# NM_017613.4(DONSON):c.1254dup (p.Lys419Ter)

https://sugi.bio/variant/donson-p-lys419ter

## Summary

**DONSON p.Lys419Ter (c.1254dup)** is classified **Pathogenic/Likely pathogenic** in DONSON (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-12-25). Very rare (popmax 0.00223%, eas); Associated with microcephaly, short stature, and limb abnormalities.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs765112107 · 4 submitters · 1 linked condition · very rare (popmax 0.00223%, eas)

## For patients & families {#patients}

This is a change in the DONSON gene that is considered likely disease-causing, submitted by 4 submitters, and is linked to microcephaly, short stature, and limb abnormalities.

*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:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0018655/index) · [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.Lys419Ter |
| Coding change (HGVS c.) | c.1254dup |
| MANE Select transcript | [NM_017613](https://www.ncbi.nlm.nih.gov/nuccore/NM_017613) |
| dbSNP | [rs765112107](https://www.ncbi.nlm.nih.gov/snp/rs765112107/) |
| Variant type | Duplication |
| Location | chr21:33581397-33581398 (GRCh38) |
| ClinVar | [VCV521608](https://www.ncbi.nlm.nih.gov/clinvar/variation/521608/) |

**All HGVS expressions:** `NC_000021.8:g.34953704dup`, `NC_000021.9:g.33581398dup`, `NM_017613.4:c.1254dup`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **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 6.234, GERP 5.82, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **nonsense (stop-gain)** — 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.
- CADD: **PHRED 33.0**. 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: **not assessed** — the release is built from a substitutions-only source, so it holds no duplication 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 **0.00223%** (eas) · FAF95 0.000542% · FAF99 0.000428% · 1/44,886 in the highest group · 15/1,613,968 alleles overall — very rare (popmax 0.00223%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.00223% | 44,886 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,486 |
| South Asian | 0.0011% | 91,088 |
| European (non-Finnish) | 0.00102% | 98,332 |

*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 **419** 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/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-12-25.

**Submitter consensus:** conflicting (2 Likely pathogenic, 2 Pathogenic).

**Submission history:** 4 submissions (2017–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet | Likely pathogenic | criteria provided, single submitter | clinical testing | 2021-08-01 |
| Ambry Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2017-04-28 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-12-25 |
| Blueprint Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2021-12-07 |

## Associated conditions {#conditions}

[microcephaly, short stature, and limb abnormalities](https://sugi.bio/atlas/disease/microcephaly-short-stature-and-limb-abnormalities/).

**Reported phenotype names (ClinVar):** Microcephaly, short stature, and limb abnormalities, Inborn genetic diseases, not provided, DONSON-related disorders, none provided.

## Similar variants {#similar}

Related DONSON variant pages (same residue, condition, or type): [DONSON p.Leu49fs](/variant/donson-p-leu49fs), [DONSON c.1047-9A>G](/variant/donson-c-1047-minus-9a-g), [DONSON c.1563+1G>T](/variant/donson-c-1563-plus-1g-t), [DONSON p.Gln428Ter](/variant/donson-p-gln428ter), [DONSON p.Phe165Ser](/variant/donson-p-phe165ser), [DONSON p.Ile307Val](/variant/donson-p-ile307val), [DONSON p.Asn417_Ser418del](/variant/donson-p-asn417-ser418del), [DONSON p.Gln101Ter](/variant/donson-p-gln101ter).

### 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 521608). 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.*