Is DNA2 p.Arg998Gln (c.2993G>A) pathogenic?

DNA2 p.Arg998Gln (c.2993G>A) is classified Uncertain significance in DNA2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-05-18). AlphaMissense: likely benign (0.2848); Very rare (popmax 0.00852%, amr); Associated with Inborn genetic diseases.

What condition is associated with DNA2 p.Arg998Gln (c.2993G>A)?

DNA2 p.Arg998Gln (c.2993G>A) is associated with Inborn genetic diseases (ClinVar).

How common is DNA2 p.Arg998Gln (c.2993G>A) in the general population?

DNA2 p.Arg998Gln (c.2993G>A) is very rare (popmax 0.00852%, amr) (gnomAD).

What do computational predictors say about DNA2 p.Arg998Gln (c.2993G>A)?

AlphaMissense predicts likely benign (score 0.2848) — an in-silico prediction, not a clinical call.

DNA2 p.Arg998Gln

c.2993G>A · rs774025815 · VCV2892939

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2848 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00852%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2848	likely benign
REVEL	0.845	moderately pathogenic-leaning
SaProt	LLR -8.17	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 5.8	GERP 1.2, phastCons 1
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

Grpmax group 0.00852% Admixed American · 5/58,672 alleles

Filtering AF 0.00329% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00211%

Overall 0.00218% 35/1,609,026 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00852%	11,734
South Asian	0.00443%	22,553
European (non-Finnish)	0.00221%	45,311

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.Arg998Gln
Coding: c.2993G>A
MANE Select: NM_001080449
dbSNP: rs774025815
Type: single nucleotide variant
Location: chr10:68416830 (GRCh38)
Gene constraint: LOEUF 1.115 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.82 · 1 PDB
Residue 998: the upf1-type sf1b helicase c-terminal 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

Similar variants

DNA2 p.Arg998Ter Uncertain significance ★ same residue
DNA2 c.2402+1G>A Uncertain significance ★★ same condition
DNA2 p.Ala1003Ser Uncertain significance ★★ ⚠ same condition
DNA2 p.Ala346Val Uncertain significance ★★ ⚠ same condition
DNA2 p.Ala51Val Uncertain significance ★★ ⚠ same condition
DNA2 p.Ala667Ser Uncertain significance ★★ ⚠ same condition
DNA2 p.Ala819Val Uncertain significance ★★ ⚠ same condition
DNA2 p.Ala874Thr Uncertain significance ★★ ⚠ 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-arg998gln (accessed [today's date]).

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