Is DNA2 p.Glu18Ter (c.52G>T) pathogenic?

DNA2 p.Glu18Ter (c.52G>T) is classified Uncertain significance in DNA2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-09-08). Very rare (popmax 8.5e-05%, nfe).

How common is DNA2 p.Glu18Ter (c.52G>T) in the general population?

DNA2 p.Glu18Ter (c.52G>T) is very rare (popmax 8.5e-05%, nfe) (gnomAD).

DNA2 p.Glu18Ter

c.52G>T · rs1554911818 · VCV493073

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 8.5e-05%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 1 of 21
Splicing
SpliceAI	Δ0.78	donor gain · deltas
Pangolin	Δ0.31	gain · loss 0.20 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 0.38	GERP -0.4, phastCons 0.002
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 8.5e-05% European (non-Finnish) · 1/1,176,046 alleles

Overall 6.88e-05% 1/1,453,966 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.Glu18Ter
Coding: c.52G>T
MANE Select: NM_001080449
dbSNP: rs1554911818
Type: single nucleotide variant
Location: chr10:68471813 (GRCh38)
Gene constraint: LOEUF 1.115 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.82 · 1 PDB

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

Similar variants

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
DNA2 p.Ala51Val 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-glu18ter (accessed [today's date]).

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