SLC22A4

protein-coding

solute carrier family 22 member 4, the group of Solute carrier family 22

Gene summary

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]

Previous symbols:

DFNB60

MANE transcript

NM_003059.3

Inheritance

ClinVar variants

P:1U:102B:58

Top phenotype

SLC22A4-related disorder

gnomAD constraint

pLI —, LoF o/e 0.64

Max pathogenic AF

—

Genomic locus

chr5:132,294,394-132,344,190

External References & Databases

Ensembl (ENSG00000197208)

Transcript & Mutation Effects

hg38 • Region Span ~49.8 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

hearing loss, autosomal recessiveLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0019588

Submitter: ClinGen

SLC22A4 was first reported in relation to autosomal recessive nonsyndromic hearing loss in 2016 (Ben Said et al., PMID: 27023905). 1 recurrent variant (missense, p.Cys113Tyr) that has been reported in at least 3 probands in 3 publications is included in this curation. The variant segregated with disease in 5 members from 1 family (PMIDs: 27023905, 33643381, 34194829). The mechanism of pathogenicity appears to be loss-of-function based on in-vitro studies looking at channel function for p.Cys113Tyr (PMID: 27023905). This gene-disease relationship is also supported by experimental evidence. Expression-level data from the gEAR database indicates solid expression in the cochlear duct and pillar cells in the organ of Corti. In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen Hearing Loss GCEP on the meeting date 9/17/2025 (SOP Version 11).

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SLC22A4 variants in ClinVar

5 Conditions Cataloged

not providedTotal: 131

not specifiedTotal: 68

SLC22A4-related disorderTotal: 32

Genetic hearing lossTotal: 1

Primary ciliary dyskinesiaTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_003059.3. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous				49 clinvar	2 clinvar	51
missense			97 clinvar	5 clinvar	2 clinvar	104
nonsense			1 clinvar			1
start loss						0
frameshift	1 clinvar		2 clinvar			3
splice donor/acceptor (+/-2bp)			2 clinvar			2
Total	1	0	102	54	4	161

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 28 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_003059.3	RefSeq	NP_003050.2	10	MANE Select
ENST00000200652.4	Ensembl	ENSP00000200652.3	10	MANE Select
ENST00000897522.1	Ensembl	ENSP00000567581.1	6	Standard
ENST00000897522.2	Ensembl	ENSP00000567581.1	6	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Choline metabolism in cancer - Homo sapiens (human)
Transport of bile salts and organic acids, metal ions and amine compounds
SLC-mediated transmembrane transport
Transport of small molecules
Organic cation transport

Biological Process

triglyceride metabolic process
sodium ion transport
body fluid secretion
carnitine metabolic process
organic cation transport

Molecular Function

nucleotide binding
protein binding
ATP binding
secondary active organic cation transmembrane transporter activity
carnitine transmembrane transporter activity

Cellular Component

mitochondrion
plasma membrane
integral component of plasma membrane
apical plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000200652
Coding exons: 10
Length: 49764
Individuals with no LoFs: 125651
Homozygous LoFs: 0
Heterozygous LoFs: 97
Defined: 125748
p: 0.000386

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.852	259	301	0.862	0.0000158	3553
Missense (PolyPhen)		57	65.647	0.86828		800
Synonymous	-1.11	140	124	1.13	0.00000678	1162
Loss of Function	1.64	16	24.8	0.644	0.00000126	266

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00057	0.00055	rare
Latino/Admixed American	0.00029	0.00029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00065	0.00065	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.00029	0.00029	rare
South Asian	0.00091	0.00091	rare
Other	0.00065	0.00065	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Sodium-ion dependent, low affinity carnitine transporter. Probably transports one sodium ion with one molecule of carnitine. Also transports organic cations such as tetraethylammonium (TEA) without the involvement of sodium. Relative uptake activity ratio of carnitine to TEA is 1.78. A key substrate of this transporter seems to be ergothioneine (ET). {ECO:0000269|PubMed:10215651, ECO:0000269|PubMed:15795384}.;
Disease: DISEASE: Rheumatoid arthritis (RA) [MIM:180300]: An inflammatory disease with autoimmune features and a complex genetic component. It primarily affects the joints and is characterized by inflammatory changes in the synovial membranes and articular structures, widespread fibrinoid degeneration of the collagen fibers in mesenchymal tissues, and by atrophy and rarefaction of bony structures. {ECO:0000269|PubMed:14608356}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.102

Intolerance Scores

LoFtool: 0.538
RVIS EVS: -0.71
RVIS percentile EVS: 14.57

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.0217

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium