DNM1L

Chr 12ADAR

dynamin 1 like

Also known as: DLP1, DRP1, DVLP, DYMPLE, EMPF, EMPF1, HDYNIV, OPA5

NCBI Gene: 10059 ENSG00000087470 UniProt: O00429 OMIM: 603850

The protein mediates mitochondrial and peroxisomal division through its GTPase activity and regulates developmentally programmed cell death. Mutations cause lethal encephalopathy due to defective mitochondrial and peroxisomal fission and optic atrophy 5, inherited in both autosomal dominant and autosomal recessive patterns. The pathogenic mechanism involves dominant-negative effects that disrupt normal organellar fission processes.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene encodes a member of the dynamin superfamily of GTPases. The encoded protein mediates mitochondrial and peroxisomal division, and is involved in developmentally regulated apoptosis and programmed necrosis. Dysfunction of this gene is implicated in several neurological disorders, including Alzheimer's disease. Mutations in this gene are associated with the autosomal dominant disorder, encephalopathy, lethal, due to defective mitochondrial and peroxisomal fission (EMPF). Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jun 2013]

GeneReviews OMIM ResearchGenerating clinical summary…

DNmechanismAD/ARLOEUF 0.512 OMIM phenotypes

Clinical Summary— DNM1L

🧬

Gene-Disease Validity (ClinGen)

Leigh syndrome · ARLimited

Limited evidence — not for standalone diagnostic reporting

3 total gene-disease associations curated

⚡

Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.32) despite low pLI — interpret in context.

📋

ClinVar Variants

68 unique Pathogenic / Likely Pathogenic· 317 VUS of 871 total submissions

Explore recent and relevant literature in Research Assistant →

📖

GeneReview available — DNM1L

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Missense constrained — critical functional residues

LoF Constraint?

0.51LOEUF

pLI 0.001

Z-score 4.13

OE 0.32 (0.21–0.51)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

3.83Z-score

OE missense 0.46 (0.41–0.52)

187 obs / 403.4 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.32 (0.21–0.51)

0≤0.351.4

Missense OE?0.46 (0.41–0.52)

0≤0.61.4

Synonymous OE?0.97

0≤1.21.6

LoF obs/exp: 14 / 43.3Missense obs/exp: 187 / 403.4Syn Z: 0.26

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongDNM1L-related developmental disorderOTHERAD

strongDNM1L-related optic atrophyDNAD

This gene — mechanism propensity

0.77top 25%

GOF

0.6444th %ile

LOF

0.3259th %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 · 1 literature citation

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.

Literature Evidence

DNWe found a defect of the fission of both mitochondria and peroxisomes, as well as a heterozygous, dominant-negative mutation in the dynamin-like protein 1 gene (DLP1).1

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

References

1.PMID 17460227 ↗

ClinVar Variant Classifications

871 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic28

Likely Pathogenic40

VUS317

Likely Benign376

Benign70

Conflicting21

Pathogenic

Likely Pathogenic

317

VUS

376

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	15	10	3	0	28
Likely Pathogenic	12	28	0	0	40
VUS	6	278	31	2	317
Likely Benign	1	3	220	152	376
Benign	0	1	65	4	70
Conflicting	—				21
Total	34	320	319	158	852

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

View in ClinVar →

36 pathogenic / likely-pathogenic (of 47) ClinVar copy-number / structural variants overlap DNM1L — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →