# NM_030640.3(DUSP16):c.1080_1083del (p.Pro361fs)

https://sugi.bio/variant/dusp16-p-pro361fs

## Summary

**DUSP16 p.Pro361fs (c.1080_1083del)** is classified **Benign** in DUSP16 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-12-31). Common (popmax 24.5%, eas) — too common for a highly-penetrant pathogenic allele.

**At a glance:** Benign · review: Single submitter · rsID rs200271649 · 1 submitter · common (popmax 24.5%, eas) — too common for a highly-penetrant pathogenic allele

## For patients & families {#patients}

This is a change in the DUSP16 gene that is classified as 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 | [DUSP16](https://sugi.bio/atlas/gene/DUSP16/) |
| Protein change (HGVS p.) | p.Pro361fs |
| Coding change (HGVS c.) | c.1080_1083del |
| MANE Select transcript | [NM_030640](https://www.ncbi.nlm.nih.gov/nuccore/NM_030640) |
| dbSNP | [rs200271649](https://www.ncbi.nlm.nih.gov/snp/rs200271649/) |
| Variant type | Deletion |
| Location | chr12:12477748-12477751 (GRCh38) |
| ClinVar | [VCV771457](https://www.ncbi.nlm.nih.gov/clinvar/variation/771457/) |

**All HGVS expressions:** `NC_000012.11:g.12630682_12630685del`, `NC_000012.12:g.12477748_12477751del`, `NG_021402.2:g.89764_89767del`, `NM_030640.2:c.1080_1083del`, `NM_030640.3:c.1080_1083del`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — common (popmax 24.5%, eas) — too common for a highly-penetrant pathogenic allele.

- **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 -1.179, GERP -2.42 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. the gene is **loss-of-function-intolerant** (LOEUF 0.502, pLI 0.97336), supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in the last exon (7 of 7)** — predicted to **escape NMD**, so the truncated protein is likely expressed. An input to PVS1, not an applied code.
- CADD: **PHRED 26.9**. 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 deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Repeat context: **simple_repeat** (GCACGCTGG). The alignment of this deletion is ambiguous inside a repeating unit, so the same change can be written several ways and a frequency lookup keyed on one representation can miss another. *A qualifier on how reliably this variant can be called and counted — not a pathogenicity signal.*
- Population frequency (gnomAD v4.1): grpmax **24.5%** (eas) · FAF95 24.2% · FAF99 24% · 11,002/44,844 in the highest group · 37,865/1,613,570 alleles overall — common (popmax 24.5%, eas) — too common for a highly-penetrant pathogenic allele.

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 24.5% | 4 |
| South Asian | 12.4% | 8 |
| Admixed American | 11.7% | 9 |
| Remaining individuals (not grpmax-eligible) | 3.27% | 31 |
| Finnish (not grpmax-eligible) | 2.71% | 37 |
| Ashkenazi Jewish (not grpmax-eligible) | 1.43% | 70 |
| Middle Eastern | 0.776% | 129 |
| African / African-American | 0.368% | 272 |
| European (non-Finnish) | 0.339% | 295 |

*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}

**DUSP16** population constraint: LOEUF 0.502, pLI 0.97336, missense-Z 1.6928. *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 **361** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 60.81, 32% of residues very-high.

**3 experimental structure(s)** (PDB): [2VSW](https://www.rcsb.org/structure/2VSW), [3TG3](https://www.rcsb.org/structure/3TG3), [4YR8](https://www.rcsb.org/structure/4YR8).

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

*Describes the biological roles of DUSP16 (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:** DUSP16's established molecular role includes phosphoprotein phosphatase activity. p.Pro361fs falls in the disordered region. In Reactome, DUSP16 is annotated in disease pathway(s) including **Signaling by MAPK mutants**, **Suppression of autophagy**.

**Disease mechanism (Reactome):** DUSP16 loss or alteration is curated in [Signaling by MAPK mutants](https://reactome.org/content/detail/R-HSA-9652817), [Suppression of autophagy](https://reactome.org/content/detail/R-HSA-9636569).

### Pathways affected {#pathways}

DUSP16 participates in **4 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Signaling by MAPK mutants](https://reactome.org/content/detail/R-HSA-9652817) | curated |
| ⚕ [Suppression of autophagy](https://reactome.org/content/detail/R-HSA-9636569) | curated |
| [Negative regulation of MAPK pathway](https://reactome.org/content/detail/R-HSA-5675221) | curated |
| [RAF-independent MAPK1/3 activation](https://reactome.org/content/detail/R-HSA-112409) | curated |

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

**Molecular function:** phosphoprotein phosphatase activity, JUN kinase binding, phosphatase activity, mitogen-activated protein kinase p38 binding, mitogen-activated protein kinase binding, protein carrier activity.

**Biological process:** dephosphorylation, negative regulation of MAPK cascade.

## Clinical significance {#significance}

**Benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2019-12-31.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2019-12-31 |

**Reported phenotype names (ClinVar):** not provided, RECLASSIFIED - ADRA2C POLYMORPHISM, RECLASSIFIED - ADRB1 POLYMORPHISM, none provided.

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 2026-10-14); 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 771457). 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.*