# NM_130443.4(DPP3):c.205G>A (p.Ala69Thr)

https://sugi.bio/variant/dpp3-p-ala69thr

## Summary

**DPP3 p.Ala69Thr (c.205G>A)** is classified **Uncertain significance** in DPP3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-22). AlphaMissense: likely benign (0.0785); Very rare (popmax 0.00549%, sas).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely benign · very rare (popmax 0.00549%, sas)

## For patients & families {#patients}

This is a change in the DPP3 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 | [DPP3](https://sugi.bio/atlas/gene/DPP3/) |
| Protein change (HGVS p.) | p.Ala69Thr |
| Coding change (HGVS c.) | c.205G>A |
| MANE Select transcript | [NM_130443](https://www.ncbi.nlm.nih.gov/nuccore/NM_130443) |
| Variant type | single nucleotide variant |
| Location | chr11:66482405-66482405 (GRCh38) |
| ClinVar | [VCV4661968](https://www.ncbi.nlm.nih.gov/clinvar/variation/4661968/) |

**All HGVS expressions:** `NC_000011.10:g.66482405G>A`, `NC_000011.9:g.66249876G>A`, `NG_032068.1:g.6997G>A`, `NM_001256670.2:c.205G>A`, `NM_005700.5:c.205G>A`, `NM_130443.4:c.205G>A`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.0785)
- REVEL 0.102 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -9.149 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 5.873, GERP 1.45, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 18.37**. 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 0.86** across the covering region of the MANE Select transcript (66,482,201–66,509,248), spanning 27,047 bp. Chi-square p 1e-05. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (G>C, Δ0.20 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 **0.00549%** (sas) · FAF95 0.0021% · FAF99 0.00136% · 5/91,088 in the highest group · 30/1,610,494 alleles overall — very rare (popmax 0.00549%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.00549% | 18,218 |
| Admixed American | 0.005% | 20,007 |
| East Asian | 0.00446% | 22,440 |
| European (non-Finnish) | 0.00161% | 62,106 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,484 |

*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}

**DPP3** population constraint: LOEUF 0.827, pLI 2.97e-13, missense-Z 1.8932. *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 **69** lies in an α-helix.

AlphaFold model confidence (whole protein): pLDDT 95.56, 92% of residues very-high.

**10 experimental structure(s)** (PDB): [3FVY](https://www.rcsb.org/structure/3FVY), [3T6B](https://www.rcsb.org/structure/3T6B), [3T6J](https://www.rcsb.org/structure/3T6J), [5E2Q](https://www.rcsb.org/structure/5E2Q), [5E33](https://www.rcsb.org/structure/5E33), [5E3A](https://www.rcsb.org/structure/5E3A).

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

*Describes the biological roles of DPP3 (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:** DPP3's established molecular role includes dipeptidyl-peptidase activity.


### Pathways affected {#pathways}

DPP3 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [KEAP1-NFE2L2 pathway](https://reactome.org/content/detail/R-HSA-9755511) | curated |
| [Neddylation](https://reactome.org/content/detail/R-HSA-8951664) | curated |

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

**Molecular function:** dipeptidyl-peptidase activity, zinc ion binding.

**Biological process:** proteolysis.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-09-22.

**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 | 2025-09-22 |

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

## Similar variants {#similar}

Related DPP3 variant pages (same residue, condition, or type): [DPP3 p.Arg76His](/variant/dpp3-p-arg76his), [DPP3 p.Leu163Met](/variant/dpp3-p-leu163met), [DPP3 p.Lys423=](/variant/dpp3-p-lys423), [DPP3 p.Phe331=](/variant/dpp3-p-phe331), [DPP3 p.Phe443=](/variant/dpp3-p-phe443), [DPP3 p.Thr401=](/variant/dpp3-p-thr401), [DPP3 c.573+1G>A](/variant/dpp3-c-573-plus-1g-a), [DPP3 p.Ala22Gly](/variant/dpp3-p-ala22gly).

### 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 4661968). 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.*