Is DNA2 p.Ala169= (c.507C>A) pathogenic?

DNA2 p.Ala169= (c.507C>A) is classified Benign in DNA2 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-02-04). Common (popmax 42.4%, afr) — too common for a highly-penetrant pathogenic allele; Associated with Seckel syndrome 8.

What condition is associated with DNA2 p.Ala169= (c.507C>A)?

DNA2 p.Ala169= (c.507C>A) is associated with Seckel syndrome 8, mitochondrial DNA deletion syndrome with progressive myopathy (ClinVar).

DNA2 p.Ala169=

Q: How common is DNA2 p.Ala169= (c.507C>A) in the general population?

DNA2 p.Ala169= (c.507C>A) is common (popmax 42.4%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.507C>A · rs3758626 · VCV257346

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

gnomAD v4.1

Common

common (popmax 42.4%, afr) — too common for a highly-penetrant pathogenic allele

Conditions

Seckel syndrome 8

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 -0.18	GERP -2.1, phastCons 0.001
Overall
CADD	6.075	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 42.4% African / African-American · 31,571/74,528 alleles

Filtering AF 42% ClinGen BA1/BS1 input FAF95, joint · FAF99 41.8%

Overall 23.9% 383,644/1,604,186 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	42.4%	2
East Asian	41.6%	2
South Asian	37.3%	3
Admixed American	33.6%	3
Middle Eastern	32.9%	3
Finnishnot grpmax-eligible	27.1%	4
Remaining individualsnot grpmax-eligible	25.5%	4
Amishnot grpmax-eligible	22%	5
Ashkenazi Jewishnot grpmax-eligible	21.6%	5
European (non-Finnish)	20.3%	5

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.Ala169=
Coding: c.507C>A
MANE Select: NM_001080449
dbSNP: rs3758626
Type: single nucleotide variant
Location: chr10:68465747 (GRCh38)
Gene constraint: LOEUF 1.115 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.82 · 1 PDB
Residue 169: the 'nuclease activity' region

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

Disease context

Seckel syndrome 8 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: mitochondrial DNA deletion syndrome with progressive myopathy

Similar variants

DNA2 p.Ala169Ser 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.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-ala169 (accessed [today's date]).

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