Is DNA2 p.Arg198Cys (c.592C>T) pathogenic?

DNA2 p.Arg198Cys (c.592C>T) is classified Uncertain significance in DNA2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-02). AlphaMissense: likely benign (0.0737); Very rare (popmax 0.00492%, sas); Associated with Inborn genetic diseases.

What condition is associated with DNA2 p.Arg198Cys (c.592C>T)?

DNA2 p.Arg198Cys (c.592C>T) is associated with Inborn genetic diseases (ClinVar).

How common is DNA2 p.Arg198Cys (c.592C>T) in the general population?

DNA2 p.Arg198Cys (c.592C>T) is very rare (popmax 0.00492%, sas) (gnomAD).

What do computational predictors say about DNA2 p.Arg198Cys (c.592C>T)?

AlphaMissense predicts likely benign (score 0.0737) — an in-silico prediction, not a clinical call.

DNA2 p.Arg198Cys

c.592C>T · rs376070435 · VCV450350

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0737 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00492%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0737	likely benign
REVEL	0.343	indeterminate
SaProt	LLR -5.72	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.2	GERP 0.68, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 57 kb · p 0.00015 · regional, not allelic
Overall
CADD	23.7	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 0.00492% South Asian · 4/81,308 alleles

Filtering AF 0.00327% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00295%

Overall 0.00376% 58/1,543,698 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00492%	20,327
East Asian	0.0048%	20,855
European (non-Finnish)	0.00428%	23,379
Ashkenazi Jewishnot grpmax-eligible	0.00352%	28,406
Remaining individualsnot grpmax-eligible	0.00336%	29,804

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.Arg198Cys
Coding: c.592C>T
MANE Select: NM_001080449
dbSNP: rs376070435
Type: single nucleotide variant
Location: chr10:68459231 (GRCh38)
Gene constraint: LOEUF 1.115 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.82 · 1 PDB
Residue 198: a UniProt-annotated variant site (in peoa6; uncertain significance; the mutant protein has a complete loss of nuclease activity and severely impaired helicase activity); the 'nuclease 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.Arg198His Conflicting classifications of pathogenicity ★ ⚠ 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-arg198cys (accessed [today's date]).

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