Is DNA2 p.Arg135Ter (c.403C>T) pathogenic?

DNA2 p.Arg135Ter (c.403C>T) is classified Uncertain significance in DNA2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-15). Very rare (popmax 0.00402%, afr).

How common is DNA2 p.Arg135Ter (c.403C>T) in the general population?

DNA2 p.Arg135Ter (c.403C>T) is very rare (popmax 0.00402%, afr) (gnomAD).

DNA2 p.Arg135Ter

c.403C>T · rs769474497 · VCV1700533

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00402%, afr)

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 3 of 21
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 8.3	GERP 1.6, 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 0.00402% African / African-American · 3/74,700 alleles

Filtering AF 0.00107% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000496%

Overall 0.000809% 13/1,606,396 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00402%	24,900
European (non-Finnish)	0.00085%	117,716

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.Arg135Ter
Coding: c.403C>T
MANE Select: NM_001080449
dbSNP: rs769474497
Type: single nucleotide variant
Location: chr10:68468161 (GRCh38)
Gene constraint: LOEUF 1.115 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.82 · 1 PDB
Residue 135: the 'nuclease activity' region

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

Similar variants

DNA2 p.Arg135Gln Uncertain significance ★★ ⚠ same residue
DNA2 p.Arg135Pro 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

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-arg135ter (accessed [today's date]).

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