SLC6A4

Chr 17AD

solute carrier family 6 member 4

Also known as: 5-HTT, 5-HTTLPR, 5HTT, HTT, OCD1, SERT, SERT1, hSERT

NCBI Gene: 6532ENSG00000108576UniProt: P31645

This gene encodes an integral membrane protein that transports the neurotransmitter serotonin from synaptic spaces into presynaptic neurons. The encoded protein terminates the action of serotonin and recycles it in a sodium-dependent manner. This protein is a target of psychomotor stimulants, such as amphetamines and cocaine, and is a member of the sodium:neurotransmitter symporter family. A repeat length polymorphism in the promoter of this gene has been shown to affect the rate of serotonin uptake. There have been conflicting results in the literature about the possible effect, if any, that this polymorphism may play in behavior and depression. [provided by RefSeq, May 2019]

Primary Disease Associations & Inheritance

{Anxiety-related personality traits}MIM #607834
{Obsessive-compulsive disorder}MIM #164230
AD
8
Active trials
10
Pathogenic / LP
155
ClinVar variants
5
Pubs (1 yr)
1.9
Missense Z
0.43
LOEUF
Clinical Summary— SLC6A4
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Gene-Disease Validity (ClinGen)
autism spectrum disorder · ADDisputed

Disputed — evidence questions this relationship

⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.24) despite low pLI — interpret in context.
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ClinVar Variants
10 Pathogenic / Likely Pathogenic· 114 VUS of 155 total submissions
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Clinical Trials
8 active or recruiting trials — potential therapeutic options may be available
📖
GeneReview available — SLC6A4
Authoritative clinical overview · Recommended first read
Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
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.
0.43LOEUF
pLI 0.246
Z-score 4.12
OE 0.24 (0.14–0.43)
Moderately constrained

More LoF-intolerant than ~75% 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.
1.93Z-score
OE missense 0.72 (0.65–0.80)
272 obs / 377.5 exp
Tolerant

Mild missense constraint

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.0.24 (0.14–0.43)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.72 (0.65–0.80)
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.0.95
0≤1.21.6
LoF obs/exp: 8 / 33.8Missense obs/exp: 272 / 377.5Syn Z: 0.52
DN
0.78top 25%
GOF
0.85top 5%
LOF
0.2289th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median · 1 literature citation
DNprediction 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.

Literature Evidence

GOFA novel, putative gain-of-function haplotype at SLC6A4 associates with obsessive-compulsive disorder.PMID:18055562

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

155 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic8
Likely Pathogenic2
VUS114
Likely Benign22
Benign7
Conflicting2
8
Pathogenic
2
Likely Pathogenic
114
VUS
22
Likely Benign
7
Benign
2
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
8
0
8
Likely Pathogenic
1
0
1
0
2
VUS
1
48
56
9
114
Likely Benign
0
3
12
7
22
Benign
0
0
6
1
7
Conflicting
—2
Total2518317155

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

View in ClinVar →

Protein Context — Lollipop Plot

SLC6A4 · protein map & ClinVar variants

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

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Depression

Intern Health Study

ENROLLING BY INVITATION
NCT01809080University of MichiganStarted 2007-05
Parkinson DiseaseParkinson'sParkinson's Disease

Serotonin Release in Premotor and Motor PD

RECRUITING
NCT05516732University of ExeterStarted 2022-07-01
Positron Emission Tomography (PET) scan using CIMBI-36 tracerMagnetic Resonance Imaging (MRI) ScanPositron Emission Tomography (PET) scan using DASB tracer
Premature Ejaculation

Therapeutic Outcomes of Selective Serotonin Reuptake Inhibitors and Phosphodiesterase-5 Inhibitors Combination Therapy Versus Monotherapy

NOT YET RECRUITING
NCT07057011Phase NASouth Valley UniversityStarted 2025-07-01
Paroxetine 20 Mg Oral Tablet
Vasovagal Syncope

Study of Atomoxetine in the Prevention of Vasovagal Syncope

RECRUITING
NCT05159687Phase PHASE3University of CalgaryStarted 2022-06-01
Atomoxetine HydrochloridePlacebo
Preterm BirthMother-Infant InteractionInfant Development

Continuous Delivery Room Skin-to-skin-study for Moderate and Late Preterm Infants

RECRUITING
NCT05975203Phase NAUniversity of CologneStarted 2023-08-04
skin-to-skin contact
Postnatal Depression

Home-based Transcranial Direct Current Stimulation in Postpartum Depression: the Feasibility Study and Pilot Study

NOT YET RECRUITING
NCT05046405Phase NAAna Ganho ÁvilaStarted 2022-10-02
Transcranial Direct Current Stimulation
PregnancyPostpartumChildbirth

HIIT vs MICT During Pregnancy and Health and Birth Outcomes in Mothers and Children

RECRUITING
NCT05009433Phase NAGdansk University of Physical Education and SportStarted 2021-06-24
High intensity interval training program for pregnant womenModerate intensity continuous training program for pregnant womenStandard obstetric care with extended education on healthy lifestyle
Parkinson DiseaseNervous System DisorderNeurodegenerative Diseases

Molecular and Functional Imaging in Monogenic PD.

RECRUITING
NCT05518617University of ExeterStarted 2022-07-01
Positron Emission Tomography (PET) scan using DASB tracer
Clinical Literature
Landmark / reviewRecent case evidence
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Escitalopram Oxalate Improved Insomnia by Targeting SLC6A4 to Regulate the Hypothalamic-Pituitary-Adrenal Axis.
Gu X et al.·Pharmacology
2026
ASSESSMENT OF THE IMTACT OF STRESS FACTORS AND VARIANTS OF POLYMORPHISM OF THE 5-HTTLPR GENE OF THE SEROTONIN TRANSPORTER (SLC6A4) ON ANXIETY IN CHILDREN IN WAR CONDITIONS.
Vdovenko VY et al.·Probl Radiac Med Radiobiol
2025
Prematurity and Epigenetic Regulation of SLC6A4: Longitudinal Insights from Birth to the First Month of Life.
Brasil AA et al.·Biomedicines
2025Open AccessNatural history
DNA Methylation of SLC6A4 and NR3C1 in Term and Preterm Infants: A Pilot Study of NICU-Associated Stress.
Malin KJ et al.·Biol Res Nurs
2026
[Effect of electroacupuncture at "Hegu" (LI4) and "Taichong" (LR3) on DNA methylation of the SLC6A4 gene promoter in the hippocampus of depressed rats].
Zhang X et al.·Zhongguo Zhen Jiu
2025
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients