DNM1L

Chr 12ADAR

dynamin 1L

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…

Primary Disease Associations & Inheritance

Encephalopathy, lethal, due to defective mitochondrial peroxisomal fission 1MIM #614388

ADAR

Optic atrophy 5MIM #610708

UniProtEncephalopathy due to defective mitochondrial and peroxisomal fission 1

Clinical highlights

Gene–disease validity (ClinGen)

Interpreting a novel variant

A dominant-negative effect is the curated mechanism (Gene2Phenotype), so a variant that simply removes the protein may not be the pathogenic class here — missense variants in functional domains often carry more weight.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.51

LOEUF

Mechanism· G2P

📖

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

Background carrier burden — how many people carry a rare variant somewhere in DNM1L?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 150

545 rare PASS variants

Rare truncating (LoF)

1 in 3,000

94 rare PASS variants

Rare synonymous (reference)

1 in 340

297 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for DNM1L. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 140	1 in 3,400
South Asian	~43k	1 in 190	1 in 940
Remaining (unassigned)	~30k	1 in 140	≈ 1 in 10,000
European (Finnish)	~27k	1 in 340	1 in 4,400
Admixed American	~22k	1 in 100	1 in 1,400
African / African American	~21k	1 in 160	1 in 1,600
East Asian	~20k	1 in 200	1 in 4,000
Ashkenazi Jewish	~13k	1 in 450	≈ 1 in 6,500
Middle Eastern	~2,884	1 in 260	≈ 1 in 2,900

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 19 of 20 coding exons well covered in gnomAD exomes; exon 4 marginal. Genomes: all 20.? see exons ↓