# NM_139159.5(DPP9):c.1896G>A (p.Pro632=)

https://sugi.bio/variant/dpp9-p-pro632

## Summary

**DPP9 p.Pro632= (c.1896G>A)** is classified **Likely benign** in DPP9 (ClinVar, Single submitter, 2 submitters; last evaluated 2025-10-01). Ultra-rare (popmax 0.0137%, nfe).

**At a glance:** Likely benign · review: Single submitter · 2 submitters · ultra-rare (popmax 0.0137%, nfe)

## For patients & families {#patients}

This is a change in the DPP9 gene that is classified as likely benign — not considered disease-causing, submitted by 2 submitters.

*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.Pro632= |
| Coding change (HGVS c.) | c.1896G>A |
| MANE Select transcript | [NM_139159](https://www.ncbi.nlm.nih.gov/nuccore/NM_139159) |
| Variant type | single nucleotide variant |
| Location | chr19:4685761-4685761 (GRCh38) |
| ClinVar | [VCV4442169](https://www.ncbi.nlm.nih.gov/clinvar/variation/4442169/) |

**All HGVS expressions:** `NC_000019.10:g.4685761C>T`, `NC_000019.9:g.4685773C>T`, `NM_001384611.1:c.1896G>A`, `NM_001384612.1:c.1896G>A`, `NM_001384613.1:c.1896G>A`, `NM_001384614.1:c.1896G>A`, `NM_001384615.1:c.1896G>A`, `NM_001384617.1:c.1896G>A`, `NM_001384618.1:c.1886-17G>A`, `NM_001384619.1:c.1863G>A`, `NM_001384620.1:c.1857G>A`, `NM_001384621.1:c.1857G>A`, `NM_001384622.1:c.1896G>A`, `NM_001384623.1:c.1809G>A`, `NM_001384624.1:c.1809G>A`, `NM_001384625.1:c.1809G>A`, `NM_001384626.1:c.1809G>A`, `NM_001384627.1:c.1809G>A`, `NM_001384628.1:c.1896G>A`, `NM_001384629.1:c.1896G>A`, `NM_001384630.1:c.1896G>A`, `NM_001384631.1:c.1656G>A`, `NM_139159.5:c.1896G>A`, `NR_158699.2:n.2153G>A`, `NR_164163.1:n.2884C>T`, `NR_169283.1:n.2114G>A`, `NR_169284.1:n.1897G>A`, `NR_169285.1:n.1984G>A`, `NR_169286.1:n.2263G>A`, `NR_169287.1:n.2085G>A`, `NR_169289.1:n.2052G>A`, `NR_169290.1:n.2149G>A`, `NR_169291.1:n.2119G>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 (below), not from a missing predictor score.
- Conservation: phyloP -11.04, GERP -3.43 — fast-evolving / accelerated position
- CADD: **PHRED 4.879**. 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: **below the reporting threshold**. This position is scored for a different substitution (C>A, Δ0.41 acceptor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.0137%** (nfe) · FAF95 0.012% · FAF99 0.0113% · 162/1,179,804 in the highest group · 180/1,612,702 alleles overall — ultra-rare (popmax 0.0137%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.0137% | 7,283 |
| Remaining individuals (not grpmax-eligible) | 0.0128% | 7,805 |
| African / African-American | 0.00668% | 14,975 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.00338% | 29,596 |
| East Asian | 0.00223% | 44,892 |
| South Asian | 0.0022% | 45,526 |
| Finnish (not grpmax-eligible) | 0.00158% | 63,094 |

*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}

**DPP9** population constraint: LOEUF 0.647, pLI 8.931e-07, missense-Z 1.4404. *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 **632** lies in a UniProt-annotated variant site (in hatis; likely pathogenic).

AlphaFold model confidence (whole protein): pLDDT 92.96, 83% of residues very-high.

**14 experimental structure(s)** (PDB): [6EOQ](https://www.rcsb.org/structure/6EOQ), [6EOR](https://www.rcsb.org/structure/6EOR), [6QZV](https://www.rcsb.org/structure/6QZV), [6X6A](https://www.rcsb.org/structure/6X6A), [6X6C](https://www.rcsb.org/structure/6X6C), [7A3F](https://www.rcsb.org/structure/7A3F).

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

*Describes the biological roles of DPP9 (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:** DPP9's established molecular role includes dipeptidyl-peptidase activity.


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

**Molecular function:** dipeptidyl-peptidase activity, identical protein binding.

**Biological process:** negative regulation of programmed cell death, pyroptotic inflammatory response.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-10-01.

**Submitter consensus:** unanimous (1/1 Likely benign).

**Submission history:** 3 submissions (2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Dr. Peter K. Rogan Lab, Western University |  | no classification provided | in vitro |  |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2025-10-01 |

**Reported phenotype names (ClinVar):** Thyroid cancer, nonmedullary, 1, Uveal melanoma, not provided, none provided.

## Similar variants {#similar}

Related DPP9 variant pages (same residue, condition, or type): [DPP9 p.Asp310Asn](/variant/dpp9-p-asp310asn), [DPP9 p.Lys509Arg](/variant/dpp9-p-lys509arg), [DPP9 p.Thr301Met](/variant/dpp9-p-thr301met), [DPP9 p.Ala184Gly](/variant/dpp9-p-ala184gly), [DPP9 p.Glu566Lys](/variant/dpp9-p-glu566lys), [DPP9 p.His83=](/variant/dpp9-p-his83), [DPP9 p.Pro322=](/variant/dpp9-p-pro322), [DPP9 p.Ser236Asn](/variant/dpp9-p-ser236asn).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 4442169). 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.*