802)

GO Cellular Component (5): plasma membrane (GO:0005886), basolateral plasma membrane (GO:0016323), lateral plasma membrane (GO:0016328), lateral wall of outer hair cell (GO:0120249), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Sensory processing of sound	1
Sensory Perception	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
inorganic anion transport	2
regulation of biological quality	2
response to chemical	2
monoatomic ion transmembrane transport	2
cellular anatomical structure	2
response to stress	1
monoatomic anion transport	1
sensory perception of mechanical stimulus	1
regulation of cell morphogenesis	1
response to oxygen-containing compound	1
response to mechanical stimulus	1
transport	1
hexose transmembrane transport	1
dicarboxylic acid transport	1
negative regulation of transmembrane transport	1
regulation of monoatomic ion transmembrane transport	1
negative regulation of monoatomic ion transport	1
response to metal ion	1
regulation of cell size	1
inner ear development	1
anatomical structure development	1
response to hormone	1
transmembrane transport	1
sulfur compound transport	1
chloride transport	1
monoatomic anion transmembrane transport	1
positive regulation of locomotion	1
positive regulation of cellular process	1
cell motility	1
regulation of cell motility	1
sulfate transmembrane transporter activity	1
secondary active transmembrane transporter activity	1
sulfur compound transmembrane transporter activity	1
sulfate transmembrane transport	1
dicarboxylic acid transmembrane transporter activity	1
oxalate transport	1
cytoskeletal protein binding	1
protein-containing complex binding	1
identical protein binding	1
protein dimerization activity	1

Protein interactions and networks

STRING

1270 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SLC26A5	CPD	O75976	915
SLC26A5	OCM2	P0CE71	903
SLC26A5	OCM	P0CE72	896
SLC26A5	SLC10A1	Q14973	845
SLC26A5	PITPNM1	O00562	775
SLC26A5	TMC1	Q8TDI8	747
SLC26A5	CFTR	P13569	714
SLC26A5	KCNQ4	P56696	696
SLC26A5	LPL	P06858	666
SLC26A5	PCDH15	Q96QU1	666
SLC26A5	GFI1	Q99684	662
SLC26A5	OTOF	Q9HC10	659
SLC26A5	MYO7A	P78427	657
SLC26A5	CDH23	Q9H251	645
SLC26A5	MYO6	Q9UM54	644

IntAct

2 interactions, top by confidence:

A	B	Type	Score
SLC26A5	ASMTL	psi-mi:“MI:0914”(association)	0.350

BioGRID (15): UBE2J1 (Two-hybrid), KIAA1244 (Affinity Capture-MS), ASMTL (Affinity Capture-MS), CCT6B (Affinity Capture-MS), DDX20 (Affinity Capture-MS), MDN1 (Affinity Capture-MS), NAA20 (Affinity Capture-MS), NAA25 (Affinity Capture-MS), PALD1 (Affinity Capture-MS), PANK4 (Affinity Capture-MS), PRPF39 (Affinity Capture-MS), SYNRG (Affinity Capture-MS), TBX18 (Affinity Capture-MS), TSHZ3 (Affinity Capture-MS), TTK (Affinity Capture-MS)

ESM2 similar proteins: A0FKN5, D7PC76, O00341, O04289, O35874, O43511, O57321, O70531, P24942, P31597, P40879, P43003, P43005, P46411, P50443, P51906, P51907, P53391, P53392, P56564, P58743, Q62273, Q65AC2, Q69DJ1, Q7SYH5, Q7T2C4, Q8BYF6, Q8CIW6, Q8GYH8, Q8JZR4, Q8N695, Q924C9, Q94LW6, Q95135, Q99NH7, Q9BEG8, Q9BXS9, Q9EPH0, Q9FEP7, Q9FY46

Diamond homologs: A0FKN5, A4IIF2, A8J6J0, D7PC76, O43511, O70531, P40879, P45380, P50443, P53391, P53392, P58735, P58743, Q5EBI0, Q5RAL2, Q62273, Q65AC2, Q69DJ1, Q7LBE3, Q7T2C4, Q8BU91, Q8CIW6, Q8GYH8, Q8HY59, Q8NG04, Q8R2Z3, Q8TE54, Q924C9, Q99NH7, Q9BEG8, Q9BXS9, Q9EPH0, Q9FY46, Q9GJY3, Q9H2B4, Q9JKQ2, Q9R154, Q9R155, Q9SAY1, Q9WVC8

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	14
Likely pathogenic	9
Uncertain significance	128
Likely benign	80
Benign	43

Top pathogenic / likely-pathogenic (23)

Variant ID	HGVS	Classification
1236171	NM_198999.3(SLC26A5):c.949del (p.Val317fs)	Pathogenic
2020423	NM_198999.3(SLC26A5):c.855del (p.Lys285fs)	Pathogenic
2112249	NM_198999.3(SLC26A5):c.1904dup (p.Gly636fs)	Pathogenic
2762194	NM_198999.3(SLC26A5):c.108_109del (p.Asp36fs)	Pathogenic
2794800	NM_198999.3(SLC26A5):c.818T>A (p.Leu273Ter)	Pathogenic
2890185	NM_198999.3(SLC26A5):c.448C>T (p.Arg150Ter)	Pathogenic
2970613	NM_198999.3(SLC26A5):c.51T>G (p.Tyr17Ter)	Pathogenic
2998324	NM_198999.3(SLC26A5):c.329dup (p.Phe111fs)	Pathogenic
3613367	NM_198999.3(SLC26A5):c.1496_1497del (p.Val499fs)	Pathogenic
3645849	NM_198999.3(SLC26A5):c.195del (p.Pro66_Ile67insTer)	Pathogenic
4704836	NM_198999.3(SLC26A5):c.1120G>T (p.Glu374Ter)	Pathogenic
4714782	NM_198999.3(SLC26A5):c.1236_1252del (p.Ala413fs)	Pathogenic
97020	NM_198999.3(SLC26A5):c.390A>C (p.Arg130Ser)	Pathogenic
97021	NM_198999.3(SLC26A5):c.209G>A (p.Trp70Ter)	Pathogenic
1465936	NM_198999.3(SLC26A5):c.1120-2A>G	Likely pathogenic
1501910	NM_198999.3(SLC26A5):c.1311+1G>T	Likely pathogenic
1967480	NM_198999.3(SLC26A5):c.293G>C (p.Gly98Ala)	Likely pathogenic
2027407	NM_198999.3(SLC26A5):c.404-1G>C	Likely pathogenic
2505543	NM_198999.3(SLC26A5):c.2146del (p.Arg716fs)	Likely pathogenic
2747819	NM_198999.3(SLC26A5):c.1986+1G>A	Likely pathogenic
2806235	NM_198999.3(SLC26A5):c.1312-1G>A	Likely pathogenic
2857928	NM_198999.3(SLC26A5):c.1515-1G>A	Likely pathogenic
4759802	NM_198999.3(SLC26A5):c.2033_2039dup (p.Ser680fs)	Likely pathogenic

SpliceAI

4559 predictions. Top by Δscore:

Variant	Effect	Δscore
7:103353919:A:AG	acceptor_gain	1.0000
7:103353920:G:GG	acceptor_gain	1.0000
7:103353959:G:GG	donor_gain	1.0000
7:103354866:A:AG	acceptor_gain	1.0000
7:103354866:AG:A	acceptor_gain	1.0000
7:103354867:G:GG	acceptor_gain	1.0000
7:103354867:GG:G	acceptor_gain	1.0000
7:103354947:CTGGT:C	donor_loss	1.0000
7:103354949:GGT:G	donor_loss	1.0000
7:103354950:G:A	donor_loss	1.0000
7:103354950:G:GG	donor_gain	1.0000
7:103354951:T:A	donor_loss	1.0000
7:103355689:T:TA	acceptor_gain	1.0000
7:103355689:TGTA:T	acceptor_loss	1.0000
7:103355692:A:AG	acceptor_gain	1.0000
7:103355692:A:T	acceptor_loss	1.0000
7:103355692:AG:A	acceptor_gain	1.0000
7:103355693:G:GG	acceptor_gain	1.0000
7:103355693:GG:G	acceptor_gain	1.0000
7:103355693:GGT:G	acceptor_gain	1.0000
7:103355693:GGTA:G	acceptor_gain	1.0000
7:103355693:GGTAT:G	acceptor_gain	1.0000
7:103355790:CCAGG:C	donor_loss	1.0000
7:103355791:CAG:C	donor_loss	1.0000
7:103355793:GG:G	donor_loss	1.0000
7:103355794:GTAT:G	donor_loss	1.0000
7:103361951:T:TA	acceptor_gain	1.0000
7:103361952:GTTA:G	acceptor_loss	1.0000
7:103361955:A:AG	acceptor_gain	1.0000
7:103361956:G:GG	acceptor_gain	1.0000

AlphaMissense

4829 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:103374574:A:G	L687P	0.999
7:103377618:C:T	G656E	0.999
7:103377619:C:G	G656R	0.999
7:103377619:C:T	G656R	0.999
7:103377627:T:A	D653V	0.999
7:103377627:T:G	D653A	0.999
7:103377628:C:G	D653H	0.999
7:103379276:A:C	N548K	0.999
7:103379276:A:T	N548K	0.999
7:103389108:A:G	W472R	0.999
7:103389108:A:T	W472R	0.999
7:103391731:A:G	L375P	0.999
7:103410485:C:T	G212E	0.999
7:103410486:C:A	G212W	0.999
7:103410486:C:G	G212R	0.999
7:103410486:C:T	G212R	0.999
7:103411567:G:C	S141R	0.999
7:103411567:G:T	S141R	0.999
7:103411569:T:G	S141R	0.999
7:103374509:C:G	A709P	0.998
7:103377626:A:C	D653E	0.998
7:103377626:A:T	D653E	0.998
7:103377627:T:C	D653G	0.998
7:103377632:A:C	F651L	0.998
7:103377632:A:T	F651L	0.998
7:103377634:A:G	F651L	0.998
7:103379280:G:T	A547E	0.998
7:103379307:A:G	F538S	0.998
7:103379310:A:T	I537K	0.998
7:103389062:C:T	G487D	0.998

dbSNP variants (sampled 300 via entrez): RS1000021013 (7:103382768 C>T), RS1000064702 (7:103437656 T>C), RS1000106419 (7:103371696 T>A), RS1000133177 (7:103388766 T>A,C), RS1000173369 (7:103384356 T>C), RS1000212003 (7:103428435 T>C), RS1000278467 (7:103421289 T>G), RS1000368515 (7:103434323 G>A), RS1000398548 (7:103390843 A>C), RS1000401124 (7:103400964 C>A,G), RS1000452377 (7:103357786 G>C,T), RS1000497598 (7:103414617 T>C), RS1000546561 (7:103433141 T>C), RS1000637334 (7:103377675 TC>T), RS1000673799 (7:103377400 A>G)

Disease associations

OMIM: gene MIM:604943 | disease phenotypes: MIM:613865

GenCC curated gene-disease

Disease	Classification	Inheritance
autosomal recessive nonsyndromic hearing loss 61	Strong	Autosomal recessive
hearing loss, autosomal recessive	Supportive	Autosomal recessive
nonsyndromic genetic hearing loss	Limited	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
nonsyndromic genetic hearing loss	Limited	AR

Mondo (4): autosomal recessive nonsyndromic hearing loss 61 (MONDO:0013471), nonsyndromic genetic hearing loss (MONDO:0019497), hearing loss disorder (MONDO:0005365), hearing loss, autosomal recessive (MONDO:0019588)

Orphanet (2): Rare autosomal recessive non-syndromic sensorineural deafness type DFNB (Orphanet:90636), Rare non-syndromic genetic deafness (Orphanet:87884)

HPO phenotypes

2 total (2 of 2 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000407	Sensorineural hearing impairment

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST007565_138	Morning person	7.000000e-22
GCST012442_42	Age-related hearing impairment	2.000000e-13
GCST012490_618	Femur bone mineral density x serum urate levels interaction	9.000000e-09
GCST012490_629	Femur bone mineral density x serum urate levels interaction	3.000000e-09

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0008328	chronotype measurement
EFO:0004531	urate measurement

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
C564609	Deafness, Autosomal Recessive (supp.)
C580334	Nonsyndromic Deafness (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: transporter — Other SLC26 anion exchangers

CTD chemical–gene interactions

7 total (human), top 7 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Tobacco Smoke Pollution	decreases expression, increases expression	2
ethyl-p-hydroxybenzoate	increases expression	1
butyraldehyde	decreases expression	1
CGP 52608	affects binding, increases reaction	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Aflatoxin B1	decreases methylation	1
Cadmium Chloride	increases expression	1

Clinical trials (associated diseases)

300 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
NCT01802190	Not specified	TERMINATED	Prevalence of POU4F3 and SLC17A8 Mutations
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
NCT07304024	PHASE1/PHASE2	RECRUITING	A Treatment for a Form of Age-Related Central Auditory Processing Disorder Consisting of Clemastine Fumarate Plus Engineered Sound