DPP6

Chr 7AD

dipeptidyl peptidase like 6

Also known as: DPL1, DPPX, MRD33, VF2

NCBI Gene: 1804ENSG00000130226UniProt: P42658OMIM: 126141

DPP6 encodes a membrane protein that promotes cell surface expression of voltage-gated potassium channels and modulates their activity and gating properties, despite lacking protease activity. Autosomal dominant mutations cause intellectual developmental disorder and paroxysmal familial ventricular fibrillation. The gene is highly constrained against loss-of-function variants (LOEUF 0.377), reflecting its important role in potassium channel regulation.

OMIMResearchSummary from RefSeq, OMIM, UniProt
MultiplemechanismADLOEUF 0.382 OMIM phenotypes
Clinical Summary— DPP6
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Gene-Disease Validity (ClinGen)
complex neurodevelopmental disorder · ADDisputed

Disputed — evidence questions this relationship

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Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.23) despite low pLI — interpret in context.
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ClinVar Variants
45 unique Pathogenic / Likely Pathogenic· 80 VUS of 354 total submissions
Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
LoF Constraint
0.38LOEUF
pLI 0.340
Z-score 4.97
OE 0.23 (0.14–0.38)
Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint
2.24Z-score
OE missense 0.71 (0.64–0.77)
324 obs / 459.3 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios
LoF OE0.23 (0.14–0.38)
0≤0.351.4
Missense OE0.71 (0.64–0.77)
0≤0.61.4
Synonymous OE1.11
0≤1.21.6
LoF obs/exp: 11 / 48.3Missense obs/exp: 324 / 459.3Syn Z: -1.23
DN
0.6163th %ile
GOF
0.6151th %ile
LOF
0.4037th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and loss-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOF1 literature citation
LOF1 literature citation · LOEUF 0.38

Literature Evidence

GOFPatch clamp experiments suggested that this novel mutation might result in a gain of function and disturb the efflux of potassium ion.PMID:29474731
LOFThis first familial case provides evidence for association between DPP6 haploinsufficiency and TS, further suggesting a plausible molecular link between TS and ASD, and might shed some light on the efficacy and tolerability profiles of antidopaminergic agents used for tic management, thus prompting PMID:25129042

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

354 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic39
Likely Pathogenic6
VUS80
Likely Benign67
Benign144
Conflicting6
39
Pathogenic
6
Likely Pathogenic
80
VUS
67
Likely Benign
144
Benign
6
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
1
38
0
39
Likely Pathogenic
1
0
5
0
6
VUS
12
57
10
1
80
Likely Benign
1
17
10
39
67
Benign
0
10
120
14
144
Conflicting
—6
Total148518354342

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

DPP6 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

3D Protein StructureAlphaFold

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →
Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients