SLC26A4

Chr 7AR

solute carrier family 26 member 4

Also known as: DFNB4, EVA, PDS, TDH2B

NCBI Gene: 5172 ENSG00000091137 UniProt: O43511 OMIM: 605646

The encoded protein is a sodium-independent transporter that mediates electroneutral exchange of chloride and iodide, as well as chloride-bicarbonate exchange. Mutations cause Pendred syndrome, the most common form of syndromic deafness, which follows autosomal recessive inheritance and typically involves both hearing loss and thyroid dysfunction. This gene is not highly constrained against loss-of-function variants, consistent with its recessive inheritance pattern.

GeneReviews OMIM ResearchSummary from RefSeq, UniProt

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. [provided by RefSeq, Jul 2008]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Deafness, autosomal recessive 4, with enlarged vestibular aqueductMIM #600791

Pendred syndromeMIM #274600

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · Pendred syndrome · AR · ClinGen 2017

Active trials

128

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.18

LOEUF

Multiple*

Mechanism· predicted

📖

GeneReview available — SLC26A4

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.18LOEUF

pLI 0.000

Z-score 0.66

OE 0.89 (0.68–1.18)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-2.01Z-score

OE missense 1.28 (1.19–1.37)

528 obs / 413.0 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.89 (0.68–1.18)

0≤0.351.4

Missense OE?1.28 (1.19–1.37)

0≤0.61.4

Synonymous OE?1.02

0≤1.21.6

LoF obs/exp: 35 / 39.5Missense obs/exp: 528 / 413.0Syn Z: -0.24

Background carrier burden — how many people carry a rare variant somewhere in SLC26A4?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 35

1,212 rare PASS variants

Rare truncating (LoF)

1 in 340

214 rare PASS variants

Rare synonymous (reference)

1 in 120

418 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for SLC26A4. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 47	1 in 350
South Asian	~43k	1 in 33	1 in 400
Remaining (unassigned)	~30k	1 in 29	1 in 350
European (Finnish)	~27k	1 in 140	1 in 3,800
Admixed American	~22k	1 in 31	1 in 340
African / African American	~21k	1 in 40	1 in 350
East Asian	~20k	1 in 38	1 in 410
Ashkenazi Jewish	~13k	1 in 290	≈ 1 in 13,000
Middle Eastern	~2,884	1 in 37	1 in 340

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 12 of 20 coding exons well covered in gnomAD exomes; exon 18 poorly covered; exons 4, 13, 14, 15, 16 and 2 more marginal. Genomes: all 20.? see exons ↓