SLC6A3

Chr 5AR

solute carrier family 6 member 3

Also known as: DAT, DAT1, PKDYS, PKDYS1

NCBI Gene: 6531 ENSG00000142319 UniProt: Q01959 OMIM: 126455

This gene encodes the dopamine transporter that mediates sodium- and chloride-dependent reuptake of dopamine from synapses. Mutations cause autosomal recessive infantile parkinsonism-dystonia through loss-of-function, resulting in impaired dopamine clearance and disrupted dopaminergic signaling. The gene shows high constraint against loss-of-function variants, consistent with the severe phenotype when both alleles are affected.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene encodes a dopamine transporter which is a member of the sodium- and chloride-dependent neurotransmitter transporter family. The 3' UTR of this gene contains a 40 bp tandem repeat, referred to as a variable number tandem repeat or VNTR, which can be present in 3 to 11 copies. Variation in the number of repeats is associated with idiopathic epilepsy, attention-deficit hyperactivity disorder, dependence on alcohol and cocaine, susceptibility to Parkinson disease and protection against nicotine dependence.[provided by RefSeq, Nov 2009]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

{Nicotine dependence, protection against}MIM #188890

Parkinsonism-dystonia, infantile, 1MIM #613135

Clinical highlights

Gene–disease validity (ClinGen · GenCC)

Definitive · SLC6A3-related dopamine transporter deficiency syndrome · AR · ClinGen 2023
Definitive · classic dopamine transporter deficiency syndrome · AR · G2P
Supportive · parkinsonism-dystonia, infantile · AR · Orphanet

Interpreting a novel variant

Loss of function is the established mechanism and the gene is intolerant of it in the population — truncating, frameshift and canonical splice variants carry more prior weight here than missense.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.25

LOEUF· LoF intol.

LOF

Mechanism· annotated

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

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?

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?

LoF OE?0.10 (0.04–0.25)

0≤0.351.4

Missense OE?0.67 (0.60–0.74)

0≤0.61.4

Synonymous OE?1.19

0≤1.21.6

LoF obs/exp: 3 / 30.9Missense obs/exp: 249 / 373.7Syn Z: -1.92

Background carrier burden — how many people carry a rare variant somewhere in SLC6A3?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 94

655 rare PASS variants

Rare truncating (LoF)

1 in 3,200

44 rare PASS variants

Rare synonymous (reference)

1 in 76

395 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for SLC6A3. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 100	1 in 2,700
South Asian	~43k	1 in 100	1 in 1,700
Remaining (unassigned)	~30k	1 in 68	≈ 1 in 7,500
European (Finnish)	~27k	1 in 240	1 in 3,800
Admixed American	~22k	1 in 100	≈ 1 in 11,000
African / African American	~21k	1 in 80	≈ 1 in 5,500
East Asian	~20k	1 in 120	≈ 1 in 20,000
Ashkenazi Jewish	~13k	1 in 550	none seen
Middle Eastern	~2,884	1 in 120	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 14 coding exons well covered in gnomAD exomes and genomes.? see exons ↓