# NM_001318503.2(DUSP9):c.842C>T (p.Ser281Phe)

https://sugi.bio/variant/dusp9-p-ser281phe

## Summary

**DUSP9 p.Ser281Phe (c.842C>T)** is classified **Uncertain significance** in DUSP9 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-21). AlphaMissense: likely benign (0.2712); Absent from gnomAD v4.1.

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely benign · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the DUSP9 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 | [DUSP9](https://sugi.bio/atlas/gene/DUSP9/) |
| Protein change (HGVS p.) | p.Ser281Phe |
| Coding change (HGVS c.) | c.842C>T |
| MANE Select transcript | [NM_001318503](https://www.ncbi.nlm.nih.gov/nuccore/NM_001318503) |
| Variant type | single nucleotide variant |
| Location | chrX:153649992-153649992 (GRCh38) |
| ClinVar | [VCV3842967](https://www.ncbi.nlm.nih.gov/clinvar/variation/3842967/) |

**All HGVS expressions:** `NC_000023.10:g.152915447C>T`, `NC_000023.11:g.153649992C>T`, `NM_001318503.2:c.842C>T`, `NM_001395.4:c.842C>T`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely benign** (0.2712)
- REVEL 0.549 (indeterminate)
- SaProt LLR -11.964 (damaging) — differs from AlphaMissense
- → **In-silico consensus:** SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate
- SpliceAI predicts **acceptor gain** (Δ 0.47) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 1.764, GERP -2.43, phastCons 0.927 — weakly conserved position
- CADD: **PHRED 29.4**. 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 0.74** across the covering region of the MANE Select transcript (153,647,954–153,650,302), spanning 2,348 bp. Chi-square p 1.1e-06. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.01**, donor loss **0.00**, acceptor gain **0.47**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.01**, donor loss **0.00**, acceptor gain **0.47**, donor gain **0.00**.
- Population frequency: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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.*

## Protein context {#protein}

Residue **281** lies in an α-helix; the tyrosine-protein phosphatase domain.

AlphaFold model confidence (whole protein): pLDDT 77.23, 43% of residues very-high.

**2 experimental structure(s)** (PDB): [2HXP](https://www.rcsb.org/structure/2HXP), [3LJ8](https://www.rcsb.org/structure/3LJ8).

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

*Describes the biological roles of DUSP9 (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:** p.Ser281Phe falls in the tyrosine-protein phosphatase domain. In Reactome, DUSP9 is annotated in disease pathway(s) including **Signaling by MAPK mutants**.

**Disease mechanism (Reactome):** DUSP9 loss or alteration is curated in [Signaling by MAPK mutants](https://reactome.org/content/detail/R-HSA-9652817).

### Pathways affected {#pathways}

DUSP9 participates in **3 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Signaling by MAPK mutants](https://reactome.org/content/detail/R-HSA-9652817) | 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 |

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-01-21.

**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 | 2025-01-21 |

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

## Similar variants {#similar}

Related DUSP9 variant pages (same residue, condition, or type): [DUSP9 p.Ala151Val](/variant/dusp9-p-ala151val), [DUSP9 p.Ala174=](/variant/dusp9-p-ala174), [DUSP9 p.Pro158=](/variant/dusp9-p-pro158), [DUSP9 p.Ala174Val](/variant/dusp9-p-ala174val), [DUSP9 p.Ala226Ser](/variant/dusp9-p-ala226ser), [DUSP9 p.Ala362Val](/variant/dusp9-p-ala362val), [DUSP9 p.Ala45Thr](/variant/dusp9-p-ala45thr), [DUSP9 p.Ala48Thr](/variant/dusp9-p-ala48thr).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 3842967). 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.*