Is DNA2 p.Ile571fs (c.1711dup) pathogenic?

DNA2 p.Ile571fs (c.1711dup) is classified Pathogenic/Likely pathogenic in DNA2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2023-01-13). Very rare (popmax 0.00402%, afr); Associated with Rothmund-Thomson syndrome.

What condition is associated with DNA2 p.Ile571fs (c.1711dup)?

DNA2 p.Ile571fs (c.1711dup) is associated with Rothmund-Thomson syndrome, Rothmund-Thomson syndrome type 4 (ClinVar).

How common is DNA2 p.Ile571fs (c.1711dup) in the general population?

DNA2 p.Ile571fs (c.1711dup) is very rare (popmax 0.00402%, afr) (gnomAD).

How is Rothmund-Thomson syndrome inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

DNA2 p.Ile571fs

c.1711dup · rs1469135249 · VCV1710083

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00402%, afr)

Conditions

Rothmund-Thomson syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 11 of 21
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 5.4	GERP 0.46, phastCons 1
Overall
CADD	29.7	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 · 3/74,546 alleles

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

Overall 0.000188% 3/1,596,288 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.Ile571fs
Coding: c.1711dup
MANE Select: NM_001080449
dbSNP: rs1469135249
Type: Duplication
Location: chr10:68432445 (GRCh38)
Gene constraint: LOEUF 1.115 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.82 · 1 PDB
Residue 571: the 'helicase activity' region

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

Disease context

Rothmund-Thomson syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Rothmund-Thomson syndrome type 4

For Rothmund-Thomson syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

DNA2 p.Ile571Arg Uncertain significance ★ same residue
DNA2 p.Ile571Val Uncertain significance ★ ⚠ same residue
DNA2 c.588-2214A>G Pathogenic/Likely pathogenic ★★ same condition
DNA2 c.2208+2456_2403-18del Pathogenic ★ same condition
DNA2 c.442-768_587+648del Pathogenic ★ same condition
DNA2 p.Leu48Pro Likely pathogenic ★ same condition
DNA2 p.Arg198His Conflicting classifications of pathogenicity ★ ⚠ same condition
DNA2 p.Leu794fs Conflicting classifications of pathogenicity ★ 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-ile571fs (accessed [today's date]).

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