Is DNA2 p.Pro296= (c.888G>A) pathogenic?

DNA2 p.Pro296= (c.888G>A) is classified Benign/Likely benign in DNA2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-01-27). Low-frequency (popmax 4.08%, afr); Associated with mitochondrial DNA deletion syndrome with progressive myopathy.

How common is DNA2 p.Pro296= (c.888G>A) in the general population?

DNA2 p.Pro296= (c.888G>A) is low-frequency (popmax 4.08%, afr) (gnomAD).

DNA2 p.Pro296=

Q: What condition is associated with DNA2 p.Pro296= (c.888G>A)?

DNA2 p.Pro296= (c.888G>A) is associated with mitochondrial DNA deletion syndrome with progressive myopathy, Seckel syndrome 8 (ClinVar).

Q: How is DNA2-related mitochondrial DNA deletion syndrome inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

c.888G>A · rs16925390 · VCV381847

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

low-frequency (popmax 4.08%, afr)

Conditions

mitochondrial DNA deletion syndrome with progressive myopathy

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -6.5	GERP -2.6
Overall
CADD	4.414	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 4.08% African / African-American · 3,055/74,796 alleles

Filtering AF 3.96% ClinGen BA1/BS1 input FAF95, joint · FAF99 3.91%

Overall 0.227% 3,629/1,601,790 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	4.08%	24
Admixed American	0.314%	318
Remaining individualsnot grpmax-eligible	0.304%	328
Middle Eastern	0.265%	378
European (non-Finnish)	0.0155%	6,447
Ashkenazi Jewishnot grpmax-eligible	0.00341%	29,310
South Asian	0.00335%	29,815
Finnishnot grpmax-eligible	0.00158%	63,214

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: DNA2
Protein: p.Pro296=
Coding: c.888G>A
MANE Select: NM_001080449
dbSNP: rs16925390
Type: single nucleotide variant
Location: chr10:68450079 (GRCh38)
Gene constraint: LOEUF 1.115 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.82 · 1 PDB
Residue 296: the 'nuclease activity' region

Full DNA2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

mitochondrial DNA deletion syndrome with progressive myopathy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Seckel syndrome 8

For DNA2-related mitochondrial DNA deletion syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: All ages

Similar variants

DNA2 p.Pro296Leu Uncertain significance ★ ⚠ same residue
DNA2 p.Ser640Leu Likely pathogenic ★★ ⚠ same condition
DNA2 p.Asn306Tyr Uncertain significance ★★ ⚠ same condition
DNA2 p.Leu1020Pro Uncertain significance ★★ ⚠ same condition
DNA2 p.Ser477Cys Uncertain significance ★★ ⚠ same condition
DNA2 p.Tyr405His Uncertain significance ★★ ⚠ same condition
DNA2 p.Val637Ile Uncertain significance ★★ ⚠ same condition
DNA2 p.Ala169= Benign ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/dna2-p-pro296 (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown