SLC6A3

Chr 5AR

solute carrier family 6 member 3

NCBI Gene: 6531 ENSG00000142319 UniProt: Q01959

Mediates sodium- and chloride-dependent transport of dopamine (PubMed:10375632, PubMed:11093780, PubMed:1406597, PubMed:15505207, PubMed:19478460, PubMed:39112701, PubMed:39112703, PubMed:39112705, PubMed:8302271). Also mediates sodium- and chloride-dependent transport of norepinephrine (also known as noradrenaline) (By similarity). Regulator of light-dependent retinal hyaloid vessel regression, downstream of OPN5 signaling (By similarity)

Primary Disease Associations & Inheritance

{Nicotine dependence, protection against}MIM #188890

Parkinsonism-dystonia, infantile, 1MIM #613135

716

ClinVar variants

Pathogenic / LP

1.00

pLI score· haploinsufficient

Active trials

Clinical Summary— SLC6A3

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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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ClinVar Variants

44 Pathogenic / Likely Pathogenic· 147 VUS of 716 total submissions

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Clinical Trials

4 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.

0.25LOEUF

pLI 0.998

Z-score 4.65

OE 0.10 (0.04–0.25)

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.

2.29Z-score

OE missense 0.67 (0.60–0.74)

249 obs / 373.7 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.0.10 (0.04–0.25)

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 (0.60–0.74)

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.1.19

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	1	0	39	0	40
Likely Pathogenic	3	1	0	0	4
VUS	1	124	21	1	147
Likely Benign	0	4	124	110	238
Benign	0	0	64	1	65
Conflicting	—				1
Total	5	129	248	112	495

SLC6A3

Primary Disease Associations & Inheritance

Population Genetics & Constraint

ClinVar Variant Classifications

Classification Summary

Curated Variants Distribution

Protein Context — Lollipop Plot

DECIPHER · Gene2Phenotype

Gene2Phenotype Curations

OMIM — Genotype-Phenotype Relationships

Gene Overview

ClinGen Curation

Disease Associations

External Resources

Variant Interpretation

Population Databases

Gene Resources