# NM_139159.5(DPP9):c.2351C>T (p.Pro784Leu)

https://sugi.bio/variant/dpp9-p-pro784leu

## Summary

**DPP9 p.Pro784Leu (c.2351C>T)** is classified **Uncertain significance** in DPP9 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-09). AlphaMissense: likely pathogenic (0.9886); Very rare (popmax 0.00077%, nfe).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely pathogenic · very rare (popmax 0.00077%, nfe)

## For patients & families {#patients}

This is a change in the DPP9 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 | [DPP9](https://sugi.bio/atlas/gene/DPP9/) |
| Protein change (HGVS p.) | p.Pro784Leu |
| Coding change (HGVS c.) | c.2351C>T |
| Variant type | single nucleotide variant |
| Location | chr19:4682819-4682819 (GRCh38) |
| ClinVar | [VCV4244555](https://www.ncbi.nlm.nih.gov/clinvar/variation/4244555/) |

**All HGVS expressions:** `NC_000019.10:g.4682819G>A`, `NC_000019.9:g.4682831G>A`, `NM_001384611.1:c.2351C>T`, `NM_001384612.1:c.2351C>T`, `NM_001384613.1:c.2351C>T`, `NM_001384614.1:c.2351C>T`, `NM_001384615.1:c.2351C>T`, `NM_001384617.1:c.2345C>T`, `NM_001384618.1:c.2324C>T`, `NM_001384619.1:c.2318C>T`, `NM_001384620.1:c.2312C>T`, `NM_001384621.1:c.2312C>T`, `NM_001384622.1:c.2351C>T`, `NM_001384623.1:c.2264C>T`, `NM_001384624.1:c.2264C>T`, `NM_001384625.1:c.2264C>T`, `NM_001384626.1:c.2264C>T`, `NM_001384627.1:c.2264C>T`, `NM_001384628.1:c.2351C>T`, `NM_001384629.1:c.2351C>T`, `NM_001384630.1:c.2204C>T`, `NM_001384631.1:c.2111C>T`, `NM_139159.5:c.2351C>T`, `NR_158699.2:n.2743C>T`, `NR_164163.1:n.277G>A`, `NR_169283.1:n.2704C>T`, `NR_169284.1:n.2487C>T`, `NR_169285.1:n.2439C>T`, `NR_169286.1:n.2853C>T`, `NR_169287.1:n.2540C>T`, `NR_169289.1:n.2507C>T`, `NR_169290.1:n.2604C>T`, `NR_169291.1:n.2574C>T`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **damaging** — a triage signal, not a reclassification.

- AlphaMissense **likely pathogenic** (0.9886)
- REVEL 0.666 (pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -16.282 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 9.794, GERP 1.83, phastCons 1 — highly conserved (agrees)
- ⚠ **Isoform check:** AlphaMissense is numbered on a different transcript (AM **P755L** vs ClinVar **P784L**) — the AlphaMissense read here may be for a different residue; verify against the ClinVar transcript.
- CADD: **PHRED 27.1**. 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 0.75** across the covering region of the MANE Select transcript (4,676,567–4,684,790), spanning 8,223 bp. Chi-square p 2e-05. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not looked up on this page** — it was served without the gene's SpliceAI index, so no lookup was made. This is a gap in this page, not in the data, and says nothing about whether a splicing effect is predicted.
- Population frequency (gnomAD v4.1): grpmax **0.00077%** (nfe) · FAF95 0.000362% · FAF99 0.000262% · 9/1,168,818 in the highest group · 9/1,589,792 alleles overall — very rare (popmax 0.00077%, nfe).

*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.*

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-08-09.

**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 | 2025-08-09 |

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

### 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 4244555). 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.*