Is DNA2 p.Lys489Arg (c.1466A>G) pathogenic?

DNA2 p.Lys489Arg (c.1466A>G) is classified Uncertain significance in DNA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-29). AlphaMissense: likely benign (0.0717); Very rare (popmax 0.000933%, nfe).

How common is DNA2 p.Lys489Arg (c.1466A>G) in the general population?

DNA2 p.Lys489Arg (c.1466A>G) is very rare (popmax 0.000933%, nfe) (gnomAD).

What do computational predictors say about DNA2 p.Lys489Arg (c.1466A>G)?

AlphaMissense predicts likely benign (score 0.0717) — an in-silico prediction, not a clinical call.

DNA2 p.Lys489Arg

c.1466A>G · VCV3697890

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0717 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000933%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0717	likely benign
REVEL	0.181	moderately benign-leaning
SaProt	LLR -7.61	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.63	donor gain · deltas
Pangolin	Δ0.56	gain · loss 0.02 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 0.38	GERP 0.36
Regional constraint	o/e 0.89	unconstrained · MANE · 57 kb · p 0.00015 · regional, not allelic
Overall
CADD	13.88	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 0.000933% European (non-Finnish) · 11/1,179,344 alleles

Filtering AF 0.000501% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000366%

Overall 0.000682% 11/1,613,196 alleles · very rare

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.Lys489Arg
Coding: c.1466A>G
MANE Select: NM_001080449
Type: single nucleotide variant
Location: chr10:68437191 (GRCh38)
Gene constraint: LOEUF 1.115 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.82 · 1 PDB
Residue 489: the 'nuclease activity' region

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

Similar variants

DNA2 p.Lys489Gln Uncertain significance ★ ⚠ 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-lys489arg (accessed [today's date]).

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