# NM_130797.4(DPP6):c.1091C>G (p.Pro364Arg)

https://sugi.bio/variant/dpp6-p-pro364arg

## Summary

**DPP6 p.Pro364Arg (c.1091C>G)** is classified **Uncertain significance** in DPP6 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2017-07-14). AlphaMissense: ambiguous (0.55); Very rare (popmax 0.000763%, nfe); Associated with Wolff-Parkinson-White syndrome.

**At a glance:** Uncertain significance · review: No assertion criteria · rsID rs756673341 · 1 submitter · 1 linked condition · AlphaMissense ambiguous · very rare (popmax 0.000763%, nfe)

## For patients & families {#patients}

This is a change in the DPP6 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to Wolff-Parkinson-White syndrome.

*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.*

|  |  |
| --- | --- |
| Clinical trials | 9 registered for this condition — see ClinicalTrials.gov |

**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.Pro364Arg |
| Coding change (HGVS c.) | c.1091C>G |
| MANE Select transcript | [NM_130797](https://www.ncbi.nlm.nih.gov/nuccore/NM_130797) |
| dbSNP | [rs756673341](https://www.ncbi.nlm.nih.gov/snp/rs756673341/) |
| Variant type | single nucleotide variant |
| Location | chr7:154772897-154772897 (GRCh38) |
| ClinVar | [VCV487598](https://www.ncbi.nlm.nih.gov/clinvar/variation/487598/) |

**All HGVS expressions:** `NC_000007.13:g.154564607C>G`, `NC_000007.14:g.154772897C>G`, `NG_033878.2:g.1029912C>G`, `NM_001039350.3:c.899C>G`, `NM_001290252.2:c.770C>G`, `NM_001364497.2:c.908C>G`, `NM_001364498.2:c.908C>G`, `NM_001364499.2:c.908C>G`, `NM_001364500.2:c.908C>G`, `NM_001364501.2:c.899C>G`, `NM_001936.5:c.905C>G`, `NM_130797.4:c.1091C>G`, `NR_157195.2:n.1541C>G`, `NR_157196.2:n.1241C>G`

## Computational & population evidence {#evidence}

**Concordance:** AlphaMissense and REVEL make no call here — the available evidence is described below.

- AlphaMissense **ambiguous** (0.55) — no call either way
- REVEL 0.414 (indeterminate)
- SaProt LLR -7.13 (tolerated)
- Conservation: phyloP 7.381, GERP 1.61, phastCons 1 — highly conserved
- CADD: **PHRED 26.9**. 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 0.83** across the covering region of the MANE Select transcript (154,052,821–154,892,477), spanning 839,656 bp. Chi-square p 1.6e-08. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.000763%** (nfe) · FAF95 0.000359% · FAF99 0.00026% · 9/1,179,550 in the highest group · 9/1,461,078 alleles overall — very rare (popmax 0.000763%, 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.*

## Gene constraint & dosage {#gene-context}

**DPP6** population constraint: LOEUF 0.751, pLI 1.1525e-10, missense-Z 1.372; ClinGen dosage — haploinsufficiency 1, triplosensitivity 0 (0–3 scale). *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 **364** lies in a β-strand.

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.


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

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

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

## Clinical significance {#significance}

**Uncertain significance** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 2017-07-14.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine | Uncertain significance | no assertion criteria provided | research | 2017-07-14 |

## Associated conditions {#conditions}

[Wolff-Parkinson-White syndrome](https://sugi.bio/atlas/disease/wolff-parkinson-white-syndrome/).

**Reported phenotype names (ClinVar):** Wolff-Parkinson-White pattern, WPW SYNDROME, Auriculoventricular accessory pathway syndrome, False bundle branch block syndrome, Anomalous ventricular excitation syndrome.

## Similar variants {#similar}

Related DPP6 variant pages (same residue, condition, or type): [DPP6 p.Met385Thr](/variant/dpp6-p-met385thr), [DPP6 p.Gly65Cys](/variant/dpp6-p-gly65cys), [DPP6 p.Gly65Val](/variant/dpp6-p-gly65val), [DPP6 p.Lys223Arg](/variant/dpp6-p-lys223arg), [DPP6 p.Pro229Thr](/variant/dpp6-p-pro229thr), [DPP6 c.1261-188G>A](/variant/dpp6-c-1261-minus-188g-a), [DPP6 c.1261-48G>A](/variant/dpp6-c-1261-minus-48g-a), [DPP6 c.1299+147A>G](/variant/dpp6-c-1299-plus-147a-g).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 487598). 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.*