Is DNA2 c.441+1G>A pathogenic?

DNA2 c.441+1G>A is classified Likely pathogenic in DNA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-15). Very rare (popmax 0.00136%, afr); Associated with mitochondrial DNA deletion syndrome with progressive myopathy.

What condition is associated with DNA2 c.441+1G>A?

DNA2 c.441+1G>A is associated with mitochondrial DNA deletion syndrome with progressive myopathy (ClinVar).

How common is DNA2 c.441+1G>A in the general population?

DNA2 c.441+1G>A is very rare (popmax 0.00136%, afr) (gnomAD).

DNA2 c.441+1G>A

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

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

VCV4531504

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

canonical splice-site (±1/±2)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00136%, afr)

Conditions

mitochondrial DNA deletion syndrome with progressive myopathy

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Consequence	canonical splice-site (±1/±2)	predicted loss-of-function
Splicing
Splice region	donor +1	canonical splice dinucleotide (donor +1) · inside the BP7-excluded zone
SpliceAI	Δ0.98	donor loss · deltas
Pangolin	Δ0.87	loss · gain 0.23 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 7.4	GERP 1.6, phastCons 1
Non-coding constraint	Z 1.69	1 kb window · o/e 0.87 · regional · uncalibrated
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00136% African / African-American · 1/73,540 alleles

Filtering AF 0.000127% ClinGen BA1/BS1 input FAF95, joint · FAF99 9.2e-05%

Overall 0.000384% 6/1,562,178 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00136%	73,540
European (non-Finnish)	0.000433%	230,995

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
Coding: c.441+1G>A
MANE Select: NM_001080449
Type: single nucleotide variant
Location: chr10:68468122 (GRCh38)
Gene constraint: LOEUF 1.115 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.82 · 1 PDB

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

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

Inheritance: Autosomal dominant
Onset: All ages

Similar variants

DNA2 p.Ser640Leu Likely pathogenic ★★ ⚠ 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
DNA2 p.Asn550Ser Benign/Likely benign ★★ same condition
DNA2 p.Leu99= Benign/Likely 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-c-441-plus-1g-a (accessed [today's date]).

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