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…

MultiplemechanismLOEUF 0.38

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

5 unique Pathogenic / Likely Pathogenic· 73 VUS of 303 total submissions

Explore recent and relevant literature in Research Assistant →

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

This gene — mechanism propensity

0.6163th %ile

GOF

0.6151th %ile

LOF

0.4037th %ile

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and gain-of-function). The Badonyi & Marsh model scores gain-of-function highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports loss-of-function (haploinsufficiency). Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOF1 literature citation · 40% of P/LP variants are LoF · LOEUF 0.38

GOF1 literature citation

Literature Evidence

GOFPatch clamp experiments suggested that this novel mutation might result in a gain of function and disturb the efflux of potassium ion.1

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 2

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

References

ClinVar Variant Classifications

303 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic2

Likely Pathogenic3

VUS73

Likely Benign66

Benign141

Conflicting6

Pathogenic

Likely Pathogenic

VUS

Likely Benign

141

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	1	1	0	2
Likely Pathogenic	2	0	1	0	3
VUS	12	54	6	1	73
Likely Benign	1	17	9	39	66
Benign	0	10	117	14	141
Conflicting	—				6
Total	15	82	134	54	291

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

View in ClinVar →

41 pathogenic / likely-pathogenic (of 49) ClinVar copy-number / structural variants overlap DPP6 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →