Is DNA2 p.Arg135Pro (c.404G>C) pathogenic?

DNA2 p.Arg135Pro (c.404G>C) is classified Uncertain significance in DNA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-04). AlphaMissense: likely pathogenic (0.7511); Very rare (popmax 0.00676%, sas).

How common is DNA2 p.Arg135Pro (c.404G>C) in the general population?

DNA2 p.Arg135Pro (c.404G>C) is very rare (popmax 0.00676%, sas) (gnomAD).

What do computational predictors say about DNA2 p.Arg135Pro (c.404G>C)?

AlphaMissense predicts likely pathogenic (score 0.7511) — an in-silico prediction, not a clinical call.

DNA2 p.Arg135Pro

c.404G>C · rs764300882 · VCV2092606

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7511 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00676%, sas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7511	likely pathogenic
REVEL	0.888	moderately pathogenic-leaning
SaProt	LLR -6.62	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.4	GERP 1.6, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 57 kb · p 0.00015 · regional, not allelic
Overall
CADD	29.0	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 0.00676% South Asian · 6/88,696 alleles

Filtering AF 0.00293% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00199%

Overall 0.000413% 6/1,454,162 alleles · very rare

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.Arg135Pro
Coding: c.404G>C
MANE Select: NM_001080449
dbSNP: rs764300882
Type: single nucleotide variant
Location: chr10:68468160 (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.Arg135Ter 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-arg135pro (accessed [today's date]).

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