KMO

Chr 1

kynurenine 3-monooxygenase

Also known as: dJ317G22.1

NCBI Gene: 8564 ENSG00000117009 UniProt: O15229 OMIM: 603538

The KMO protein is a mitochondrial outer membrane enzyme that catalyzes the hydroxylation of L-kynurenine to form 3-hydroxy-L-kynurenine, which is required for synthesis of quinolinic acid, a neurotoxic compound that affects NMDA receptor signaling during brain development. Mutations cause autosomal recessive developmental delay and seizures, with the gene being loss-of-function intolerant (pLI near 0, LOEUF 0.698). The phenotype involves neurological manifestations affecting brain development, with potential effects on other organ systems including pancreatic, cardiac, and gastrointestinal function.

GeneReviews OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a mitochondrion outer membrane protein that catalyzes the hydroxylation of L-tryptophan metabolite, L-kynurenine, to form L-3-hydroxykynurenine. Studies in yeast identified this gene as a therapeutic target for Huntington disease. [provided by RefSeq, Oct 2011]

GeneReviews OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.70

Clinical Summary— KMO

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Gene-Disease Validity (ClinGen)

pellagra · ARNo Known Disease Relationship

No known disease relationship

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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

50 VUS of 68 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 — KMO

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?

0.70LOEUF

pLI 0.000

Z-score 2.79

OE 0.43 (0.28–0.70)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.83Z-score

OE missense 0.68 (0.60–0.77)

180 obs / 263.4 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.43 (0.28–0.70)

0≤0.351.4

Missense OE?0.68 (0.60–0.77)

0≤0.61.4

Synonymous OE?1.19

0≤1.21.6

LoF obs/exp: 12 / 27.9Missense obs/exp: 180 / 263.4Syn Z: -1.40

This gene — mechanism propensity

0.81top 10%

GOF

0.6444th %ile

LOF

0.2288th %ile

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

DNprediction above median

GOFprediction 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

68 submitted variants in ClinVar

ClinVar

Classification Summary

VUS50

Likely Benign6

Benign3

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	2	48	0	0	50
Likely Benign	0	6	0	0	6
Benign	0	1	1	1	3
Total	2	55	1	1	59

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

View in ClinVar →

64 pathogenic / likely-pathogenic (of 86) ClinVar copy-number / structural variants overlap KMO — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →