SLC12A6

Chr 15ARAD

solute carrier family 12 member 6

Also known as: ACCPN, CMT2II, KCC3, KCC3A, KCC3B

NCBI Gene: 9990ENSG00000140199UniProt: Q9UHW9

This gene is a member of the K-Cl cotransporter (KCC) family. K-Cl cotransporters are integral membrane proteins that lower intracellular chloride concentrations below the electrochemical equilibrium potential. The proteins encoded by this gene are activated by cell swelling induced by hypotonic conditions. Alternate splicing results in multiple transcript variants encoding different isoforms. Mutations in this gene are associated with agenesis of the corpus callosum with peripheral neuropathy. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

Agenesis of the corpus callosum with peripheral neuropathyMIM #218000
AR
Charcot-Marie-Tooth disease, axonal, type 2IIMIM #620068
AD
200
ClinVar variants
13
Pathogenic / LP
0.01
pLI score
0
Active trials
Clinical Summary— SLC12A6
⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.26) despite low pLI — interpret in context.
📋
ClinVar Variants
13 Pathogenic / Likely Pathogenic· 91 VUS of 200 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
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.
0.40LOEUF
pLI 0.011
Z-score 5.49
OE 0.26 (0.18–0.40)
Moderately constrained

More LoF-intolerant than ~75% of genes

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.
2.96Z-score
OE missense 0.67 (0.62–0.73)
436 obs / 648.0 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

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.0.26 (0.18–0.40)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.67 (0.62–0.73)
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.0.99
0≤1.21.6
LoF obs/exp: 17 / 64.6Missense obs/exp: 436 / 648.0Syn Z: 0.08

ClinVar Variant Classifications

200 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic4
Likely Pathogenic9
VUS91
Likely Benign71
Benign22
Conflicting3
4
Pathogenic
9
Likely Pathogenic
91
VUS
71
Likely Benign
22
Benign
3
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
4
0
4
Likely Pathogenic
7
0
2
0
9
VUS
1
62
16
12
91
Likely Benign
0
0
24
47
71
Benign
0
1
19
2
22
Conflicting
—3
Total8636561200

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

View in ClinVar →

Protein Context — Lollipop Plot

SLC12A6 · protein map & ClinVar variants

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

Gene2Phenotype Curations

SLC12A6-related agenesis of the corpus callosum with peripheral neuropathy

definitive
ARLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Agenesis of the corpus callosum with peripheral neuropathy

MIM #218000

Molecular basis of disorder known

Autosomal recessive

Charcot-Marie-Tooth disease, axonal, type 2II

MIM #620068

Molecular basis of disorder known

Autosomal dominant
📖
GeneReview available — SLC12A6
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Truncating SLC12A6 variants cause different clinical phenotypes in humans and dogs.
Van Poucke M et al.·Eur J Hum Genet
2019
SLC gene mutations and pediatric neurological disorders: diverse clinical phenotypes in a Saudi Arabian population.
Mir A et al.·Hum Genet
2022
Late-onset sensory-motor axonal neuropathy, a novel SLC12A6-related phenotype.
Løseth S et al.·Brain
2023
Novel heterozygous variants of SLC12A6 in Japanese families with Charcot-Marie-Tooth disease.
Ando M et al.·Ann Clin Transl Neurol
2022
De novo variants in SLC12A6 cause sporadic early-onset progressive sensorimotor neuropathy.
Park J et al.·J Med Genet
2020
Expanding the phenotype of SLC12A6-associated sensorimotor neuropathy.
Bogdanova-Mihaylova P et al.·BMJ Case Rep
2021Case report
Unveiling causal regulatory mechanisms through cell-state parallax.
Wu AP et al.·Nat Commun
2025Functional
Whole-exome sequencing identifies a heterozygous mutation in SLC12A6 associated with hereditary sensory and motor neuropathy.
Shi J et al.·Neuromuscul Disord
2021
Identification of a novel SLC12A6 pathogenic variant associated with hereditary motor and sensory neuropathy with agenesis of the corpus callosum (HMSN/ACC) in a non-French-Canadian family.
Rius R et al.·Neurol India
2018Case report
Rare variants of the gene encoding the potassium chloride co-transporter 3 are associated with bipolar disorder.
Meyer J et al.·Int J Neuropsychopharmacol
2005
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