Is DNA2 p.Gln701Glu (c.2101C>G) pathogenic?

DNA2 p.Gln701Glu (c.2101C>G) is classified Uncertain significance in DNA2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-08-07). AlphaMissense: likely benign (0.1013); Ultra-rare (popmax 0.0165%, mid); Associated with Inborn genetic diseases.

What condition is associated with DNA2 p.Gln701Glu (c.2101C>G)?

DNA2 p.Gln701Glu (c.2101C>G) is associated with Inborn genetic diseases (ClinVar).

How common is DNA2 p.Gln701Glu (c.2101C>G) in the general population?

DNA2 p.Gln701Glu (c.2101C>G) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about DNA2 p.Gln701Glu (c.2101C>G)?

AlphaMissense predicts likely benign (score 0.1013) — an in-silico prediction, not a clinical call.

DNA2 p.Gln701Glu

c.2101C>G · rs774205067 · VCV2181420

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1013 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1013	likely benign
REVEL	0.22	benign-leaning
SaProt	LLR -8.23	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.31	acceptor loss, 3 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 9.7	GERP 1.7, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 57 kb · p 0.00015 · regional, not allelic
Overall
CADD	23.2	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 0.0165% Middle Eastern · 1/6,056 alleles

Filtering AF 0.00851% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00667%

Overall 0.00151% 22/1,458,596 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,056
South Asian	0.0144%	6,945
Remaining individualsnot grpmax-eligible	0.00641%	15,598
East Asian	0.00223%	44,840
European (non-Finnish)	0.000255%	392,813

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.Gln701Glu
Coding: c.2101C>G
MANE Select: NM_001080449
dbSNP: rs774205067
Type: single nucleotide variant
Location: chr10:68430543 (GRCh38)
Gene constraint: LOEUF 1.115 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.82 · 1 PDB
Residue 701: 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

Similar variants

DNA2 p.Gln701Arg 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-gln701glu (accessed [today's date]).

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