SLC6A1

Chr 3AD

solute carrier family 6 member 1

Also known as: GABATHG, GABATR, GAT1, MAE, hGAT-1

NCBI Gene: 6529 ENSG00000157103 UniProt: P30531 OMIM: 137165

The protein functions as a gamma-aminobutyric acid (GABA) transporter that removes GABA from the synaptic cleft and restores it to presynaptic terminals. Mutations cause myoclonic-atonic epilepsy through autosomal dominant inheritance. The gene is highly intolerant to loss-of-function variants, suggesting mutations predominantly cause disease through haploinsufficiency affecting GABAergic neurotransmission.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene is a gamma-aminobutyric acid (GABA) transporter that localizes to the plasma membrane. The encoded protein removes GABA from the synaptic cleft, restoring it to presynaptic terminals. [provided by RefSeq, Jan 2017]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Myoclonic-atonic epilepsyMIM #616421

Clinical highlights

Gene–disease validity (ClinGen · GenCC)

Definitive · epilepsy with myoclonic atonic seizures · AD · Illumina
Supportive · myoclonic-astatic epilepsy · Unknown · Orphanet

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype) 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

0.15

LOEUF· LoF intol.

LOF*

Mechanism· G2P

📖

GeneReview available — SLC6A1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.15LOEUF

pLI 1.000

Z-score 5.05

OE 0.03 (0.01–0.15)

Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint?

4.18Z-score

OE missense 0.39 (0.34–0.45)

144 obs / 370.1 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.03 (0.01–0.15)

0≤0.351.4

Missense OE?0.39 (0.34–0.45)

0≤0.61.4

Synonymous OE?1.10

0≤1.21.6

LoF obs/exp: 1 / 31.7Missense obs/exp: 144 / 370.1Syn Z: -0.96

Background carrier burden — how many people carry a rare variant somewhere in SLC6A1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 190

484 rare PASS variants

Rare truncating (LoF)

1 in 570

28 rare PASS variants

Rare synonymous (reference)

1 in 69

339 rare PASS variants

Rare missense and truncating variants are carried at similar rates in SLC6A1; this gene does not show strong loss-of-function constraint by this measure. 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 240	1 in 9,300
South Asian	~43k	1 in 240	1 in 5,400
Remaining (unassigned)	~30k	1 in 180	≈ 1 in 30,000
European (Finnish)	~27k	1 in 260	1 in 1,100
Admixed American	~22k	1 in 200	≈ 1 in 22,000
African / African American	~21k	1 in 110	≈ 1 in 10,000
East Asian	~20k	1 in 200	1 in 2,300
Ashkenazi Jewish	~13k	1 in 1,100	none seen
Middle Eastern	~2,884	1 in 170	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): 10 of 14 coding exons well covered in gnomAD exomes; exons 5, 13, 14, 16 marginal. Genomes: all 14.? see exons ↓