SLC12A1

Chr 15AR

solute carrier family 12 member 1

ENSG00000074803 UniProt: Q13621 OMIM: 600839

This gene encodes a sodium-potassium-chloride cotransporter expressed on the luminal membrane of the thick ascending limb of Henle's loop, where it mediates NaCl reabsorption and plays an essential role in urine concentration and volume regulation. Mutations cause Bartter syndrome type 1, an autosomal recessive tubulopathy affecting kidney function. The gene shows extremely low tolerance to loss-of-function variants (pLI near 1), indicating that complete loss of function is highly deleterious.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

Renal sodium, potassium and chloride non-electrogenic ion symporter that mediates the transepithelial NaCl reabsorption in the thick ascending limb and plays an essential role in the urinary concentration and volume regulation (PubMed:21321328). It can substitute NH4(+) for K(+), enabling NH4(+) apical transmembrane transport in the medullary thick ascending limb (MTAL). This function is crucial for maintaining ammonium homeostasis by the kidney, particularly during metabolic acidosis (By similarity)

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Bartter syndrome, type 1MIM #601678

UniProtBartter syndrome 1, antenatal

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · obsolete antenatal Bartter syndrome · AR · ClinGen 2022

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.82

LOEUF

Multiple*

Mechanism· predicted

Some data sources returned errors (1)

ncbi: Error: NCBI fetch failed: 429 https://eutils.ncbi.nlm.nih.gov/entrez/eutils/esearch.fcgi

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.82LOEUF

pLI 0.000

Z-score 2.63

OE 0.62 (0.47–0.82)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.16Z-score

OE missense 0.86 (0.80–0.93)

502 obs / 580.7 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.62 (0.47–0.82)

0≤0.351.4

Missense OE?0.86 (0.80–0.93)

0≤0.61.4

Synonymous OE?1.05

0≤1.21.6

LoF obs/exp: 35 / 56.3Missense obs/exp: 502 / 580.7Syn Z: -0.60

Background carrier burden — how many people carry a rare variant somewhere in SLC12A1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 42

1,516 rare PASS variants

Rare truncating (LoF)

1 in 410

225 rare PASS variants

Rare synonymous (reference)

1 in 78

567 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for SLC12A1. 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 55	1 in 660
South Asian	~43k	1 in 48	1 in 490
Remaining (unassigned)	~30k	1 in 34	1 in 340
European (Finnish)	~27k	1 in 210	1 in 1,300
Admixed American	~22k	1 in 39	1 in 390
African / African American	~21k	1 in 29	1 in 660
East Asian	~20k	1 in 35	1 in 330
Ashkenazi Jewish	~13k	1 in 100	≈ 1 in 4,400
Middle Eastern	~2,884	1 in 49	≈ 1 in 720

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): 20 of 26 coding exons well covered in gnomAD exomes; exons 5, 7, 14, 19, 23, 24 marginal. Genomes: all 26.? see exons ↓