# NM_017613.4(DONSON):c.1452G>A (p.Leu484=)

https://sugi.bio/variant/donson-p-leu484

## Summary

**DONSON p.Leu484= (c.1452G>A)** is classified **Uncertain significance** in DONSON (ClinVar, Single submitter, 1 submitter; last evaluated 2022-04-13). Very rare (popmax 0.00666%, amr).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs751836395 · 1 submitter · very rare (popmax 0.00666%, amr)

## For patients & families {#patients}

This is a change in the DONSON 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 | [DONSON](https://sugi.bio/atlas/gene/DONSON/) |
| Protein change (HGVS p.) | p.Leu484= |
| Coding change (HGVS c.) | c.1452G>A |
| MANE Select transcript | [NM_017613](https://www.ncbi.nlm.nih.gov/nuccore/NM_017613) |
| dbSNP | [rs751836395](https://www.ncbi.nlm.nih.gov/snp/rs751836395/) |
| Variant type | single nucleotide variant |
| Location | chr21:33579461-33579461 (GRCh38) |
| ClinVar | [VCV1955419](https://www.ncbi.nlm.nih.gov/clinvar/variation/1955419/) |

**All HGVS expressions:** `NC_000021.8:g.34951767C>T`, `NC_000021.9:g.33579461C>T`, `NG_052981.1:g.41425C>T`, `NG_052981.2:g.41425C>T`, `NM_017613.4:c.1452G>A`

## 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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **acceptor gain** (Δ 0.39) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 0.24, GERP -1.47, phastCons 0.845 — weakly conserved position
- CADD: **PHRED 12.56**. 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 deltas (raw): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.39**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.39**, donor gain **0.00**.
- Pangolin: Δ**0.36** (gain), gain 0.36 / loss 0.00. Agrees with SpliceAI. 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 **0.00666%** (amr) · FAF95 0.00226% · FAF99 0.00135% · 4/60,018 in the highest group · 4/1,461,860 alleles overall — very rare (popmax 0.00666%, 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}

**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 **484** 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}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-04-13.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-04-13 |

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

## Similar variants {#similar}

Related DONSON variant pages (same residue, condition, or type): [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.Arg293Ter](/variant/donson-p-arg293ter), [DONSON p.Arg442Ter](/variant/donson-p-arg442ter), [DONSON p.Gln428Ter](/variant/donson-p-gln428ter), [DONSON p.Phe165Ser](/variant/donson-p-phe165ser), [DONSON p.Ala32Gly](/variant/donson-p-ala32gly), [DONSON p.Ala429Glu](/variant/donson-p-ala429glu).

### 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 1955419). 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.*