# NM_017613.4(DONSON):c.1313_1314del (p.Pro438fs)

https://sugi.bio/variant/donson-p-pro438fs

## Summary

**DONSON p.Pro438fs (c.1313_1314del)** is classified **Pathogenic** in DONSON (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-15). Ultra-rare (popmax 0.0165%, mid).

**At a glance:** Pathogenic · review: Single submitter · rsID rs760760475 · 1 submitter · ultra-rare (popmax 0.0165%, mid)

## For patients & families {#patients}

This is a change in the DONSON gene that is reported as disease-causing, but on limited review, 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 | [DONSON](https://sugi.bio/atlas/gene/DONSON/) |
| Protein change (HGVS p.) | p.Pro438fs |
| Coding change (HGVS c.) | c.1313_1314del |
| MANE Select transcript | [NM_017613](https://www.ncbi.nlm.nih.gov/nuccore/NM_017613) |
| dbSNP | [rs760760475](https://www.ncbi.nlm.nih.gov/snp/rs760760475/) |
| Variant type | Deletion |
| Location | chr21:33581338-33581339 (GRCh38) |
| ClinVar | [VCV1937858](https://www.ncbi.nlm.nih.gov/clinvar/variation/1937858/) |

**All HGVS expressions:** `NC_000021.8:g.34953644_34953645del`, `NC_000021.9:g.33581338_33581339del`, `NM_017613.4:c.1313_1314del`

## 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 -4.724, GERP -6.78 — fast-evolving / accelerated position
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.918, pLI 4.6796e-10. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 8 of 10**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.0165%** (mid) · FAF95 0.000247% · FAF99 0.000159% · 1/6,050 in the highest group · 9/1,461,854 alleles overall — ultra-rare (popmax 0.0165%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.0165% | 6,050 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,506 |
| European (non-Finnish) | 0.000593% | 168,570 |

*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}

**DONSON** population constraint: LOEUF 0.918, pLI 4.6796e-10, missense-Z -0.70976. *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 **438** lies in a UniProt-annotated variant site (in missla).

AlphaFold model confidence (whole protein): pLDDT 72.94, 41% of residues very-high.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-09-15.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2022-09-15 |

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

## Similar variants {#similar}

Related DONSON variant pages (same residue, condition, or type): [DONSON p.Glu17fs](/variant/donson-p-glu17fs), [DONSON c.1563+1del](/variant/donson-c-1563-plus-1del), [DONSON p.Ala104fs](/variant/donson-p-ala104fs), [DONSON p.Arg442fs](/variant/donson-p-arg442fs), [DONSON p.Asn417_Ser418del](/variant/donson-p-asn417-ser418del), [DONSON p.Glu471fs](/variant/donson-p-glu471fs), [DONSON p.Gly313fs](/variant/donson-p-gly313fs), [DONSON p.Leu186fs](/variant/donson-p-leu186fs).

### 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 1937858). 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.*