DNA2 p.Ser454=
c.1362G>A · rs74537378 · VCV380533
Benign
Multiple submitters
Classification
Benign
ClinVar
Review
Multiple submitters ★★☆☆
ClinVar · 4 submitters
gnomAD v4.1
Common
common (popmax 9.11%, afr) — too common for a highly-penetrant pathogenic allele
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation carries the signal. | ||
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
|---|---|---|
| Constraint at this position | ||
| Conservation | phyloP -0.13 | GERP -3.4, phastCons 0.68 |
| Overall | ||
| CADD | 9.392 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
9.11%
African / African-American · 6,829/74,976 alleles
Filtering AF
8.93%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 8.85%
Overall
0.485%
7,826/1,612,490 alleles · common
| Ancestry group | Frequency | 1 in |
|---|---|---|
| African / African-Americangrpmax | 9.11% | 11 |
| Remaining individualsnot grpmax-eligible | 0.663% | 151 |
| Admixed American | 0.558% | 179 |
| Middle Eastern | 0.429% | 233 |
| South Asian | 0.0199% | 5,034 |
| European (non-Finnish) | 0.0173% | 5,781 |
| Ashkenazi Jewishnot grpmax-eligible | 0.00338% | 29,550 |
| East Asian | 0.00223% | 44,822 |
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.Ser454=
- Coding
- c.1362G>A
- MANE Select
- NM_001080449
- dbSNP
- rs74537378
- Type
- single nucleotide variant
- Location
- chr10:68442970 (GRCh38)
- Gene constraint
- LOEUF 1.115 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 87.82 · 1 PDB
- Residue 454
- the 'nuclease activity' region
Similar variants
- DNA2 p.Ser454Ter Conflicting classifications of pathogenicity ★ 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
- DNA2 p.Ala346Val 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-ser454 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown