SLC6A8

Chr XXLR

solute carrier family 6 member 8

NCBI Gene: 6535ENSG00000130821UniProt: P48029

Creatine:sodium symporter which mediates the uptake of creatine (PubMed:17465020, PubMed:22644605, PubMed:25861866, PubMed:7945388, PubMed:7953292, PubMed:9882430). Plays an important role in supplying creatine to the brain via the blood-brain barrier (By similarity)

Primary Disease Associations & Inheritance

Cerebral creatine deficiency syndrome 1MIM #300352
XLR
1514
ClinVar variants
93
Pathogenic / LP
1.00
pLI score· haploinsufficient
2
Active trials
Clinical Summary— SLC6A8
⚡
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
93 Pathogenic / Likely Pathogenic· 170 VUS of 1514 total submissions
💊
Clinical Trials
2 active or recruiting trials — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
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.
0.21LOEUF
pLI 0.998
Z-score 4.18
OE 0.04 (0.01–0.21)
Highly constrained

Highly LoF-intolerant (top ~10% 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.
3.05Z-score
OE missense 0.46 (0.40–0.54)
118 obs / 255.0 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.0.04 (0.01–0.21)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.46 (0.40–0.54)
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.1.14
0≤1.21.6
LoF obs/exp: 1 / 22.3Missense obs/exp: 118 / 255.0Syn Z: -1.17

ClinVar Variant Classifications

1514 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic60
Likely Pathogenic33
VUS170
Likely Benign187
Benign8
Conflicting3
60
Pathogenic
33
Likely Pathogenic
170
VUS
187
Likely Benign
8
Benign
3
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
22
1
37
0
60
Likely Pathogenic
20
7
5
1
33
VUS
4
124
32
10
170
Likely Benign
0
5
85
97
187
Benign
0
3
4
1
8
Conflicting
—3
Total46140163109461

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

View in ClinVar →

Protein Context — Lollipop Plot

SLC6A8 · protein map & ClinVar variants

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

Gene2Phenotype Curations

SLC6A8-related creatine deficiency syndrome

definitive
Monoallelic X HemizygousLoss 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

Cerebral creatine deficiency syndrome 1

MIM #300352

Molecular basis of disorder known

X-linked recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Clinical Characteristics, Developmental Trajectory, and Caregiver Burden of Patients With Creatine Transporter Deficiency (SLC6A8).
Curie A et al.·Neurology
2024Cohort
X-linked creatine transporter (SLC6A8) deficiency in females: Difficult to recognize, but a potentially treatable disease.
Mejdahl Nielsen M et al.·Mol Genet Metab
2023Review
Phenylbutyrate for monogenetic epilepsy: Literature review.
Stone A et al.·Epilepsy Res
2025Review
SLC gene mutations and pediatric neurological disorders: diverse clinical phenotypes in a Saudi Arabian population.
Mir A et al.·Hum Genet
2022
Novel Corrector for Variants of SLC6A8: A Therapeutic Opportunity for Creatine Transporter Deficiency.
Gechijian LN et al.·ACS Chem Biol
2024
Deciphering neuronal deficit and protein profile changes in human brain organoids from patients with creatine transporter deficiency.
Broca-Brisson L et al.·Elife
2023Cohort
Experimental and Computational Analysis of Newly Identified Pathogenic Mutations in the Creatine Transporter SLC6A8.
Ferrada E et al.·J Mol Biol
2024
Current and potential new treatment strategies for creatine deficiency syndromes.
Fernandes-Pires G et al.·Mol Genet Metab
2022Review
[Clinical features and genetic analysis of 17 Chinese pedigrees affected with X-linked intellectual disability].
Li Y et al.·Zhonghua Yi Xue Yi Chuan Xue Za Zhi
2024
Treatment of X-linked creatine transporter (SLC6A8) deficiency: systematic review of the literature and three new cases.
Dunbar M et al.·Mol Genet Metab
2014Meta-analysis
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
Fragile X Syndrome (FXS)Creatine Transporter Deficiency

Optical Imaging in X-linked Disorders.

NOT YET RECRUITING
NCT06868979Phase NAHospices Civils de LyonStarted 2025-03
Clinical assessmentParental questionnairesCognitive assessment
Creatine Transporter Defect

Relevant Outcome Measures for Creatine Transporter Deficiency Patient

RECRUITING
NCT06018519Phase NAHospices Civils de LyonStarted 2023-03-13
Clinical endpointsParental questionnairesQuality of life scale

External Resources

Links to major genomics databases and tools