SLC25A15

Chr 13AR

solute carrier family 25 member 15

Also known as: D13S327, HHH, LNC-HC, ORC1, ORNT1

NCBI Gene: 10166 ENSG00000102743 UniProt: Q9Y619 OMIM: 603861

The encoded protein transports ornithine across the inner mitochondrial membrane and is essential for the urea cycle, functioning in ammonium detoxification and arginine biosynthesis. Mutations cause hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome through autosomal recessive inheritance. The pathogenic mechanism involves dominant negative effects that disrupt normal mitochondrial ornithine transport.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene is a member of the mitochondrial carrier family. The encoded protein transports ornithine across the inner mitochondrial membrane from the cytosol to the mitochondrial matrix. The protein is an essential component of the urea cycle, and functions in ammonium detoxification and biosynthesis of the amino acid arginine. Mutations in this gene result in hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome. There is a pseudogene of this locus on the Y chromosome.[provided by RefSeq, May 2009]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 1.381 OMIM phenotype

Clinical Summary— SLC25A15

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Gene-Disease Validity (ClinGen)

ornithine translocase deficiency · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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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

89 unique Pathogenic / Likely Pathogenic· 161 VUS of 510 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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GeneReview available — SLC25A15

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.38LOEUF

pLI 0.000

Z-score 0.56

OE 0.83 (0.52–1.38)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.10Z-score

OE missense 0.98 (0.86–1.11)

160 obs / 163.6 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.83 (0.52–1.38)

0≤0.351.4

Missense OE?0.98 (0.86–1.11)

0≤0.61.4

Synonymous OE?1.09

0≤1.21.6

LoF obs/exp: 11 / 13.2Missense obs/exp: 160 / 163.6Syn Z: -0.56

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveSLC25A15-related hyperornithinemia-hyperammonemia-homocitrullinuria syndromeLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.79top 25%

GOF

0.6541th %ile

LOF

0.2970th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

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

ClinVar Variant Classifications

510 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic29

Likely Pathogenic60

VUS161

Likely Benign198

Benign41

Conflicting15

Pathogenic

Likely Pathogenic

161

VUS

198

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	21	2	6	0	29
Likely Pathogenic	44	16	0	0	60
VUS	1	101	55	4	161
Likely Benign	0	3	82	113	198
Benign	0	2	37	2	41
Conflicting	—				15
Total	66	124	180	119	504

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

View in ClinVar →

47 pathogenic / likely-pathogenic (of 54) ClinVar copy-number / structural variants overlap SLC25A15 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →