Is DNA2 p.Ile387Ser (c.1160T>G) pathogenic?

DNA2 p.Ile387Ser (c.1160T>G) is classified Uncertain significance in DNA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-21). AlphaMissense: likely benign (0.1549); Absent from gnomAD v4.1; Associated with mitochondrial DNA deletion syndrome with progressive myopathy.

What condition is associated with DNA2 p.Ile387Ser (c.1160T>G)?

DNA2 p.Ile387Ser (c.1160T>G) is associated with mitochondrial DNA deletion syndrome with progressive myopathy (ClinVar).

How common is DNA2 p.Ile387Ser (c.1160T>G) in the general population?

DNA2 p.Ile387Ser (c.1160T>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about DNA2 p.Ile387Ser (c.1160T>G)?

AlphaMissense predicts likely benign (score 0.1549) — an in-silico prediction, not a clinical call.

DNA2 p.Ile387Ser

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.1160T>G · VCV4854731

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1549 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

mitochondrial DNA deletion syndrome with progressive myopathy

Computational evidence

Protein change
AlphaMissense	0.1549	likely benign
REVEL	0.763	pathogenic-leaning
SaProt	LLR -9.27	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.5	GERP -1.1, phastCons 0.99
Regional constraint	o/e 0.89	unconstrained · MANE · 57 kb · p 0.00015 · regional, not allelic
Overall
CADD	23.4	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: DNA2
Protein: p.Ile387Ser
Coding: c.1160T>G
MANE Select: NM_001080449
Type: single nucleotide variant
Location: chr10:68444981 (GRCh38)
Gene constraint: LOEUF 1.115 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.82 · 1 PDB
Residue 387: 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

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

Inheritance: Autosomal dominant
Onset: All ages

Similar variants

DNA2 p.Ile387Thr Uncertain significance ★ ⚠ same residue
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

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-ile387ser (accessed [today's date]).

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