# NM_021233.3(DNASE2B):c.731A>T (p.Asp244Val)

https://sugi.bio/variant/dnase2b-p-asp244val

## Summary

**DNASE2B p.Asp244Val (c.731A>T)** is classified **Uncertain significance** in DNASE2B (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-06). AlphaMissense: likely benign (0.1358); Very rare (popmax 0.00204%, nfe).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs759428794 · 1 submitter · AlphaMissense likely benign · very rare (popmax 0.00204%, nfe)

## For patients & families {#patients}

This is a change in the DNASE2B gene that is currently of uncertain significance — a definitive interpretation has not yet been established, 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 | [DNASE2B](https://sugi.bio/atlas/gene/DNASE2B/) |
| Protein change (HGVS p.) | p.Asp244Val |
| Coding change (HGVS c.) | c.731A>T |
| MANE Select transcript | [NM_021233](https://www.ncbi.nlm.nih.gov/nuccore/NM_021233) |
| dbSNP | [rs759428794](https://www.ncbi.nlm.nih.gov/snp/rs759428794/) |
| Variant type | single nucleotide variant |
| Location | chr1:84412532-84412532 (GRCh38) |
| ClinVar | [VCV2294149](https://www.ncbi.nlm.nih.gov/clinvar/variation/2294149/) |

**All HGVS expressions:** `NC_000001.10:g.84878215A>T`, `NC_000001.11:g.84412532A>T`, `NM_021233.3:c.731A>T`, `NM_058248.2:c.107A>T`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.1358)
- REVEL 0.071 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -7.594 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- SpliceAI predicts **donor gain** (Δ 0.42) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 0.716, GERP -1.07 — weakly conserved position
- CADD: **PHRED 17.88**. 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.*
- Regional missense constraint: **o/e 0.95** across the covering region of the MANE Select transcript (84,398,565–84,414,865), spanning 16,300 bp. Chi-square p 0.34. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.07**, acceptor gain **0.00**, donor gain **0.42**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.07**, acceptor gain **0.00**, donor gain **0.42**.
- Pangolin: Δ**0.20** (loss), gain 0.15 / loss 0.20. SpliceAI calls gain. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.00204%** (nfe) · FAF95 0.00138% · FAF99 0.00116% · 24/1,177,984 in the highest group · 24/1,610,460 alleles overall — very rare (popmax 0.00204%, nfe).

*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}

**DNASE2B** population constraint: LOEUF 1.21, pLI 2.4275e-14, missense-Z 0.67724. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 91.22, 82% of residues very-high.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-06-06.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-06-06 |

**Reported phenotype names (ClinVar):** not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related DNASE2B variant pages (same residue, condition, or type): [DNASE2B p.Ala216Thr](/variant/dnase2b-p-ala216thr), [DNASE2B p.Arg270Gln](/variant/dnase2b-p-arg270gln), [DNASE2B p.Arg327Gln](/variant/dnase2b-p-arg327gln), [DNASE2B p.Asn104Thr](/variant/dnase2b-p-asn104thr), [DNASE2B p.Asn111Thr](/variant/dnase2b-p-asn111thr), [DNASE2B p.Asn278Ile](/variant/dnase2b-p-asn278ile), [DNASE2B p.Asn287Ser](/variant/dnase2b-p-asn287ser), [DNASE2B p.Asp304Glu](/variant/dnase2b-p-asp304glu).

### 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 2294149). 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.*