# NM_001375.3(DNASE2):c.435C>T (p.Ser145=)

https://sugi.bio/variant/dnase2-p-ser145

## Summary

**DNASE2 p.Ser145= (c.435C>T)** is classified **Benign** in DNASE2 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-02-04). Common (popmax 66.4%, eas) — too common for a highly-penetrant pathogenic allele.

**At a glance:** Benign · review: Multiple submitters · rsID rs2293682 · 6 submitters · common (popmax 66.4%, eas) — too common for a highly-penetrant pathogenic allele

## For patients & families {#patients}

This is a change in the DNASE2 gene that is classified as benign — not considered disease-causing, submitted by 6 submitters.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [DNASE2](https://sugi.bio/atlas/gene/DNASE2/) |
| Protein change (HGVS p.) | p.Ser145= |
| Coding change (HGVS c.) | c.435C>T |
| MANE Select transcript | [NM_001375](https://www.ncbi.nlm.nih.gov/nuccore/NM_001375) |
| dbSNP | [rs2293682](https://www.ncbi.nlm.nih.gov/snp/rs2293682/) |
| Variant type | single nucleotide variant |
| Location | chr19:12878746-12878746 (GRCh38) |
| ClinVar | [VCV1168081](https://www.ncbi.nlm.nih.gov/clinvar/variation/1168081/) |

**All HGVS expressions:** `NC_000019.10:g.12878746G>A`, `NC_000019.9:g.12989560G>A`, `NM_001375.3:c.435C>T`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — common (popmax 66.4%, eas) — too common for a highly-penetrant pathogenic allele.

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 1.943, GERP -2.8, phastCons 0.982 — weakly conserved position
- CADD: **PHRED 5.286**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (G>C, Δ0.55 acceptor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **66.4%** (eas) · FAF95 65.8% · FAF99 65.5% · 29,776/44,844 in the highest group · 429,671/1,613,616 alleles overall — common (popmax 66.4%, eas) — too common for a highly-penetrant pathogenic allele.

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 66.4% | 2 |
| South Asian | 41.8% | 2 |
| Finnish (not grpmax-eligible) | 33.2% | 3 |
| Admixed American | 32% | 3 |
| Remaining individuals (not grpmax-eligible) | 27.7% | 4 |
| African / African-American | 25.9% | 4 |
| European (non-Finnish) | 23.5% | 4 |
| Middle Eastern | 20.7% | 5 |
| Ashkenazi Jewish (not grpmax-eligible) | 20.5% | 5 |
| Amish (not grpmax-eligible) | 19% | 5 |

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**DNASE2** population constraint: LOEUF 1.195, pLI 1.8542e-08, missense-Z 0.88396. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **145** lies in a disulfide bond.

AlphaFold model confidence (whole protein): pLDDT 91.52, 84% of residues very-high.

## What this gene does {#gene-function}

*Describes the biological roles of DNASE2 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** DNASE2's established molecular role includes deoxyribonuclease II activity.


### Pathways affected {#pathways}

DNASE2 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Lysosome Vesicle Biogenesis](https://reactome.org/content/detail/R-HSA-432720) | curated |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** deoxyribonuclease II activity.

**Biological process:** apoptotic cell clearance.

## Clinical significance {#significance}

**Benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-02-04.

**Submitter consensus:** unanimous (6/6 Benign).

**Submission history:** 6 submissions (2022–2026); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Breakthrough Genomics, Breakthrough Genomics | Benign | criteria provided, single submitter | not provided |  |
| Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan | Benign | criteria provided, single submitter | clinical testing | 2024-01-24 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-02-04 |
| Mayo Clinic Laboratories, Mayo Clinic | Benign | criteria provided, single submitter | clinical testing | 2022-09-06 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Benign | criteria provided, single submitter | clinical testing | 2026-01-21 |
| Blueprint Genetics | Benign | criteria provided, single submitter | clinical testing | 2024-11-28 |

**Reported phenotype names (ClinVar):** not provided, not specified, AllHighlyPenetrant, none provided.

## Similar variants {#similar}

Related DNASE2 variant pages (same residue, condition, or type): [DNASE2 p.Ser145Ile](/variant/dnase2-p-ser145ile), [DNASE2 c.709+4A>T](/variant/dnase2-c-709-plus-4a-t), [DNASE2 p.Ala332Asp](/variant/dnase2-p-ala332asp), [DNASE2 p.Arg321Trp](/variant/dnase2-p-arg321trp), [DNASE2 p.Asn69Ser](/variant/dnase2-p-asn69ser), [DNASE2 p.Cys159Trp](/variant/dnase2-p-cys159trp), [DNASE2 p.Glu43Gly](/variant/dnase2-p-glu43gly), [DNASE2 p.Gly241Ser](/variant/dnase2-p-gly241ser).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-07-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 1168081). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*