Is DNA2 p.Ser779fs (c.2335del) pathogenic?

DNA2 p.Ser779fs (c.2335del) is classified Uncertain significance in DNA2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-05-14). Ultra-rare (popmax 0.06%, amr).

How common is DNA2 p.Ser779fs (c.2335del) in the general population?

DNA2 p.Ser779fs (c.2335del) is ultra-rare (popmax 0.06%, amr) (gnomAD).

DNA2 p.Ser779fs

c.2335del · rs745893364 · VCV2042140

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.06%, amr)

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 15 of 21
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 9.8	GERP 1.7, phastCons 1
Overall
CADD	32.0	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 0.06% Admixed American · 33/54,960 alleles

Filtering AF 0.0439% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0384%

Overall 0.0112% 176/1,574,450 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.06%	1,665
South Asian	0.028%	3,573
Middle Eastern	0.0169%	5,922
African / African-American	0.0152%	6,578
Ashkenazi Jewishnot grpmax-eligible	0.0105%	9,535
European (non-Finnish)	0.00828%	12,072
East Asian	0.00682%	14,655
Remaining individualsnot grpmax-eligible	0.00659%	15,175
Finnishnot grpmax-eligible	0.0016%	62,412

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.Ser779fs
Coding: c.2335del
MANE Select: NM_001080449
dbSNP: rs745893364
Type: Deletion
Location: chr10:68422764 (GRCh38)
Gene constraint: LOEUF 1.115 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.82 · 1 PDB
Residue 779: the upf1-type sf1b helicase atp-binding domain; the 'helicase activity' region

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

Similar variants

DNA2 p.Ser779= Likely benign ★ same residue
DNA2 c.73_74+10del Likely pathogenic ★★ same type
DNA2 p.Asn463fs Uncertain significance ★★ same type
DNA2 p.Cys415fs Uncertain significance ★★ same type
DNA2 p.Leu1054fs Uncertain significance ★★ same type
DNA2 p.Ser725_Leu726insTer Uncertain significance ★★ same type
DNA2 p.Val418_Pro419del Uncertain significance ★★ same type
DNA2 c.1057+19del Benign ★★ 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-ser779fs (accessed [today's date]).

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