Is DNA2 p.Arg998Ter (c.2992C>T) pathogenic?

DNA2 p.Arg998Ter (c.2992C>T) is classified Uncertain significance in DNA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-31). Ultra-rare (popmax 0.0165%, mid).

How common is DNA2 p.Arg998Ter (c.2992C>T) in the general population?

DNA2 p.Arg998Ter (c.2992C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

DNA2 p.Arg998Ter

c.2992C>T · rs759174372 · VCV2427996

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 20 of 21
REVEL	0.067	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.29	loss · gain 0.01 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 3.4	GERP 0.16, phastCons 1
Overall
CADD	39.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,066 alleles

Filtering AF 0.0024% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0021%

Overall 0.0028% 45/1,609,276 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,066
Remaining individualsnot grpmax-eligible	0.00482%	20,759
European (non-Finnish)	0.00323%	31,006
African / African-American	0.00268%	37,322
East Asian	0.00223%	44,852

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.Arg998Ter
Coding: c.2992C>T
MANE Select: NM_001080449
dbSNP: rs759174372
Type: single nucleotide variant
Location: chr10:68416831 (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

Similar variants

DNA2 p.Arg998Gln 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-arg998ter (accessed [today's date]).

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