Is DNA2 p.Arg286Gln (c.857G>A) pathogenic?

DNA2 p.Arg286Gln (c.857G>A) is classified Uncertain significance in DNA2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-12). AlphaMissense: likely benign (0.0775); Ultra-rare (popmax 0.0626%, eas).

How common is DNA2 p.Arg286Gln (c.857G>A) in the general population?

DNA2 p.Arg286Gln (c.857G>A) is ultra-rare (popmax 0.0626%, eas) (gnomAD).

What do computational predictors say about DNA2 p.Arg286Gln (c.857G>A)?

AlphaMissense predicts likely benign (score 0.0775) — an in-silico prediction, not a clinical call.

DNA2 p.Arg286Gln

c.857G>A · rs557583178 · VCV1300307

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0775 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0626%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0775	likely benign
REVEL	0.248	benign-leaning
SaProt	LLR -4.14	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.6	GERP -1.7, phastCons 0.95
Regional constraint	o/e 0.89	unconstrained · MANE · 57 kb · p 0.00015 · regional, not allelic
Overall
CADD	14.19	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0626% East Asian · 28/44,730 alleles

Filtering AF 0.0444% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0383%

Overall 0.00299% 48/1,604,422 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0626%	1,598
Admixed American	0.00513%	19,489
Ashkenazi Jewishnot grpmax-eligible	0.00341%	29,312
African / African-American	0.00267%	37,450
South Asian	0.00112%	89,612
European (non-Finnish)	0.00111%	90,370

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.Arg286Gln
Coding: c.857G>A
MANE Select: NM_001080449
dbSNP: rs557583178
Type: single nucleotide variant
Location: chr10:68450110 (GRCh38)
Gene constraint: LOEUF 1.115 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.82 · 1 PDB
Residue 286: the 'nuclease activity' region

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

Similar variants

DNA2 p.Arg286= Likely benign ★ same residue
DNA2 c.588-2214A>G Pathogenic/Likely pathogenic ★★ same type
DNA2 p.Ser640Leu Likely pathogenic ★★ ⚠ same type
DNA2 c.2402+1G>A Uncertain significance ★★ same type
DNA2 c.257+3A>G Uncertain significance ★★ same type
DNA2 p.Ala1003Ser Uncertain significance ★★ ⚠ same type
DNA2 p.Ala221Glu Uncertain significance ★★ ⚠ same type
DNA2 p.Ala346Val Uncertain significance ★★ ⚠ same type

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-arg286gln (accessed [today's date]).

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