SLC22A4

Chr 5

solute carrier family 22 member 4

Also known as: DFNB60, ETTh, OCTN1

NCBI Gene: 6583ENSG00000197208UniProt: Q9H015

Polyspecific organic cation transporters in the liver, kidney, intestine, and other organs are critical for elimination of many endogenous small organic cations as well as a wide array of drugs and environmental toxins. The encoded protein is an organic cation transporter and plasma integral membrane protein containing eleven putative transmembrane domains as well as a nucleotide-binding site motif. Transport by this protein is at least partially ATP-dependent. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

{Rheumatoid arthritis, susceptibility to}MIM #180300
203
ClinVar variants
16
Pathogenic / LP
0.00
pLI score
1
Active trials
Clinical Summary— SLC22A4
🧬
Gene-Disease Validity (ClinGen)
hearing loss, autosomal recessive · ARLimited

Limited evidence — not for standalone diagnostic reporting

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
16 Pathogenic / Likely Pathogenic· 97 VUS of 203 total submissions
💊
Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
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.
0.98LOEUF
pLI 0.000
Z-score 1.64
OE 0.64 (0.43–0.98)
Tolerant

Typical tolerance to LoF variation

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.
0.85Z-score
OE missense 0.86 (0.78–0.95)
259 obs / 300.6 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.0.64 (0.43–0.98)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.86 (0.78–0.95)
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.1.13
0≤1.21.6
LoF obs/exp: 16 / 24.8Missense obs/exp: 259 / 300.6Syn Z: -1.11

ClinVar Variant Classifications

203 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic15
Likely Pathogenic1
VUS97
Likely Benign63
Benign25
Conflicting2
15
Pathogenic
1
Likely Pathogenic
97
VUS
63
Likely Benign
25
Benign
2
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
15
0
15
Likely Pathogenic
0
0
1
0
1
VUS
3
87
7
0
97
Likely Benign
0
2
15
46
63
Benign
0
4
15
6
25
Conflicting
—2
Total3935352203

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

View in ClinVar →

Protein Context — Lollipop Plot

SLC22A4 · protein map & ClinVar variants

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

{Rheumatoid arthritis, susceptibility to}

MIM #180300

Molecular basis of disorder known

Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Pharmacological and pathophysiological roles of carnitine/organic cation transporters (OCTNs: SLC22A4, SLC22A5 and Slc22a21).
Tamai I·Biopharm Drug Dispos
2013Review
The Human OCTN Sub-Family: Gene and Protein Structure, Expression, and Regulation.
Galluccio M et al.·Int J Mol Sci
2024Review
The potential therapeutic effects of ergothioneine in pre-eclampsia.
Kerley RN et al.·Free Radic Biol Med
2018Review
Genes, diet and inflammatory bowel disease.
Ferguson LR et al.·Mutat Res
2007Review
Relationship between CARD15, SLC22A4/5, and DLG5 polymorphisms and early-onset inflammatory bowel diseases: an Italian multicentric study.
Ferraris A et al.·Inflamm Bowel Dis
2006
DNA Methylation-Based Epigenetic Repression of SLC22A4 Promotes Resistance to Cytarabine in Acute Myeloid Leukemia.
Buelow DR et al.·Clin Transl Sci
2021
Novel pathogenic mutations and further evidence for clinical relevance of genes and variants causing hearing impairment in Tunisian population.
Souissi A et al.·J Adv Res
2021
Genetic progress towards the molecular basis of autoimmunity.
Pearce SH et al.·Trends Mol Med
2006Review
SLC22A4, RUNX1, and SUMO4 polymorphisms are not associated with rheumatoid arthritis: a case-control study in a Spanish population.
Orozco G et al.·J Rheumatol
2006
Role of SLC22A4, SLC22A5, and RUNX1 genes in rheumatoid arthritis.
Martínez A et al.·J Rheumatol
2006
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Chronic Myeloid Leukemia, Chronic PhaseWithdrawal;Drug

Efficacy and Safety of TKIs' Withdrawal After a Two-step Dose Reduction in Patients with Chronic Myeloid Leukemia

ACTIVE NOT RECRUITING
NCT04147533Phase PHASE2Masaryk UniversityStarted 2020-06-16
Imatinib withdrawalDasatinibNilotinib

External Resources

Links to major genomics databases and tools