DPP6

Chr 7AD

dipeptidyl peptidase like 6

Also known as: DPL1, DPPX, MRD33, VF2

NCBI Gene: 1804ENSG00000130226UniProt: P42658

This gene encodes a single-pass type II membrane protein that is a member of the peptidase S9B family of serine proteases. This protein has no detectable protease activity, most likely due to the absence of the conserved serine residue normally present in the catalytic domain of serine proteases. However, it does bind specific voltage-gated potassium channels and alters their expression and biophysical properties. Variations in this gene may be associated with susceptibility to amyotrophic lateral sclerosis and with idiopathic ventricular fibrillation. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2014]

Primary Disease Associations & Inheritance

{Ventricular fibrillation, paroxysmal familial, 2}MIM #612956
AD
Intellectual developmental disorder, autosomal dominant 33MIM #616311
AD
UniProtFamilial paroxysmal ventricular fibrillation 2
337
ClinVar variants
43
Pathogenic / LP
0.34
pLI score
0
Active trials
Clinical Summary— DPP6
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Gene-Disease Validity (ClinGen)
complex neurodevelopmental disorder · ADDisputed

Disputed — evidence questions this relationship

⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.23) despite low pLI — interpret in context.
📋
ClinVar Variants
43 Pathogenic / Likely Pathogenic· 79 VUS of 337 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
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?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
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?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.23 (0.14–0.38)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.71 (0.64–0.77)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.11
0≤1.21.6
LoF obs/exp: 11 / 48.3Missense obs/exp: 324 / 459.3Syn Z: -1.23

ClinVar Variant Classifications

337 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic38
Likely Pathogenic5
VUS79
Likely Benign65
Benign144
Conflicting6
38
Pathogenic
5
Likely Pathogenic
79
VUS
65
Likely Benign
144
Benign
6
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
1
37
0
38
Likely Pathogenic
0
0
5
0
5
VUS
8
55
15
1
79
Likely Benign
0
13
14
38
65
Benign
0
10
120
14
144
Conflicting
—6
Total87919153337

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.

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

{Ventricular fibrillation, paroxysmal familial, 2}

MIM #612956

Molecular basis of disorder known

Autosomal dominant

Intellectual developmental disorder, autosomal dominant 33

MIM #616311

Molecular basis of disorder known

Autosomal dominant
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Association between DPP6 gene rs10260404 polymorphism and increased risk of sporadic amyotrophic lateral sclerosis (sALS): a meta-analysis.
Miah MM et al.·Neurol Sci
2024Meta-analysis
GWAS Identifies DPP6 as Risk Gene of Cognitive Decline in Parkinson's Disease.
Li C et al.·J Gerontol A Biol Sci Med Sci
2024
A novel DPP6 variant in Chinese families causes early repolarization syndrome.
Ji CC et al.·Exp Cell Res
2019
Loss of DPP6 in neurodegenerative dementia: a genetic player in the dysfunction of neuronal excitability.
Cacace R et al.·Acta Neuropathol
2019
Implication of LRRC4C and DPP6 in neurodevelopmental disorders.
Maussion G et al.·Am J Med Genet A
2017
Haplotype-sharing analysis implicates chromosome 7q36 harboring DPP6 in familial idiopathic ventricular fibrillation.
Alders M et al.·Am J Hum Genet
2009
Spectrum of Rare and Common Genetic Variants in Arrhythmogenic Cardiomyopathy Patients.
Lippi M et al.·Biomolecules
2022Cohort
Beta Cell Imaging-From Pre-Clinical Validation to First in Man Testing.
Demine S et al.·Int J Mol Sci
2020Review
Pharmacogenetics of tardive dyskinesia: an updated review of the literature.
Lanning RK et al.·Pharmacogenomics
2016Review
Dipeptidyl peptidase-like protein 6 is required for normal electrophysiological properties of cerebellar granule cells.
Nadin BM et al.·J Neurosci
2010
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools