DNM1L

Chr 12ADAR

dynamin 1 like

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

NCBI Gene: 10059ENSG00000087470UniProt: O00429

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]

Primary Disease Associations & Inheritance

Encephalopathy, lethal, due to defective mitochondrial peroxisomal fission 1MIM #614388
ADAR
Optic atrophy 5MIM #610708
AD
UniProtEncephalopathy due to defective mitochondrial and peroxisomal fission 1
681
ClinVar variants
75
Pathogenic / LP
0.00
pLI score
0
Active trials
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
75 Pathogenic / Likely Pathogenic· 254 VUS of 681 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Missense constrained — critical functional residues
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
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?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
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?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.32 (0.21–0.51)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.46 (0.41–0.52)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.97
0≤1.21.6
LoF obs/exp: 14 / 43.3Missense obs/exp: 187 / 403.4Syn Z: 0.26

ClinVar Variant Classifications

681 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic47
Likely Pathogenic28
VUS254
Likely Benign301
Benign33
Conflicting18
47
Pathogenic
28
Likely Pathogenic
254
VUS
301
Likely Benign
33
Benign
18
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
9
8
30
0
47
Likely Pathogenic
8
14
6
0
28
VUS
3
217
34
0
254
Likely Benign
1
1
173
126
301
Benign
0
1
30
2
33
Conflicting
—18
Total21241273128681

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

View in ClinVar →

Protein Context — Lollipop Plot

DNM1L · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

DNM1L-related developmental disorder

strong
ADUndeterminedAltered Gene Product Structure
Dev. Disorders
G2P ↗
missense variantinframe deletioninframe insertion

DNM1L-related optic atrophy

strong
ADDominant NegativeAltered Gene Product Structure
Eye
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
DYNAMIN 1-LIKE; DNM1L
MIM #603850 · *

Encephalopathy, lethal, due to defective mitochondrial peroxisomal fission 1

MIM #614388

Molecular basis of disorder known

Autosomal dominantAutosomal recessive

Optic atrophy 5

MIM #610708

Molecular basis of disorder known

Autosomal dominant
📖
GeneReview available — DNM1L
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Targeting DNM1L/DRP1-FIS1 axis inhibits high-grade glioma progression by impeding mitochondrial respiratory cristae remodeling.
Li X et al.·J Exp Clin Cancer Res
2024Functional
The NLRX1-SLC39A7 complex orchestrates mitochondrial dynamics and mitophagy to rejuvenate intervertebral disc by modulating mitochondrial Zn(2+) trafficking.
Song Y et al.·Autophagy
2024
Recurrent De Novo and Biallelic Variation of ATAD3A, Encoding a Mitochondrial Membrane Protein, Results in Distinct Neurological Syndromes.
Harel T et al.·Am J Hum Genet
2016
De Novo DNM1L Pathogenic Variant Associated with Lethal Encephalocardiomyopathy-Case Report and Literature Review.
Magistrati M et al.·Int J Mol Sci
2025Review
BCL2L13 promotes mitophagy through DNM1L-mediated mitochondrial fission in glioblastoma.
Wang J et al.·Cell Death Dis
2023
A novel variant of DNM1L expanding the clinical phenotypic spectrum: a case report and literature review.
Zhang Z et al.·BMC Pediatr
2024Review
De Novo DNM1L Variant in a Teenager With Progressive Paroxysmal Dystonia and Lethal Super-refractory Myoclonic Status Epilepticus.
Ryan CS et al.·J Child Neurol
2018Review
Genetic Variants That Impact Alternative Polyadenylation in Cancer Represent Candidate Causal Risk Loci.
Li B et al.·Cancer Res
2023
[DNM1L gene variant caused encephalopathy, lethal, due to defective mitochondrial peroxisomal fission 1: three cases report and literature review].
Pan Z et al.·Zhonghua Er Ke Za Zhi
2021Review
Deubiquitination of DNM1L by USP3 triggers the development and metastasis of gallbladder carcinoma.
Liang R et al.·Biol Direct
2025
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools