SLC6A8

Chr XXLR

solute carrier family 6 member 8

Also known as: CCDS1, CRT, CRT-1, CRT1, CRTR, CT1, CTR5

NCBI Gene: 6535 ENSG00000130821 UniProt: P48029 OMIM: 300036

The encoded protein is a creatine transporter that mediates cellular uptake of creatine and supplies creatine to the brain via the blood-brain barrier. Mutations cause X-linked cerebral creatine deficiency syndrome 1, characterized by intellectual disability, speech delay, and seizures. This gene follows X-linked recessive inheritance and is highly constrained against loss-of-function variants.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene is a plasma membrane protein whose function is to transport creatine into and out of cells. Defects in this gene can result in X-linked creatine deficiency syndrome. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2008]

OMIM ResearchGenerating clinical summary…

LOFmechanismXLRLOEUF 0.211 OMIM phenotype

VCEP Guidelines: Cerebral Creatine DeficiencyPilot

View Specifications ClinGen Panel

Clinical Summary— SLC6A8

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Gene-Disease Validity (ClinGen)

creatine transporter deficiency · XLDefinitive

Definitive — sufficient evidence for diagnostic panels

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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.

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Clinical Trials

2 active or recruiting trials — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

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?

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?

LoF OE?0.04 (0.01–0.21)

0≤0.351.4

Missense OE?0.46 (0.40–0.54)

0≤0.61.4

Synonymous OE?1.14

0≤1.21.6

LoF obs/exp: 1 / 22.3Missense obs/exp: 118 / 255.0Syn Z: -1.17

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveSLC6A8-related creatine deficiency syndromeLOFXLR

This gene — mechanism propensity

0.4785th %ile

GOF

0.74top 25%

LOF

0.51top 25%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and gain-of-function). The Badonyi & Marsh model scores gain-of-function highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports loss-of-function (haploinsufficiency). Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFLOEUF 0.21 · ClinGen HI: Sufficient evidence for dosage pathogenicity

GOFprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.