# NM_130797.4(DPP6):c.157_184del (p.Pro53fs)

https://sugi.bio/variant/dpp6-p-pro53fs

## Summary

**DPP6 p.Pro53fs (c.157_184del)** is classified **Conflicting classifications of pathogenicity** in DPP6 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2022-12-21). Very rare (popmax 0.00497%, amr).

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs2129062565 · 2 submitters · very rare (popmax 0.00497%, amr)

## For patients & families {#patients}

This is a change in the DPP6 gene that is of uncertain or conflicting significance (submitters disagree on it), 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 | [DPP6](https://sugi.bio/atlas/gene/DPP6/) |
| Protein change (HGVS p.) | p.Pro53fs |
| Coding change (HGVS c.) | c.157_184del |
| MANE Select transcript | [NM_130797](https://www.ncbi.nlm.nih.gov/nuccore/NM_130797) |
| dbSNP | [rs2129062565](https://www.ncbi.nlm.nih.gov/snp/rs2129062565/) |
| Variant type | Deletion |
| Location | chr7:154052967-154052994 (GRCh38) |
| ClinVar | [VCV1677676](https://www.ncbi.nlm.nih.gov/clinvar/variation/1677676/) |

**All HGVS expressions:** `NC_000007.13:g.153750062_153750089del`, `NC_000007.14:g.154052977_154053004del`, `NG_033878.2:g.309992_310019del`, `NM_001039350.3:c.51+165243_51+165270del`, `NM_001290253.2:c.157_184del`, `NM_001364497.2:c.60+303969_60+303996del`, `NM_001364498.2:c.60+303969_60+303996del`, `NM_001364499.2:c.60+303969_60+303996del`, `NM_001364500.2:c.60+303969_60+303996del`, `NM_001364501.2:c.51+165243_51+165270del`, `NM_130797.3:c.157_184del`, `NM_130797.4:c.157_184del`

## 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 0.887, GERP -4.28, phastCons 0.009 — weakly conserved position
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.751, pLI 1.1525e-10. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 1 of 26**, so the transcript is predicted to undergo NMD.
- 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, segmental_duplication** ((GGC)n, chr7:150036751). 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; short reads may not map uniquely here, so both the call and its population frequency are less reliable. *A qualifier on how reliably this variant can be called and counted — not a pathogenicity signal.*
- Population frequency (gnomAD v4.1): grpmax **0.00497%** (amr) · 1/20,120 in the highest group · 3/1,114,996 alleles overall — very rare (popmax 0.00497%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.00497% | 20,120 |
| Finnish (not grpmax-eligible) | 0.00464% | 21,546 |
| European (non-Finnish) | 0.00011% | 912,642 |

*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}

**DPP6** population constraint: LOEUF 0.751, pLI 1.1525e-10, missense-Z 1.372; ClinGen dosage — haploinsufficiency 1/3, triplosensitivity 0/3. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **complex neurodevelopmental disorder** — Disputed (AD)

## Protein context {#protein}

Residue **53** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 87.41, 76% of residues very-high.

**8 experimental structure(s)** (PDB): [1XFD](https://www.rcsb.org/structure/1XFD), [7E87](https://www.rcsb.org/structure/7E87), [7E89](https://www.rcsb.org/structure/7E89), [7E8B](https://www.rcsb.org/structure/7E8B), [7E8E](https://www.rcsb.org/structure/7E8E), [7E8G](https://www.rcsb.org/structure/7E8G).

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

*Describes the biological roles of DPP6 (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:** DPP6's established molecular role includes potassium channel regulator activity. p.Pro53fs falls in the disordered region.


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

**Molecular function:** potassium channel regulator activity.

**Biological process:** regulation of potassium ion transmembrane transport.

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2022-12-21.

**Submitter consensus:** conflicting (1 Uncertain significance, 1 Likely pathogenic).

**Submission history:** 2 submissions (2021–2022); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| AiLife Diagnostics, AiLife Diagnostics | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-12-03 |
| Center for Personalized Medicine, Children's Hospital Los Angeles | Likely pathogenic | criteria provided, single submitter | clinical testing | 2022-12-21 |

**Reported phenotype names (ClinVar):** not provided, See cases, none provided.

## Similar variants {#similar}

Related DPP6 variant pages (same residue, condition, or type): [DPP6 c.627+20964_627+20966del](/variant/dpp6-c-627-plus-20964-627-plus-20966del), [DPP6 p.Asp865fs](/variant/dpp6-p-asp865fs), [DPP6 c.1136+40del](/variant/dpp6-c-1136-plus-40del), [DPP6 c.1261-48_1261-40del](/variant/dpp6-c-1261-minus-48-1261-minus-40del), [DPP6 c.243+13del](/variant/dpp6-c-243-plus-13del), [DPP6 c.51+164380_51+164383del](/variant/dpp6-c-51-plus-164380-51-plus-164383del), [DPP6 c.-88del](/variant/dpp6-c-minus-88del), [DPP6 c.49_51+7del](/variant/dpp6-c-49-51-plus-7del).

### 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 1677676). 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.*