DPP6

Chr 7

dipeptidyl peptidase like 6

Also known as: DPL1, DPPX, MRD33, VF2

NCBI Gene: 1804 ENSG00000130226 UniProt: P42658

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.

ResearchSummary from RefSeq, OMIM, UniProt

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]

ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

UniProtFamilial paroxysmal ventricular fibrillation 2

UniProtIntellectual developmental disorder, autosomal dominant 33

Clinical highlights

Gene–disease validity (ClinGen)

Disputed · complex neurodevelopmental disorder · AD · ClinGen 2021

evidence questions this relationship

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.38

LOEUF

Multiple*

Mechanism· predicted

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

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 OE?0.23 (0.14–0.38)

0≤0.351.4

Missense OE?0.71 (0.64–0.77)

0≤0.61.4

Synonymous OE?1.11

0≤1.21.6

LoF obs/exp: 11 / 48.3Missense obs/exp: 324 / 459.3Syn Z: -1.23

Background carrier burden — how many people carry a rare variant somewhere in DPP6?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 46

1,252 rare PASS variants

Rare truncating (LoF)

1 in 1,200

166 rare PASS variants

Rare synonymous (reference)

1 in 43

541 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for DPP6. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 69	1 in 1,400
South Asian	~43k	1 in 43	1 in 1,400
Remaining (unassigned)	~30k	1 in 41	1 in 630
European (Finnish)	~27k	1 in 110	1 in 1,200
Admixed American	~22k	1 in 39	1 in 1,000
African / African American	~21k	1 in 41	1 in 1,100
East Asian	~20k	1 in 51	1 in 3,800
Ashkenazi Jewish	~13k	1 in 260	≈ 1 in 4,300
Middle Eastern	~2,884	1 in 41	≈ 1 in 2,800

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 23 of 26 coding exons well covered in gnomAD exomes; exons 1, 4, 5 marginal. Genomes: 25 of 26 (exon 25 below).? see exons ↓