# NM_001080449.3(DNA2):c.2400A>G (p.Ala800=)

https://sugi.bio/variant/dna2-p-ala800

## Summary

**DNA2 p.Ala800= (c.2400A>G)** is classified **Likely benign** in DNA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-11). Very rare (popmax 0.00501%, amr).

**At a glance:** Likely benign · review: Single submitter · rsID rs2051681425 · 1 submitter · very rare (popmax 0.00501%, amr)

## For patients & families {#patients}

This is a change in the DNA2 gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter.

*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 | [DNA2](https://sugi.bio/atlas/gene/DNA2/) |
| Protein change (HGVS p.) | p.Ala800= |
| Coding change (HGVS c.) | c.2400A>G |
| MANE Select transcript | [NM_001080449](https://www.ncbi.nlm.nih.gov/nuccore/NM_001080449) |
| dbSNP | [rs2051681425](https://www.ncbi.nlm.nih.gov/snp/rs2051681425/) |
| Variant type | single nucleotide variant |
| Location | chr10:68422699-68422699 (GRCh38) |
| ClinVar | [VCV2876026](https://www.ncbi.nlm.nih.gov/clinvar/variation/2876026/) |

**All HGVS expressions:** `NC_000010.10:g.70182456T>C`, `NC_000010.11:g.68422699T>C`, `NG_034247.1:g.54275A>G`, `NM_001080449.3:c.2400A>G`, `NR_102264.2:n.2374A>G`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **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 0.047, GERP -3.42, phastCons 0.969 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 8.293**. 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 (T>A, Δ0.44 donor loss), 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 **0.00501%** (amr) · FAF95 0.00133% · FAF99 0.000668% · 3/59,926 in the highest group · 3/1,461,194 alleles overall — very rare (popmax 0.00501%, amr).

*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}

**DNA2** population constraint: LOEUF 1.115, pLI 6.8618e-27, missense-Z 1.224. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **mitochondrial disease** — Moderate (AD)

## Protein context {#protein}

Residue **800** lies in the upf1-type sf1b helicase atp-binding domain; the 'helicase activity' region.

AlphaFold model confidence (whole protein): pLDDT 87.82, 61% of residues very-high.

**1 experimental structure(s)** (PDB): [5EAY](https://www.rcsb.org/structure/5EAY).

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

*Describes the biological roles of DNA2 (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:** DNA2's established molecular role includes DNA binding. p.Ala800= falls in the upf1-type sf1b helicase atp-binding domain. In Reactome, DNA2 is annotated in disease pathway(s) including **Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA1 binding function**, **Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA2/RAD51/RAD51C binding function**.

**Disease mechanism (Reactome):** DNA2 loss or alteration is curated in [Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA1 binding function](https://reactome.org/content/detail/R-HSA-9704331), [Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA2/RAD51/RAD51C binding function](https://reactome.org/content/detail/R-HSA-9704646), [Defective homologous recombination repair (HRR) due to BRCA1 loss of function](https://reactome.org/content/detail/R-HSA-9701192).

### Pathways affected {#pathways}

DNA2 participates in **16 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA1 binding function](https://reactome.org/content/detail/R-HSA-9704331) | curated |
| ⚕ [Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA2/RAD51/RAD51C binding function](https://reactome.org/content/detail/R-HSA-9704646) | curated |
| ⚕ [Defective homologous recombination repair (HRR) due to BRCA1 loss of function](https://reactome.org/content/detail/R-HSA-9701192) | curated |
| ⚕ [Impaired BRCA2 binding to PALB2](https://reactome.org/content/detail/R-HSA-9709603) | curated |
| ⚕ [Impaired BRCA2 binding to RAD51](https://reactome.org/content/detail/R-HSA-9709570) | curated |
| [G2/M DNA damage checkpoint](https://reactome.org/content/detail/R-HSA-69473) | curated |
| [HDR through Homologous Recombination (HRR)](https://reactome.org/content/detail/R-HSA-5685942) | curated |
| [HDR through Single Strand Annealing (SSA)](https://reactome.org/content/detail/R-HSA-5685938) | curated |
| [Homologous DNA Pairing and Strand Exchange](https://reactome.org/content/detail/R-HSA-5693579) | curated |
| [Presynaptic phase of homologous DNA pairing and strand exchange](https://reactome.org/content/detail/R-HSA-5693616) | curated |
| [Processing of DNA double-strand break ends](https://reactome.org/content/detail/R-HSA-5693607) | curated |
| [Regulation of TP53 Activity through Phosphorylation](https://reactome.org/content/detail/R-HSA-6804756) | curated |
| [Removal of the Flap Intermediate](https://reactome.org/content/detail/R-HSA-69166) | curated |
| [Removal of the Flap Intermediate from the C-strand](https://reactome.org/content/detail/R-HSA-174437) | curated |
| [Resolution of D-loop Structures through Holliday Junction Intermediates](https://reactome.org/content/detail/R-HSA-5693568) | curated |
| [Resolution of D-loop Structures through Synthesis-Dependent Strand Annealing (SDSA)](https://reactome.org/content/detail/R-HSA-5693554) | curated |

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

**Molecular function:** DNA binding, DNA helicase activity, nuclease activity, ATP hydrolysis activity, 5'-flap endonuclease activity, single-stranded DNA helicase activity.

**Biological process:** DNA replication checkpoint signaling, DNA double-strand break processing, DNA replication, mitochondrial DNA replication, base-excision repair, DNA replication, Okazaki fragment processing.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-12-11.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2023-12-11 |

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

## Similar variants {#similar}

Related DNA2 variant pages (same residue, condition, or type): [DNA2 c.588-2214A>G](/variant/dna2-c-588-minus-2214a-g), [DNA2 p.Ser640Leu](/variant/dna2-p-ser640leu), [DNA2 c.2402+1G>A](/variant/dna2-c-2402-plus-1g-a), [DNA2 c.257+3A>G](/variant/dna2-c-257-plus-3a-g), [DNA2 p.Ala1003Ser](/variant/dna2-p-ala1003ser), [DNA2 p.Ala221Glu](/variant/dna2-p-ala221glu), [DNA2 p.Ala346Val](/variant/dna2-p-ala346val), [DNA2 p.Ala51Val](/variant/dna2-p-ala51val).

### 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 2876026). 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.*