SLC12A5

Chr 20

solute carrier family 12 member 5

NCBI Gene: 57468ENSG00000124140UniProt: Q9H2X9

Mediates electroneutral potassium-chloride cotransport in mature neurons and is required for neuronal Cl(-) homeostasis (PubMed:12106695). As major extruder of intracellular chloride, it establishes the low neuronal Cl(-) levels required for chloride influx after binding of GABA-A and glycine to their receptors, with subsequent hyperpolarization and neuronal inhibition (By similarity). Involved in the regulation of dendritic spine formation and maturation (PubMed:24668262)

Primary Disease Associations & Inheritance

UniProtDevelopmental and epileptic encephalopathy 34
UniProtEpilepsy, idiopathic generalized 14
491
ClinVar variants
21
Pathogenic / LP
1.00
pLI score· haploinsufficient
0
Active trials
Clinical Summary— SLC12A5
🧬
Gene-Disease Validity (ClinGen)
developmental and epileptic encephalopathy · ARLimited

Limited evidence — not for standalone diagnostic reporting

⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
21 Pathogenic / Likely Pathogenic· 168 VUS of 491 total submissions
Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Dual constrained — LoF & missense intolerant
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.14LOEUF
pLI 1.000
Z-score 6.58
OE 0.05 (0.02–0.14)
Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
4.70Z-score
OE missense 0.50 (0.46–0.55)
347 obs / 696.1 exp
Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.05 (0.02–0.14)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.50 (0.46–0.55)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.92
0≤1.21.6
LoF obs/exp: 3 / 56.3Missense obs/exp: 347 / 696.1Syn Z: 1.01

ClinVar Variant Classifications

491 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic15
Likely Pathogenic6
VUS168
Likely Benign266
Benign28
Conflicting8
15
Pathogenic
6
Likely Pathogenic
168
VUS
266
Likely Benign
28
Benign
8
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
8
0
7
0
15
Likely Pathogenic
5
1
0
0
6
VUS
1
149
15
3
168
Likely Benign
0
1
111
154
266
Benign
0
0
22
6
28
Conflicting
—8
Total14151155163491

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

SLC12A5 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

SLC12A5-related epilepsy of infancy with migrating focal seizures

strong
ARUndeterminedAltered Gene Product Structure
Dev. Disorders
G2P ↗
missense variantinframe deletioninframe insertion

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype

OMIM

No OMIM entries found.

📖
GeneReview available — SLC12A5
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Pathogenic potential of human SLC12A5 variants causing KCC2 dysfunction.
Fukuda A et al.·Brain Res
2019Review
SLC12A5 promotes hepatocellular carcinoma growth and ferroptosis resistance by inducing ER stress and cystine transport changes.
Tong Q et al.·Cancer Med
2023
Overexpression of SLC12A5 is associated with tumor progression and poor survival in ovarian carcinoma.
Yang GP et al.·Int J Gynecol Cancer
2019
A Pan-Cancer Analysis of SLC12A5 Reveals Its Correlations with Tumor Immunity.
Jiang Y et al.·Dis Markers
2021
ETV4‑mediated transcriptional activation of SLC12A5 exacerbates ferroptosis resistance and glucose metabolism reprogramming in breast cancer cells.
Wang H et al.·Mol Med Rep
2024
The Multifaceted Roles of KCC2 in Cortical Development.
Virtanen MA et al.·Trends Neurosci
2021Review
Solute carrier family 12 member 5 promotes tumor invasion/metastasis of bladder urothelial carcinoma by enhancing NF-κB/MMP-7 signaling pathway.
Liu JY et al.·Cell Death Dis
2017
Novel Homozygous Full Gene Deletion of SLC12A5 in a Newborn With Refractory Seizures.
Wainman LM et al.·Am J Med Genet A
2025Case report
The neuronal K(+)Cl(-) co-transporter 2 (Slc12a5) modulates insulin secretion.
Kursan S et al.·Sci Rep
2017
Expanding the clinical and genetic landscape of (developmental) epileptic encephalopathy with spike-and-wave activation in sleep: results from studies of a Turkish cohort.
Türkyılmaz A et al.·Neurogenetics
2024Cohort
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools