DNA2

Chr 10ADAR

DNA replication helicase/nuclease 2

Also known as: DNA2L, RTS4, hDNA2

NCBI Gene: 1763 ENSG00000138346 UniProt: P51530 OMIM: 601810

The protein functions as a conserved helicase/nuclease that maintains mitochondrial and nuclear DNA stability. Mutations cause autosomal dominant progressive external ophthalmoplegia with mitochondrial DNA deletions (PEOA6) and autosomal recessive conditions including Seckel syndrome 8 and Rothmund-Thomson syndrome type 4. The pathogenic mechanism involves impaired DNA maintenance leading to mitochondrial DNA instability in the dominant form and broader DNA repair defects in the recessive disorders.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a member of the DNA2/NAM7 helicase family. The encoded protein is a conserved helicase/nuclease involved in the maintenance of mitochondrial and nuclear DNA stability. Mutations in this gene are associated with autosomal dominant progressive external ophthalmoplegia-6 (PEOA6) and Seckel syndrome 8. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Sep 2014]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 6MIM #615156

Rothmund-Thomson syndrome, type 4MIM #620819

Seckel syndrome 8MIM #615807

Clinical highlights

Gene–disease validity (ClinGen)

Moderate · mitochondrial disease · AD · ClinGen 2026

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.93

LOEUF

Multiple*

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.93LOEUF

pLI 0.000

Z-score 1.97

OE 0.70 (0.54–0.93)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.74Z-score

OE missense 0.91 (0.85–0.98)

524 obs / 573.6 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.70 (0.54–0.93)

0≤0.351.4

Missense OE?0.91 (0.85–0.98)

0≤0.61.4

Synonymous OE?0.96

0≤1.21.6

LoF obs/exp: 36 / 51.3Missense obs/exp: 524 / 573.6Syn Z: 0.47

Background carrier burden — how many people carry a rare variant somewhere in DNA2?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 48

1,266 rare PASS variants

Rare truncating (LoF)

1 in 300

224 rare PASS variants

Rare synonymous (reference)

1 in 110

411 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for DNA2. 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 71	1 in 640
South Asian	~43k	1 in 41	1 in 310
Remaining (unassigned)	~30k	1 in 60	1 in 270
European (Finnish)	~27k	1 in 81	1 in 460
Admixed American	~22k	1 in 58	1 in 310
African / African American	~21k	1 in 41	1 in 310
East Asian	~20k	1 in 75	1 in 420
Ashkenazi Jewish	~13k	1 in 200	1 in 770
Middle Eastern	~2,884	1 in 55	1 in 350

Each group is summed over the variants that are rare in that group. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 19 of 21 coding exons well covered in gnomAD exomes; exons 11, 21 marginal. Genomes: all 21.? see exons ↓