SLC26A4

Summary

SLC26A4 (solute carrier family 26 member 4, HGNC:8818) is a protein-coding gene on chromosome 7q22.3, encoding Pendrin (O43511). Sodium-independent transporter of chloride and iodide.

Mutations in this gene are associated with Pendred syndrome, the most common form of syndromic deafness, an autosomal-recessive disease. It is highly homologous to the SLC26A3 gene; they have similar genomic structures and this gene is located 3’ of the SLC26A3 gene. The encoded protein has homology to sulfate transporters.

Source: NCBI Gene 5172 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Pendred syndrome (Definitive, ClinGen) — +4 more curated relationships
• GWAS associations: 4
• Clinical variants (ClinVar): 1,748 total — 244 pathogenic, 248 likely-pathogenic
• Phenotypes (HPO): 49
• Druggable target: yes
• MANE Select transcript: NM_000441

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:8818
Approved symbol	SLC26A4
Name	solute carrier family 26 member 4
Location	7q22.3
Locus type	gene with protein product
Status	Approved
Aliases	PDS
Ensembl gene	ENSG00000091137
Ensembl biotype	protein_coding
OMIM	605646
Entrez	5172

Gene structure

Transcript identifiers

Ensembl transcripts: 11 — 5 protein_coding, 5 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000440056, ENST00000460748, ENST00000477350, ENST00000480841, ENST00000492030, ENST00000497446, ENST00000644269, ENST00000644846, ENST00000888699, ENST00000888700, ENST00000888701

RefSeq mRNA: 1 — MANE Select: NM_000441 NM_000441

CCDS: CCDS5746

Canonical transcript exons

ENST00000644269 — 21 exons

Exon	Start	End
ENSE00000715622	107663296	107663435
ENSE00000715623	107672138	107672248
ENSE00000715624	107674164	107674348
ENSE00000715626	107674945	107675109
ENSE00000715627	107683202	107683354
ENSE00000715628	107683455	107683537
ENSE00000715629	107689053	107689200
ENSE00000715631	107690124	107690237
ENSE00000881769	107710054	107710199
ENSE00001173990	107661639	107661805
ENSE00003511451	107694621	107694716
ENSE00003517415	107704331	107704385
ENSE00003569509	107700083	107700175
ENSE00003575998	107695933	107696039
ENSE00003582425	107701827	107702057
ENSE00003616417	107712539	107712622
ENSE00003618534	107698042	107698111
ENSE00003622266	107701101	107701196
ENSE00003691843	107694403	107694480
ENSE00003818963	107660828	107660855
ENSE00003821746	107715423	107717809

Expression profiles

Bgee: expression breadth ubiquitous, 190 present calls, max score 98.58.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.3374 / max 110.7625, expressed in 102 samples.

FANTOM5 promoters (13 alternative TSS)

Promoter ID	TPM avg	Samples expressed
80457	0.0875	22
80465	0.0813	40
80466	0.0515	16
80453	0.0161	4
80459	0.0157	6
80455	0.0156	7
80460	0.0154	6
80456	0.0127	7
80454	0.0124	4
80463	0.0110	6

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
palpebral conjunctiva	UBERON:0001812	98.58	gold quality
right lobe of thyroid gland	UBERON:0001119	97.75	gold quality
thyroid gland	UBERON:0002046	97.35	gold quality
left lobe of thyroid gland	UBERON:0001120	97.05	gold quality
cortical plate	UBERON:0005343	80.56	gold quality
calcaneal tendon	UBERON:0003701	79.12	gold quality
Brodmann (1909) area 23	UBERON:0013554	77.58	gold quality
endothelial cell	CL:0000115	76.83	silver quality
nephron tubule	UBERON:0001231	75.70	gold quality
nasal cavity epithelium	UBERON:0005384	75.61	gold quality
renal glomerulus	UBERON:0000074	74.59	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	73.68	silver quality
middle temporal gyrus	UBERON:0002771	72.84	silver quality
metanephric glomerulus	UBERON:0004736	72.42	gold quality
right frontal lobe	UBERON:0002810	71.90	gold quality
blood vessel layer	UBERON:0004797	71.76	gold quality
cingulate cortex	UBERON:0003027	71.72	gold quality
Brodmann (1909) area 9	UBERON:0013540	71.61	gold quality
anterior cingulate cortex	UBERON:0009835	71.45	gold quality
primary visual cortex	UBERON:0002436	71.30	gold quality
kidney epithelium	UBERON:0004819	71.23	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	70.65	gold quality
prefrontal cortex	UBERON:0000451	70.03	gold quality
adult mammalian kidney	UBERON:0000082	69.77	gold quality
cortex of kidney	UBERON:0001225	69.33	gold quality
descending thoracic aorta	UBERON:0002345	69.29	gold quality
neocortex	UBERON:0001950	68.97	gold quality
kidney	UBERON:0002113	68.83	gold quality
mucosa of stomach	UBERON:0001199	68.74	gold quality
pigmented layer of retina	UBERON:0001782	68.31	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-GEOD-131882	yes	4595.65
E-CURD-119	yes	27.50
E-ANND-3	yes	5.47
E-MTAB-7249	no	7.76

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): FOXC1, FOXI1, HSF1, STAT6

miRNA regulators (miRDB)

121 targeting SLC26A4, 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-3613-3P	100.00	76.36	7965
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-574-5P	100.00	66.01	989
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-33A-5P	99.99	68.62	1055
HSA-MIR-33B-5P	99.99	68.58	1062
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-512-3P	99.97	67.35	1049
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-493-5P	99.96	72.47	2382
HSA-MIR-96-5P	99.95	72.80	2140
HSA-MIR-9718	99.94	68.91	918
HSA-MIR-548J-3P	99.94	72.61	4881

Literature-anchored findings (GeneRIF, showing 40)

• Sequence analysis of the PDS gene performed with DNA from Pendred’s syndrome revealed the presence of a deletion of thymidine 279 in exon 3, a point mutation that results in a frameshift and a premature stop codon at codon 96 in the pendrin molecule. (PMID:11716048)
• Detected five new mutations (X871M, T132I, IVS1-2A>G, Y556H and 406del5). (PMID:11748854)
• Functional characterization of three novel tissue-specific anion exchangers SLC26A7, -A8, and -A9. (SLC26A7).(SLC26A8).(SLC26A9) three entries (PMID:11834742)
• protein mislocalization and loss of iodide efflux in mutations: thyroid dysfunction in Pendred syndrome. loss of pendrin iodide transport for all mislocalizing mutations. variable thyroid dysfunction in affected subjects. (PMID:11932316)
• Hypermethylation of the Pendred syndrome gene SLC26A4 is an early event in thyroid tumorigenesis. (PMID:12727855)
• work suggests that the pendrin gene should be considered a new susceptibility gene to autoimmune thyroid diseases (PMID:12727986)
• Homozygous missense mutation leading to the amino acid substitution S133T was detected in a family of Turkish origin. V138F is a founder mutation in our cohort of German families with Pendred’s syndrome. (PMID:12788906)
• pendrin has a role in apical iodide efflux (PMID:14715652)
• pendrin is responsible for the iodide efflux in thyroid cells where intracellular iodide concentration is high and that the general function of pendrin in other tissues is to transport chloride through exchange with other anions. (PMID:15155570)
• Mutations of SLC26A4 is associated with Pendred’s syndrome (PMID:15355436)
• Pendrin is a slow-folding protein with a propensity to form aggregates when overexpressed. Thus, we describe a system for the reversible induction of ER stress that is based entirely on the heterologous overexpression of GFP-pendrin. (PMID:15784681)
• SLC26A4 mutations were found in 22 of the 25 probands with enlarged vestibular aqueduct or Mondini’s dysplasia (PMID:15905611)
• SLC26A4-induced chloride transport is electroneutral when expressed in human cellular systems. (PMID:16260428)
• pendrin and thyroglobulin are downstream targets in vivo of TTF-1, whose action is a prime factor in controlling thyroid differentiation in vivo (PMID:16260629)
• SLC26A4 could be the second most frequent gene implicated in nonsyndromic deafness after GJB2 (PMID:16570074)
• PDS IVS7-2 A-G mutation is associated with enlarged vestibular aqueduct syndrome. (PMID:17007371)
• In a population of pediatric patients with an enlarged vestibular aqueduct and hearing loss, SLC26A4 mutations are a contributor to the phenotype (PMID:17309986)
• 15 patients from 13 unrelated Chinese families with deafness and enlarged vestibular aqueduct were analyzed for SLC26A4; the SLC26A4 mutation spectrum in the Chinese was different from other reported populations (PMID:17443271)
• A large percentage of patients with enlarged vestibular aqueduct lack mutations in the SLC26A4 coding region in one or both alleles. (PMID:17503324)
• variability in the degree of hearing loss is seen across genotypes implicating other genetic and/or environmental factors in the pathogenesis of Pendred syndrome, non-syndromic enlarged vestibular aqueduct, and Mondini dysplasia (PMID:17690912)
• Biallelic mutations in the SLC26A4 gene in 6 of 7 probands with Pendred syndrome in Taiwan, including a novel missense mutation. (PMID:17697873)
• For the Chinese mutation spectrum of SLC26A4 gene, IVS 7-2A>G mutation was the most common form accounting for 57.63% (102/177) of all the mutant alleles. (PMID:17718863)
• novel 11 bp duplication was found in a family with Pendred syndrome, showing a high intrafamilial phenotypic variability (PMID:17766716)
• no apparent correlation found between phenotypes and genotypes in hearing loss patients (PMID:17851929)
• Papillary thyroid cancers Papillary thyroid cancers with no 131I uptake had slightly reduced NIS, significantly reduced thyroglobulin,thyroperoxidase and pendrin and significantly increased GLUT-1 gene expression levels. (PMID:17854396)
• The identification of these two frequent PDS mutations will facilitate the molecular diagnosis of Pendred syndrome in Thai populations. (PMID:18250610)
• The mutant carrier rate for SLC26A4 was 15.2%, including 6.23% single mutant carriers (PMID:18274916)
• Mutations of SLC26A4 gene are one of the factors, which are at the base of congenital hearing losses [review] (PMID:18283249)
• SLC26A4 gene mutation is associated with Pendred syndrome and DFNB4 hearing loss (PMID:18285825)
• The processing of pendrin mutant protein is determined by mutant specific mechanisms, and that a mutant specific method would be required to rescue the conformational defects of each folding mutant. (PMID:18310264)
• Pendrin-mediated bicarbonate ion secretion in the renal tubule and anion transport in the endolymph may be regulated transcriptionally by systemic pH and aldosterone. (PMID:18322141)
• A high SLC26A4 IVS7-2 A>G mutation frequency for deafness in Chinese patients was found. The IVS7-2 A>G mutation was frequently found in Han deaf groups. Expression in Tibetan, Hui, and other western minorities was lower than Han deaf population. (PMID:18335745)
• Screening revealed that in Japanese, mutation in SLC26A4 is the major causes of hearing loss. (PMID:18368581)
• Pendrin induced expression of MUC5AC, a major product of mucus in asthma and COPD, in airway epithelial cells (PMID:18424749)
• A novel c.1458_1459insT SLC26A4 mutation was detected in Israel deaf with vestibular aqueduct abnormalities. (PMID:18427006)
• Our results suggest that GJB2 and SLC26A4 mutations together make up a major cause of congenital hearing loss in the Korean population (PMID:18585793)
• pendrin regulates airway surface liquid thickness and may be an important contributor to asthma exacerbations induced by viral infections or allergens (PMID:18641360)
• 408 subjects with sensorineural hearing loss (12.5%) carried at least one c.919-2A>G allele, with 158 (4.8%) homozygotes and 250 (7.6%) heterozygotes (PMID:18641518)
• potential role of pendrin in mediating apical iodide efflux into the lumen of thyroid follicles, and functional role in the kidney and the inner ear (PMID:18692402)
• The finding of higher PDS, TPO and TSH-R mRNA expression in paediatric vs. adult primary tumour tissues supports the hypothesis that this might contribute to the increased functional activity of metastases in the paediatric group. (PMID:18710471)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	slc26a4	ENSDARG00000069431
mus_musculus	Slc26a4	ENSMUSG00000020651
rattus_norvegicus	Slc26a4	ENSRNOG00000058692

Paralogs (9): SLC26A3 (ENSG00000091138), SLC26A8 (ENSG00000112053), SLC26A1 (ENSG00000145217), SLC26A7 (ENSG00000147606), SLC26A2 (ENSG00000155850), SLC26A5 (ENSG00000170615), SLC26A9 (ENSG00000174502), SLC26A11 (ENSG00000181045), SLC26A6 (ENSG00000225697)

Protein

Protein identifiers

Pendrin — O43511 (reviewed: O43511)

Alternative names: Sodium-independent chloride/iodide transporter, Solute carrier family 26 member 4

All UniProt accessions (3): O43511, A0A2R8Y4W7, C9JQG1

UniProt curated annotations — full annotation on UniProt →

Function. Sodium-independent transporter of chloride and iodide. Mediates electroneutral chloride-bicarbonate, chloride-iodide and chloride-formate exchange with 1:1 stoichiometry. Mediates electroneutral iodide-bicarbonate exchange.

Subunit / interactions. Interacts with IQGAP1; this interaction enhances the chloride-bicarbonate exchange activity of SLC26A4.

Subcellular location. Cell membrane. Apical cell membrane.

Tissue specificity. Highly expressed in the kidney (at protein level). High expression in adult thyroid, lower expression in adult and fetal kidney and fetal brain. Not expressed in other tissues.

Disease relevance. Pendred syndrome (PDS) [MIM:274600] An autosomal recessive disorder characterized by congenital sensorineural hearing loss in association with thyroid goiter. The disorder may account for up to 10% of the cases of hereditary deafness. The deafness is most often associated with a Mondini cochlear defect. Deafness occurs early, starting at birth or during the first years of life. It is bilateral, sometimes asymmetrical, fluctuant and often progressive. Thyroid perturbations, such as thyroid goiter and/or hypothyroidism appear most commonly during adolescence, but they can be congenital or appear later. The disease is caused by variants affecting the gene represented in this entry. Deafness, autosomal recessive, 4 (DFNB4) [MIM:600791] 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. DFNB4 is associated with an enlarged vestibular aqueduct. The disease is caused by variants affecting the gene represented in this entry.

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

Isoforms (2)

UniProt ID	Names	Canonical?
O43511-1	1	yes
O43511-2	2

RefSeq proteins (1): NP_000432* (*=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), 6 shown:

• chloride(in) = chloride(out) (RHEA:29823)
• iodide(out) = iodide(in) (RHEA:66324)
• formate(in) + chloride(out) = formate(out) + chloride(in) (RHEA:72267)
• hydrogencarbonate(in) + chloride(out) = hydrogencarbonate(out) + chloride(in) (RHEA:72363)
• iodide(in) + hydrogencarbonate(out) = iodide(out) + hydrogencarbonate(in) (RHEA:72375)
• iodide(in) + chloride(out) = iodide(out) + chloride(in) (RHEA:72379)

UniProt features (105 total): sequence variant 77, topological domain 13, transmembrane region 12, chain 1, domain 1, splice variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O43511-F1	82.72	0.51

Function

Pathways and Gene Ontology

Reactome pathways

8 pathways

ID	Pathway
R-HSA-427601	Inorganic anion exchange by SLC26 transporters
R-HSA-5619046	Defective SLC26A4 causes Pendred syndrome (PDS)
R-HSA-1643685	Disease
R-HSA-382551	Transport of small molecules
R-HSA-425393
R-HSA-425407	SLC-mediated transmembrane transport
R-HSA-5619102	SLC transporter disorders
R-HSA-5619115	Disorders of transmembrane transporters

MSigDB gene sets: 253 (showing top): BENPORATH_ES_WITH_H3K27ME3, GOBP_SENSORY_PERCEPTION_OF_MECHANICAL_STIMULUS, GOBP_INORGANIC_ANION_TRANSPORT, RIZKI_TUMOR_INVASIVENESS_3D_DN, HUMMERICH_SKIN_CANCER_PROGRESSION_UP, MORF_RAD51L3, GOBP_ORGANIC_ACID_TRANSPORT, GOBP_CHLORIDE_TRANSPORT, DELYS_THYROID_CANCER_DN, GOBP_ORGANIC_ANION_TRANSPORT, GOBP_SULFUR_COMPOUND_TRANSPORT, GOBP_DICARBOXYLIC_ACID_TRANSPORT, GOBP_OXALATE_TRANSPORT, GOBP_REGULATION_OF_PH, GOCC_APICAL_PLASMA_MEMBRANE

GO Biological Process (10): monoatomic ion transport (GO:0006811), regulation of pH (GO:0006885), sensory perception of sound (GO:0007605), inorganic anion transport (GO:0015698), iodide transport (GO:0015705), regulation of protein localization (GO:0032880), sulfate transmembrane transport (GO:1902358), chloride transmembrane transport (GO:1902476), oxalate transport (GO:0019532), transmembrane transport (GO:0055085)

GO Molecular Function (7): secondary active sulfate transmembrane transporter activity (GO:0008271), chloride transmembrane transporter activity (GO:0015108), iodide transmembrane transporter activity (GO:0015111), sulfate transmembrane transporter activity (GO:0015116), oxalate transmembrane transporter activity (GO:0019531), chloride:bicarbonate antiporter activity (GO:0140900), protein binding (GO:0005515)

GO Cellular Component (5): plasma membrane (GO:0005886), membrane (GO:0016020), apical plasma membrane (GO:0016324), brush border membrane (GO:0031526), extracellular exosome (GO:0070062)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
SLC-mediated transport of inorganic anions	1
SLC transporter disorders	1
Transport of small molecules	1
Disorders of transmembrane transporters	1
Disease	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
transport	3
inorganic anion transport	2
monoatomic anion transmembrane transporter activity	2
monoatomic cation homeostasis	1
biological regulation	1
sensory perception of mechanical stimulus	1
monoatomic anion transport	1
intracellular protein localization	1
regulation of localization	1
transmembrane transport	1
sulfur compound transport	1
chloride transport	1
monoatomic anion transmembrane transport	1
dicarboxylic acid transport	1
cellular process	1
sulfate transmembrane transporter activity	1
secondary active transmembrane transporter activity	1
chloride transmembrane transport	1
iodide transport	1
sulfur compound transmembrane transporter activity	1
sulfate transmembrane transport	1
dicarboxylic acid transmembrane transporter activity	1
oxalate transport	1
solute:inorganic anion antiporter activity	1
chloride transmembrane transporter activity	1
bicarbonate:monoatomic anion antiporter activity	1
binding	1
membrane	1
cell periphery	1
cellular anatomical structure	1
apical part of cell	1
plasma membrane region	1
brush border	1
apical plasma membrane	1
cell projection membrane	1
extracellular vesicle	1

Protein interactions and networks

STRING

1606 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SLC26A4	GJB2	P29033	961
SLC26A4	FOXI1	Q12951	944
SLC26A4	KCNJ10	P78508	927
SLC26A4	SLC5A5	Q92911	924
SLC26A4	IYD	Q6PHW0	908
SLC26A4	OTOF	Q9HC10	899
SLC26A4	TG	P01266	896
SLC26A4	TPO	P07202	861
SLC26A4	DUOXA2	Q1HG44	851
SLC26A4	MYO15A	Q9UKN7	825
SLC26A4	DUOX2	Q9NRD8	817
SLC26A4	SLC5A8	Q8N695	812
SLC26A4	GJB3	O75712	810
SLC26A4	TMC1	Q8TDI8	794
SLC26A4	TSHR	P16473	790

IntAct

4 interactions, top by confidence:

A	B	Type	Score
OR11G2	MLNR	psi-mi:“MI:0914”(association)	0.350
SLC26A4	ATP12A	psi-mi:“MI:0914”(association)	0.350
SLC26A4	UPK3BL1	psi-mi:“MI:0914”(association)	0.350

BioGRID (38): MAD2L1 (Affinity Capture-MS), ATP6V0A1 (Affinity Capture-MS), MAD2L1BP (Affinity Capture-MS), ATP2B3 (Affinity Capture-MS), TMEM164 (Affinity Capture-MS), ATP2A3 (Affinity Capture-MS), OMA1 (Affinity Capture-MS), SCCPDH (Affinity Capture-MS), SLC26A4 (Affinity Capture-MS), ATP12A (Affinity Capture-MS), FNDC3A (Affinity Capture-MS), TMEM55A (Affinity Capture-MS), SLC26A4 (PCA), XRCC5 (Cross-Linking-MS (XL-MS)), ACBD3 (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

2 interactions.

A	Effect	B	Mechanism
STAT6	“up-regulates quantity by expression”	SLC26A4	“transcriptional regulation”
RNF5	“down-regulates quantity by destabilization”	SLC26A4	ubiquitination

Disease & clinical

Clinical variants and AI predictions

ClinVar

1748 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	244
Likely pathogenic	248
Uncertain significance	379
Likely benign	569
Benign	49

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1065045	NM_000441.2(SLC26A4):c.703C>T (p.Gln235Ter)	Pathogenic
1065203	NM_000441.2(SLC26A4):c.1786C>T (p.Gln596Ter)	Pathogenic
1065204	NM_000441.2(SLC26A4):c.317C>A (p.Ala106Asp)	Pathogenic
1065207	NM_000441.2(SLC26A4):c.387del (p.Phe130fs)	Pathogenic
1065211	NM_000441.2(SLC26A4):c.415+2T>C	Pathogenic
1065213	NM_000441.2(SLC26A4):c.1299dup (p.Ala434fs)	Pathogenic
1069540	NM_000441.2(SLC26A4):c.365del (p.Phe122fs)	Pathogenic
1069794	NM_000441.2(SLC26A4):c.2139del (p.Arg714fs)	Pathogenic
1070057	NM_000441.2(SLC26A4):c.918+1G>C	Pathogenic
1070843	NM_000441.2(SLC26A4):c.1984dup (p.Cys662fs)	Pathogenic
1072520	NM_000441.2(SLC26A4):c.1194_1198del (p.Phe398fs)	Pathogenic
1073601	NC_000007.13:g.(?107303728)(107303890_?)del	Pathogenic
1073602	NC_000007.13:g.(?107301201)(107324012_?)del	Pathogenic
1074515	NM_000441.2(SLC26A4):c.1001+2T>A	Pathogenic
1075541	NM_000441.2(SLC26A4):c.170C>A (p.Ser57Ter)	Pathogenic
1076867	NM_000441.2(SLC26A4):c.675del (p.Ala226fs)	Pathogenic
1185073	NM_000441.2(SLC26A4):c.593_600+8del	Pathogenic
1185667	NM_000441.2(SLC26A4):c.3G>A (p.Met1Ile)	Pathogenic
1185668	NM_000441.2(SLC26A4):c.79T>C (p.Tyr27His)	Pathogenic
1185669	NM_000441.2(SLC26A4):c.305-1G>A	Pathogenic
1185671	NM_000441.2(SLC26A4):c.600+2T>C	Pathogenic
1185672	NM_000441.2(SLC26A4):c.667_669dup (p.Phe223dup)	Pathogenic
1185673	NM_000441.2(SLC26A4):c.698_701del (p.Val233fs)	Pathogenic
1185690	NM_000441.2(SLC26A4):c.1342-1_1342insCTG	Pathogenic
1185693	NM_000441.2(SLC26A4):c.1803+1G>C	Pathogenic
1185694	NM_000441.2(SLC26A4):c.1828del (p.Ser610fs)	Pathogenic
1185695	NM_000441.2(SLC26A4):c.2039del (p.Val680fs)	Pathogenic
1297065	NM_000441.2(SLC26A4):c.1594A>C (p.Ser532Arg)	Pathogenic
1297067	NM_000441.2(SLC26A4):c.421T>C (p.Phe141Leu)	Pathogenic
1297068	NM_000441.2(SLC26A4):c.624_632delinsACTTGGC (p.Gly209fs)	Pathogenic

SpliceAI

3194 predictions. Top by Δscore:

Variant	Effect	Δscore
7:107661630:G:A	acceptor_gain	1.0000
7:107661801:TGCAG:T	donor_loss	1.0000
7:107661802:GCAGG:G	donor_loss	1.0000
7:107661803:CAGG:C	donor_loss	1.0000
7:107661804:AGG:A	donor_loss	1.0000
7:107661805:GGTAG:G	donor_loss	1.0000
7:107661806:GTA:G	donor_loss	1.0000
7:107661807:T:A	donor_loss	1.0000
7:107672245:G:GG	donor_gain	1.0000
7:107672255:A:AG	donor_gain	1.0000
7:107674943:A:AG	acceptor_gain	1.0000
7:107674943:AGTT:A	acceptor_gain	1.0000
7:107674944:G:GG	acceptor_gain	1.0000
7:107674944:GTT:G	acceptor_gain	1.0000
7:107674944:GTTG:G	acceptor_gain	1.0000
7:107675110:G:GG	donor_gain	1.0000
7:107683200:A:AG	acceptor_gain	1.0000
7:107683201:G:GG	acceptor_gain	1.0000
7:107683290:T:G	donor_gain	1.0000
7:107683449:TTTCA:T	acceptor_loss	1.0000
7:107683450:TTCA:T	acceptor_loss	1.0000
7:107683451:TCAG:T	acceptor_loss	1.0000
7:107683452:CAGAC:C	acceptor_loss	1.0000
7:107683453:A:AG	acceptor_gain	1.0000
7:107683453:A:C	acceptor_loss	1.0000
7:107683453:AGAC:A	acceptor_gain	1.0000
7:107683454:G:GA	acceptor_gain	1.0000
7:107683454:GA:G	acceptor_gain	1.0000
7:107683454:GAC:G	acceptor_gain	1.0000
7:107683454:GACG:G	acceptor_gain	1.0000

AlphaMissense

5069 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:107663403:G:A	G91E	0.999
7:107663414:G:A	G95R	0.998
7:107663414:G:C	G95R	0.998
7:107663414:G:T	G95W	0.998
7:107663415:G:A	G95E	0.998
7:107663435:G:T	G102W	0.998
7:107674338:G:A	G197E	0.998
7:107675024:C:A	A227D	0.998
7:107690140:G:A	G389E	0.998
7:107694652:T:C	L458P	0.998
7:107663390:G:C	D87H	0.997
7:107663402:G:A	G91R	0.997
7:107663402:G:C	G91R	0.997
7:107663435:G:A	G102R	0.997
7:107663435:G:C	G102R	0.997
7:107672180:G:A	G116D	0.997
7:107672225:G:A	G131E	0.997
7:107672248:G:A	G139R	0.997
7:107672248:G:C	G139R	0.997
7:107674181:A:C	S145R	0.997
7:107674183:T:A	S145R	0.997
7:107674183:T:G	S145R	0.997
7:107674337:G:A	G197R	0.997
7:107674337:G:C	G197R	0.997
7:107689165:G:C	A372P	0.997
7:107690139:G:T	G389W	0.997
7:107690145:A:C	S391R	0.997
7:107690147:C:A	S391R	0.997
7:107690147:C:G	S391R	0.997
7:107690200:G:C	R409P	0.997

dbSNP variants (sampled 300 via entrez): RS1000000226 (7:107692699 C>T), RS1000063932 (7:107661036 C>G), RS1000100319 (7:107699149 A>AT), RS1000112087 (7:107708603 C>T), RS1000313632 (7:107683528 T>A,C), RS1000332830 (7:107689482 G>A,T), RS1000359592 (7:107706453 T>C), RS1000382297 (7:107681716 C>T), RS1000385750 (7:107695276 C>T), RS1000494902 (7:107685319 T>C), RS1000501918 (7:107677750 T>G), RS1000527330 (7:107674869 T>A,G), RS1000532906 (7:107659540 A>G), RS1000537937 (7:107660864 G>T), RS1000576464 (7:107674565 A>G)

Disease associations

OMIM: gene MIM:605646 | disease phenotypes: MIM:274600, MIM:600791, MIM:128600, MIM:220290, MIM:607197, MIM:613612, MIM:608716, MIM:194200

GenCC curated gene-disease

Disease	Classification	Inheritance
Pendred syndrome	Definitive	Autosomal recessive
autosomal recessive nonsyndromic hearing loss 4	Definitive	Autosomal recessive
hearing loss, autosomal recessive	Supportive	Autosomal recessive
athyreosis	Supportive	Autosomal dominant
thyroid hypoplasia	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
Pendred syndrome	Definitive	AR

Mondo (14): Pendred syndrome (MONDO:0010134), autosomal recessive nonsyndromic hearing loss 4 (MONDO:0010933), hearing loss disorder (MONDO:0005365), ear malformation (MONDO:0007500), RASopathy (MONDO:0021060), sensorineural hearing loss disorder (MONDO:0020678), hearing loss, autosomal recessive (MONDO:0019588), COG5-congenital disorder of glycosylation (MONDO:0013325), nonsyndromic genetic hearing loss (MONDO:0019497), microcephaly 5, primary, autosomal recessive (MONDO:0012106), Wolff-Parkinson-White syndrome (MONDO:0008685), congenital hypothyroidism (MONDO:0018612), athyreosis (MONDO:0019855), thyroid hypoplasia (MONDO:0019861)

Orphanet (10): Pendred syndrome (Orphanet:705), Rare autosomal recessive non-syndromic sensorineural deafness type DFNB (Orphanet:90636), Rare genetic deafness (Orphanet:96210), RASopathy (Orphanet:536391), Rare autosomal dominant non-syndromic sensorineural deafness type DFNA (Orphanet:90635), COG5-CDG (Orphanet:263487), Rare non-syndromic genetic deafness (Orphanet:87884), Autosomal recessive primary microcephaly (Orphanet:2512), Congenital hypothyroidism (Orphanet:442), NON RARE IN EUROPE: Wolff-Parkinson-White syndrome (Orphanet:907)

HPO phenotypes

49 total (30 of 49 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000112	Nephropathy
HP:0000158	Macroglossia
HP:0000239	Large fontanelles
HP:0000271	Abnormality of the face
HP:0000280	Coarse facial features
HP:0000282	Facial edema
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:0000952	Jaundice
HP:0001249	Intellectual disability
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001254	Lethargy
HP:0001262	Excessive daytime somnolence
HP:0001263	Global developmental delay
HP:0001324	Muscle weakness
HP:0001510	Growth delay
HP:0001537	Umbilical hernia
HP:0001615	Hoarse cry
HP:0001751	Abnormal vestibular function
HP:0002019	Constipation
HP:0002093	Respiratory insufficiency
HP:0002167	Abnormal speech pattern
HP:0002321	Vertigo
HP:0002777	Tracheal stenosis

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST002065_14	Alcohol consumption	9.000000e-06
GCST005956_26	Waist-to-hip ratio adjusted for BMI	2.000000e-08
GCST005962_48	Waist-to-hip ratio adjusted for BMI x sex x age interaction (4df test)	2.000000e-06
GCST006016_15	Serum alkaline phosphatase levels	2.000000e-08

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0004329	alcohol drinking
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0008007	age at assessment
EFO:0008343	sex interaction measurement
EFO:0004533	alkaline phosphatase measurement

MeSH disease descriptors (8)

Descriptor	Name	Tree numbers
D003409	Congenital Hypothyroidism	C05.116.099.343.347; C05.116.132.256; C16.320.240.625; C19.297.155; C19.874.482.281
D034381	Hearing Loss	C09.218.458.341; C10.597.751.418.341; C23.888.592.763.393.341
D014927	Wolff-Parkinson-White Syndrome	C14.280.067.780.977; C14.280.123.750.977; C16.131.240.400.980
C564609	Deafness, Autosomal Recessive (supp.)
C566366	Deafness, Autosomal Recessive 4 (supp.)
C563871	Microcephaly, Primary Autosomal Recessive, 5 (supp.)
C580334	Nonsyndromic Deafness (supp.)
C536648	Pendred syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4523138 (SINGLE PROTEIN)

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: transporter — Chloride/bicarbonate exchangers

ChEMBL bioactivities

19 potent at pChembl≥5 of 20 total, top 17 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.32	IC50	480	nM	CHEMBL6145989
6.31	IC50	490	nM	CHEMBL1416075
6.19	IC50	650	nM	CHEMBL1409977
5.84	IC50	1440	nM	CHEMBL1897294
5.51	IC50	3100	nM	CHEMBL6120880
5.39	IC50	4100	nM	CHEMBL1370459
5.32	IC50	4800	nM	CHEMBL1404124
5.30	IC50	5000	nM	CHEMBL4474736
5.30	IC50	5000	nM	CHEMBL4515533
5.30	IC50	5000	nM	CHEMBL1313061
5.25	IC50	5600	nM	CHEMBL1544526
5.16	IC50	7000	nM	CHEMBL4474736
5.10	IC50	8000	nM	CHEMBL4474736
5.10	IC50	8000	nM	CHEMBL4515533
5.09	IC50	8200	nM	CHEMBL6103470
5.05	IC50	9000	nM	CHEMBL4474736
5.05	IC50	9000	nM	CHEMBL4515533

PubChem BioAssay actives

1 with measured affinity, of 46 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
N-(4-chlorophenyl)-3-[(3-fluorophenoxy)methyl]-1-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxamide	1552551: Inhibition of human PDS stably expressed in FRT cells coexpressing EYFP-H148Q/I152L/F46L assessed as reduction in I-/Cl- exchange incubated for 10 mins by fluorescence based assay	ic50	7.0000	uM

CTD chemical–gene interactions

22 total (human), top 22 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Acetaminophen	decreases expression, increases expression	2
Benzo(a)pyrene	decreases expression, decreases methylation, increases methylation	2
Chlorides	affects transport, increases transport	2
Nickel	increases expression	2
Tobacco Smoke Pollution	affects expression, increases expression	2
bisphenol F	affects cotreatment, increases methylation	1
butyraldehyde	decreases expression	1
formic acid	increases transport	1
ceric oxide	affects cotreatment, increases expression	1
2-palmitoylglycerol	increases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Amiodarone	decreases expression	1
Cadmium	decreases expression, increases abundance	1
Iodides	affects transport	1
Phenobarbital	affects expression	1
Rifampin	decreases expression	1
Fatty Acids, Omega-3	increases expression	1
Aflatoxin B1	decreases methylation	1
Antirheumatic Agents	increases expression	1
Cadmium Chloride	decreases expression, increases abundance	1
Antigens, Dermatophagoides	affects cotreatment, increases expression	1
Fatty Acids, Omega-6	decreases expression	1

ChEMBL screening assays

37 unique, capped per target: 37 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4017609	Binding	Chaperone activity at recombinant human C-terminal FLAG-tagged pendrin P123S mutant expressed in HEK293 cells assessed as increase in localization of protein mutant in plasma membrane after 12 hrs by DAPI staining based immunofluorescence m	Discovery of (2-aminophenyl)methanol as a new molecular chaperone that rescues the localization of P123S mutant pendrin stably expressed in HEK293 cells. — Bioorg Med Chem

Cellosaurus cell lines

20 cell lines: 20 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_C4S9	CSUXHEi001-A	Induced pluripotent stem cell	Male
CVCL_C4SA	CSUXHEi002-A	Induced pluripotent stem cell	Female
CVCL_RL24	PDSH723R01#5	Induced pluripotent stem cell	Female
CVCL_RL25	PDSH723R01#12	Induced pluripotent stem cell	Female
CVCL_RL26	PDSH723R01#16	Induced pluripotent stem cell	Female
CVCL_RL27	PDSHM147V#3	Induced pluripotent stem cell	Female
CVCL_RL28	PDSHM147V#13	Induced pluripotent stem cell	Female
CVCL_RL29	PDSHM147V#18	Induced pluripotent stem cell	Female
CVCL_RL30	PDSHT410M#3	Induced pluripotent stem cell	Female
CVCL_RL31	PDSHT410M#11	Induced pluripotent stem cell	Female

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
NCT05970445	Not specified	UNKNOWN	Clinical Phenotypic Characteristics of SC26A4
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