SLC6A18

Chr 5

solute carrier family 6 member 18

Also known as: Xtrp2

NCBI Gene: 348932 ENSG00000164363 UniProt: Q96N87 OMIM: 610300

SLC6A18 encodes a sodium-coupled transporter protein that belongs to the SLC6 family, though it lacks detectable neutral amino acid transporter activity. Mutations cause iminoglycinuria (autosomal recessive), a generally benign condition characterized by excessive urinary excretion of glycine, proline, and hydroxyproline. The gene shows low constraint against loss-of-function variants, consistent with the mild clinical phenotype associated with its dysfunction.

OMIM ResearchSummary from RefSeq, UniProt

The SLC6 family of proteins, which includes SLC6A18, act as specific transporters for neurotransmitters, amino acids, and osmolytes like betaine, taurine, and creatine. SLC6 proteins are sodium cotransporters that derive the energy for solute transport from the electrochemical gradient for sodium ions (Hoglund et al., 2005 [PubMed 16125675]).[supplied by OMIM, Apr 2010]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 1.47

Clinical Summary— SLC6A18

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

120 VUS of 160 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.47LOEUF

pLI 0.000

Z-score -0.42

OE 1.09 (0.81–1.47)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.19Z-score

OE missense 0.97 (0.90–1.06)

395 obs / 406.0 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?1.09 (0.81–1.47)

0≤0.351.4

Missense OE?0.97 (0.90–1.06)

0≤0.61.4

Synonymous OE?0.95

0≤1.21.6

LoF obs/exp: 31 / 28.5Missense obs/exp: 395 / 406.0Syn Z: 0.53

This gene — mechanism propensity

0.7327th %ile

GOF

0.84top 5%

LOF

0.2386th %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

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.

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

ClinVar Variant Classifications

160 submitted variants in ClinVar

ClinVar

Classification Summary

VUS120

Likely Benign21

Benign14

120

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0	0
Likely Pathogenic	0	0	0	0	0
VUS	1	118	1	0	120
Likely Benign	0	18	0	3	21
Benign	0	8	1	5	14
Total	1	144	2	8	155

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

View in ClinVar →

137 pathogenic / likely-pathogenic (of 165) ClinVar copy-number / structural variants overlap SLC6A18 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →