LONP1

Chr 19AR

lon peptidase 1, mitochondrial

Also known as: CODASS, LON, LONP, LonHS, PIM1, PRSS15, hLON

NCBI Gene: 9361 ENSG00000196365 UniProt: P36776 OMIM: 605490

This gene encodes an ATP-dependent serine protease in the mitochondrial matrix that degrades misfolded, damaged, or short-lived regulatory proteins and participates in mitochondrial gene expression regulation and genome maintenance. Biallelic mutations cause CODAS syndrome, an autosomal recessive disorder characterized by cerebral, ocular, dental, auricular, and skeletal abnormalities. The gene is highly constrained against loss-of-function variants (pLI 0.999, LOEUF 0.244), indicating that heterozygous loss-of-function mutations are likely not tolerated.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a mitochondrial matrix protein that belongs to the Lon family of ATP-dependent proteases. This protein mediates the selective degradation of misfolded, unassembled or oxidatively damaged polypeptides in the mitochondrial matrix. It may also have a chaperone function in the assembly of inner membrane protein complexes, and participate in the regulation of mitochondrial gene expression and maintenance of the integrity of the mitochondrial genome. Decreased expression of this gene has been noted in a patient with hereditary spastic paraplegia (PMID:18378094). Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Feb 2013]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 0.241 OMIM phenotype

Clinical Summary— LONP1

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Gene-Disease Validity (ClinGen)

Leigh syndrome · ARLimited

Limited evidence — not for standalone diagnostic reporting

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

25 unique Pathogenic / Likely Pathogenic· 396 VUS of 1173 total submissions

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GeneReview available — LONP1

Authoritative clinical overview · Recommended first read

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.24LOEUF

pLI 0.999

Z-score 5.37

OE 0.12 (0.06–0.24)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

0.43Z-score

OE missense 0.95 (0.89–1.02)

605 obs / 635.4 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.12 (0.06–0.24)

0≤0.351.4

Missense OE?0.95 (0.89–1.02)

0≤0.61.4

Synonymous OE?1.35

0≤1.21.6

LoF obs/exp: 5 / 43.0Missense obs/exp: 605 / 635.4Syn Z: -4.80

ClinVar Variant Classifications

1173 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic10

Likely Pathogenic15

VUS396

Likely Benign549

Benign87

Conflicting95

Pathogenic

Likely Pathogenic

396

VUS

549

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	6	4	0	0	10
Likely Pathogenic	10	5	0	0	15
VUS	10	358	26	2	396
Likely Benign	1	86	177	285	549
Benign	0	12	40	35	87
Conflicting	—				95
Total	27	465	243	322	1,152

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

View in ClinVar →

7 pathogenic / likely-pathogenic (of 15) ClinVar copy-number / structural variants overlap LONP1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →