Is DNA2 p.Arg698His (c.2093G>A) pathogenic?

DNA2 p.Arg698His (c.2093G>A) is classified Uncertain significance in DNA2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-12). AlphaMissense: likely pathogenic (0.8659); Very rare (popmax 0.00446%, eas); Associated with Inborn genetic diseases.

What condition is associated with DNA2 p.Arg698His (c.2093G>A)?

DNA2 p.Arg698His (c.2093G>A) is associated with Inborn genetic diseases (ClinVar).

How common is DNA2 p.Arg698His (c.2093G>A) in the general population?

DNA2 p.Arg698His (c.2093G>A) is very rare (popmax 0.00446%, eas) (gnomAD).

What do computational predictors say about DNA2 p.Arg698His (c.2093G>A)?

AlphaMissense predicts likely pathogenic (score 0.8659) — an in-silico prediction, not a clinical call.

DNA2 p.Arg698His

c.2093G>A · rs367905585 · VCV1312785

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.8659 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.8659	likely pathogenic
REVEL	0.917	moderately pathogenic-leaning
SaProt	LLR -8.64	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.30 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.6	GERP 1.7, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 57 kb · p 0.00015 · regional, not allelic
Overall
CADD	33.0	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

Grpmax group 0.00446% East Asian · 2/44,834 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000788%

Overall 0.00174% 28/1,609,896 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.00678%	14,742
East Asiangrpmax	0.00446%	22,417
African / African-American	0.00401%	24,953
Remaining individualsnot grpmax-eligible	0.00321%	31,179
Finnishnot grpmax-eligible	0.00157%	63,880
European (non-Finnish)	0.00153%	65,447

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg698His
Coding: c.2093G>A
MANE Select: NM_001080449
dbSNP: rs367905585
Type: single nucleotide variant
Location: chr10:68430551 (GRCh38)
Gene constraint: LOEUF 1.115 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.82 · 1 PDB
Residue 698: the upf1-type sf1b helicase atp-binding domain; the 'helicase activity' region

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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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-arg698his (accessed [today's date]).

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