DPP6

Summary

DPP6 (dipeptidyl peptidase like 6, HGNC:3010) is a protein-coding gene on chromosome 7q36.2, encoding A-type potassium channel modulatory protein DPP6 (P42658). Promotes cell surface expression of the potassium channel KCND2.

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.

Source: NCBI Gene 1804 — RefSeq curated summary.

At a glance

• Gene–disease (curated): paroxysmal familial ventricular fibrillation (Supportive, GenCC) — +4 more curated relationships
• GWAS associations: 27
• Clinical variants (ClinVar): 314 total — 2 pathogenic, 2 likely-pathogenic
• Phenotypes (HPO): 18
• Dosage sensitivity (ClinGen): haploinsufficiency little evidence, triplosensitivity no evidence
• MANE Select transcript: NM_130797

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3010
Approved symbol	DPP6
Name	dipeptidyl peptidase like 6
Location	7q36.2
Locus type	gene with protein product
Status	Approved
Aliases	DPPX, DPL1
Ensembl gene	ENSG00000130226
Ensembl biotype	protein_coding
OMIM	126141
Entrez	1804

Gene structure

Transcript identifiers

Ensembl transcripts: 23 — 9 protein_coding, 8 protein_coding_CDS_not_defined, 6 retained_intron

ENST00000332007, ENST00000377770, ENST00000404039, ENST00000406326, ENST00000427557, ENST00000462622, ENST00000471100, ENST00000478614, ENST00000479637, ENST00000480367, ENST00000481593, ENST00000484789, ENST00000488512, ENST00000493268, ENST00000496611, ENST00000619756, ENST00000706130, ENST00000706151, ENST00000706152, ENST00000706153, ENST00000706154, ENST00000706155, ENST00000706156

RefSeq mRNA: 10 — MANE Select: NM_130797 NM_001039350, NM_001290252, NM_001290253, NM_001364497, NM_001364498, NM_001364499, NM_001364500, NM_001364502, NM_001936, NM_130797

CCDS: CCDS75682, CCDS75683, CCDS75684, CCDS78290, CCDS78291, CCDS94238, CCDS94239

Canonical transcript exons

ENST00000377770 — 26 exons

Exon	Start	End
ENSE00000730516	154769417	154769571
ENSE00000730522	154801355	154801462
ENSE00000730523	154803864	154803955
ENSE00000843070	154772845	154772942
ENSE00000843075	154880888	154880942
ENSE00000843076	154885633	154885744
ENSE00000843079	154889457	154889530
ENSE00001377056	154052398	154053063
ENSE00001549428	154892334	154894285
ENSE00002210923	154727767	154727887
ENSE00002271724	154637821	154637873
ENSE00002305969	154669360	154669441
ENSE00003472908	154889272	154889344
ENSE00003511625	154794079	154794202
ENSE00003512336	154875906	154876100
ENSE00003520070	154795845	154795883
ENSE00003540573	154867995	154868093
ENSE00003555191	154804917	154804964
ENSE00003575353	154872624	154872693
ENSE00003580288	154853780	154853827
ENSE00003582120	154474939	154475037
ENSE00003591401	154566842	154566916
ENSE00003598278	154887676	154887734
ENSE00003631590	154806994	154807112
ENSE00003653234	154540532	154540626
ENSE00003659278	154446214	154446328

Expression profiles

Bgee: expression breadth ubiquitous, 221 present calls, max score 99.75.

FANTOM5 (CAGE): breadth broad, TPM avg 8.7768 / max 516.7301, expressed in 252 samples.

FANTOM5 promoters (29 alternative TSS)

Promoter ID	TPM avg	Samples expressed
82181	1.8936	115
82162	1.2846	148
82182	1.0416	102
82186	0.8604	91
82184	0.5442	95
82183	0.4398	92
82161	0.3893	112
82167	0.2415	125
82158	0.1897	89
82180	0.1897	83

Top tissues by expression

293 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
middle temporal gyrus	UBERON:0002771	99.75	gold quality
Brodmann (1909) area 23	UBERON:0013554	99.38	gold quality
endothelial cell	CL:0000115	99.27	gold quality
pons	UBERON:0000988	98.09	gold quality
lateral nuclear group of thalamus	UBERON:0002736	97.45	gold quality
primary visual cortex	UBERON:0002436	96.83	gold quality
superior frontal gyrus	UBERON:0002661	96.83	gold quality
postcentral gyrus	UBERON:0002581	96.38	gold quality
entorhinal cortex	UBERON:0002728	96.37	gold quality
parietal lobe	UBERON:0001872	96.34	gold quality
CA1 field of hippocampus	UBERON:0003881	96.28	gold quality
medial globus pallidus	UBERON:0002477	96.06	gold quality
occipital lobe	UBERON:0002021	95.96	gold quality
superior vestibular nucleus	UBERON:0007227	95.61	gold quality
cerebellar cortex	UBERON:0002129	95.33	gold quality
cerebellar hemisphere	UBERON:0002245	95.28	gold quality
cerebellar vermis	UBERON:0004720	95.24	gold quality
right hemisphere of cerebellum	UBERON:0014890	95.22	gold quality
cerebellum	UBERON:0002037	95.21	gold quality
globus pallidus	UBERON:0001875	95.20	gold quality
prefrontal cortex	UBERON:0000451	95.02	gold quality
frontal cortex	UBERON:0001870	94.98	gold quality
lateral globus pallidus	UBERON:0002476	94.64	gold quality
substantia nigra pars compacta	UBERON:0001965	94.31	gold quality
neocortex	UBERON:0001950	94.27	gold quality
cerebral cortex	UBERON:0000956	94.12	gold quality
Ammon’s horn	UBERON:0001954	93.92	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	93.83	gold quality
substantia nigra pars reticulata	UBERON:0001966	93.78	gold quality
right frontal lobe	UBERON:0002810	93.78	gold quality

Single-cell (SCXA)

Detected in 9 experiment(s), a significant marker in 7.

Experiment	Marker?	Max mean expression
E-HCAD-35	yes	87.53
E-CURD-119	yes	31.98
E-HCAD-25	yes	24.99
E-GEOD-84465	yes	22.98
E-MTAB-5061	yes	14.64
E-GEOD-83139	yes	9.09
E-ANND-3	yes	5.57
E-MTAB-6058	no	300.22
E-GEOD-124858	no	3.57

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): DNMT3A, DNMT3B, FOXC1

miRNA regulators (miRDB)

53 targeting DPP6, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4481	100.00	66.42	1669
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-4745-5P	99.98	65.95	1028
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-8075	99.97	67.20	962
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-381-3P	99.93	71.87	2854
HSA-MIR-218-5P	99.93	72.22	2103
HSA-MIR-300	99.92	71.76	2856
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-765	99.84	68.24	2442
HSA-MIR-4307	99.82	70.45	3374
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-4645-3P	99.76	69.33	993
HSA-MIR-200A-5P	99.76	69.10	949
HSA-MIR-200B-5P	99.76	69.05	948
HSA-MIR-92A-2-5P	99.75	67.01	2164
HSA-MIR-11181-3P	99.75	66.38	2205
HSA-MIR-6745	99.74	65.33	1321
HSA-MIR-4524A-3P	99.72	66.85	2406
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-33A-3P	99.70	70.27	3362
HSA-MIR-6883-5P	99.69	68.05	3785
HSA-MIR-5093	99.67	69.26	2291
HSA-MIR-409-3P	99.50	66.33	1192

Functional genomics

ClinGen dosage: haploinsufficiency 1 (little evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 33)

• DPPX is an essential component of the native cardiac I(to) channel complex in human heart (PMID:15890703)
• The emerging diversity of DPPX splice variants, differing only in the N-terminus of the protein, opens up intriguing possibilities for the modulation of Kv4 channels. (PMID:16764835)
• Analysis of the differential expression of two distinct forms of mRNA for the cow and rat orthologs. Names the variants S and L. (PMID:1729689)
• The strongest association for ALS was a variant in the gene encoding DPP6. (PMID:18057069)
• Study identified a SNP in the DPP6 gene that is consistently strongly associated with susceptibility to amyotrophic lateral sclerosis in different populations of European ancestry, with an overall P value of 5.04 x 10(-8.) (PMID:18084291)
• biophysical and biochemical methods indicate that I(SA) channels carry four subunits each of Kv4.2 and DPP6. (PMID:18364354)
• demonstrated a 20-fold increase in DPP6 mRNA levels in the myocardium of familial idiopathic ventricular fibrillation carriers as compared to controls (PMID:19285295)
• Genetic variation in DPP6, which is located in intron 3 and expressed predominantly in the nervous system, may be a risk factor for susceptibility to progressive spinal muscular atrophy. (PMID:19332697)
• There was no evidence of association of dipeptidyl-peptidase 6 alleles with amyotrophic lateral sclerosis. Our negative results agree with those recently reported in additional Polish and Italian cohorts. (PMID:19525032)
• REVIEW: role in health and disease (PMID:19676137)
• KV4.2 channel fast inactivation induced by DPP10a or DPP6a is mediated by a common N-terminal inactivation motif via a pore-blocking mechanism. (PMID:19901547)
• This study indicated that mutations in dpp6 genes are unlikely to be a common cause of ALS in the French and French Canadian populations. (PMID:20001489)
• The rs10260404 polymorphism is not associated with an increased risk of sporadic amyotrophic lateral sclerosis in Chinese patients. (PMID:20137488)
• DPP6 expression seems to be critical for the expression of a high-frequency electrophysiological phenotype in cerebellar granule cells by increasing leak conductance, A-type current levels and kinetics, and Na(+) current amplitude. (PMID:20573902)
• a genome-wide association study of amyotrophic lateral sclerosis identified the DPP6 locus as a candidate for more in-depth studies (PMID:20685689)
• Findings of this study indicate that an altered response of Kv4/DPP6 to long-term neuroleptic administration is involved in neuroleptic-induced TD. (PMID:21826085)
• Results showed that DPP6, SPHKAP and ID4 were down regulated in acute myeloid leukemia (AML) patients. (PMID:22479372)
• These results, inflated by the limited sample size determined by the rarity of this condition, suggest a possible role of this gene in the susceptibility to PrMS, at least in Southern Europeans. (PMID:23069673)
• Antibodies to DPPX are associated with a protracted encephalitis characterized by central nervous system hyperexcitability. (PMID:23225603)
• DPP6-mediated Purkinje fibers early-repolarization syndrome might be a novel molecular paradigm for some forms of idiopathic ventricular fibrillation. (PMID:23532596)
• Two DPP6 de novo deletions and one missense mutation in familial microcephalic patients were identified. (PMID:23832105)
• WT PrP(C), in a DPP6-dependent manner, modulated Kv4.2 channel properties, causing an increase in peak amplitude (PMID:24225951)
• DPP6 is critical for synaptic integration and excitation. (PMID:24677629)
• This first familial case provides evidence for association between DPP6 haploinsufficiency and Gilles de la Tourette syndrome. (PMID:25129042)
• the cysteine-rich domain of DPP6 plays an important role in protein folding of DPP6 that is required for transport of DPP6/Kv4.2 complexes out of the ER (PMID:25190807)
• we expanded our knowledge of familial IVF linked to the DPP6 gene and discuss its (extended) clinical characteristics. In addition, its relationship with the Purkinje network is further explored. (PMID:26681609)
• These data suggest that the proband’s autism may be due to the inheritance of disruptions in both DPP6 and LRRC4C, and may highlight the importance of the netrin G family and potassium channel interacting molecules in neurodevelopmental disorders. (PMID:27759917)
• A novel missense mutation (c.1578G>C/p.Q526H) of DPP6 was identified and co-segregated with affected patients in a family with suspicious idiopathic ventricular fibrillation. (PMID:29474731)
• In an unresolved autosomal dominant dementia family significantly linked to 7q36, there was a chromosomal inversion of ca. 4 Mb, segregating on the disease haplotype and disrupting the coding sequence of DPP6. The missense variants found in patients destabilize DPP6 and reduce its membrane expression. DPP6 loss plays a in dementia. (PMID:30874922)
• The slope of the activation curve of DPP6-L747P was slightly decreased. (PMID:31476289)
• Dipeptidyl peptidase like 6 promoter methylation is a potential prognostic biomarker for pancreatic ductal adenocarcinoma. (PMID:32701143)
• Neuronal Differentiation of Induced Pluripotent Stem Cells from Schizophrenia Patients in Two-Dimensional and in Three-Dimensional Cultures Reveals Increased Expression of the Kv4.2 Subunit DPP6 That Contributes to Decreased Neuronal Activity. (PMID:33143549)
• Association between DPP6 gene rs10260404 polymorphism and increased risk of sporadic amyotrophic lateral sclerosis (sALS): a meta-analysis. (PMID:38381392)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	dpp6b	ENSDARG00000024744
danio_rerio	dpp6a	ENSDARG00000076826
mus_musculus	Dpp6	ENSMUSG00000061576
rattus_norvegicus	Dpp6	ENSRNOG00000030547
drosophila_melanogaster	CG3744	FBGN0039240
caenorhabditis_elegans	dpf-3	WBGENE00001056

Paralogs (6): DPP8 (ENSG00000074603), FAP (ENSG00000078098), DPP9 (ENSG00000142002), APEH (ENSG00000164062), DPP10 (ENSG00000175497), DPP4 (ENSG00000197635)

Protein

Protein identifiers

A-type potassium channel modulatory protein DPP6 — P42658 (reviewed: P42658)

Alternative names: DPPX, Dipeptidyl aminopeptidase-like protein 6, Dipeptidyl aminopeptidase-related protein, Dipeptidyl peptidase 6, Dipeptidyl peptidase IV-like protein, Dipeptidyl peptidase VI

All UniProt accessions (8): P42658, A0A087WTG7, A0A994J521, A0A994J5Q6, A0A994J7K0, E9PDL2, E9PF59, Q8IYG9

UniProt curated annotations — full annotation on UniProt →

Function. Promotes cell surface expression of the potassium channel KCND2. Modulates the activity and gating characteristics of the potassium channel KCND2. Has no dipeptidyl aminopeptidase activity.

Subunit / interactions. Homodimer (in vitro). Interacts with KCND2. Identified in a complex with KCND2 and KCNIP2. Forms an octameric complex composed of four DPP6 subunits bound to the KCND2 tetramer. Interacts with KCND3; this interaction modulates the channel gating kinetics namely channel activation and inactivation kinetics and rate of recovery from inactivation.

Subcellular location. Cell membrane.

Tissue specificity. Expressed predominantly in brain.

Post-translational modifications. N-glycosylated.

Disease relevance. Familial paroxysmal ventricular fibrillation 2 (VF2) [MIM:612956] A cardiac arrhythmia marked by fibrillary contractions of the ventricular muscle due to rapid repetitive excitation of myocardial fibers without coordinated contraction of the ventricle and by absence of atrial activity. The disease is caused by variants affecting the gene represented in this entry. A genetic variation 340 bases upstream from the ATG start site of the DPP6 gene is the cause of familial paroxysmal ventricular fibrillation type 2. Intellectual developmental disorder, autosomal dominant 33 (MRD33) [MIM:616311] A disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. MRD33 patients manifest microcephaly in addition to intellectual disability. The disease is caused by variants affecting the gene represented in this entry.

Miscellaneous. Genetic variation in DPP6 may influence susceptibility to amyotrophic lateral sclerosis (ALS). ALS is a severely disabling and lethal disorder caused by progressive degeneration of motor neurons in the brain, spinal cord and brainstem.

Similarity. Belongs to the peptidase S9B family.

Isoforms (2)

UniProt ID	Names	Canonical?
P42658-1	DPPX-L	yes
P42658-2	DPPX-S

RefSeq proteins (10): NP_001034439, NP_001277181, NP_001277182, NP_001351426, NP_001351427, NP_001351428, NP_001351429, NP_001351431, NP_001927, NP_570629* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001375	Peptidase_S9_cat	Domain
IPR002469	Peptidase_S9B_N	Domain
IPR029058	AB_hydrolase_fold	Homologous_superfamily
IPR050278	Serine_Prot_S9B/DPPIV	Family

Pfam: PF00326, PF00930

UniProt features (94 total): strand 49, helix 14, turn 10, glycosylation site 7, disulfide bond 4, topological domain 2, sequence variant 2, sequence conflict 2, chain 1, splice variant 1, transmembrane region 1, region of interest 1

Structure

Experimental structures (PDB)

8 structures.

PDB	Method	Resolution (Å)
7UKG	ELECTRON MICROSCOPY	2.24
1XFD	X-RAY DIFFRACTION	3
7E87	ELECTRON MICROSCOPY	3.4
7E8E	ELECTRON MICROSCOPY	3.9
7E89	ELECTRON MICROSCOPY	4
7E8B	ELECTRON MICROSCOPY	4.2
7E8G	ELECTRON MICROSCOPY	4.5
7E8H	ELECTRON MICROSCOPY	4.5

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P42658-F1	87.41	0.76

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Disulfide bonds (4): 411–418, 527–530, 536–554, 735–846

Glycosylation sites (7): 566, 813, 173, 319, 404, 471, 535

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 188 (showing top): GOBP_POTASSIUM_ION_TRANSPORT, BENPORATH_ES_WITH_H3K27ME3, GRUETZMANN_PANCREATIC_CANCER_DN, JAEGER_METASTASIS_DN, GOBP_PROTEIN_LOCALIZATION_TO_CELL_PERIPHERY, GOBP_MONOATOMIC_CATION_TRANSPORT, MODULE_66, MCLACHLAN_DENTAL_CARIES_DN, WONG_ENDMETRIUM_CANCER_DN, DELYS_THYROID_CANCER_DN, MODULE_113, JOSEPH_RESPONSE_TO_SODIUM_BUTYRATE_DN, GOBP_LOCALIZATION_WITHIN_MEMBRANE, GNF2_RAB3A, GOBP_REGULATION_OF_TRANSPORT

GO Biological Process (3): proteolysis (GO:0006508), protein localization to plasma membrane (GO:0072659), regulation of potassium ion transmembrane transport (GO:1901379)

GO Molecular Function (3): serine-type peptidase activity (GO:0008236), potassium channel regulator activity (GO:0015459), protein binding (GO:0005515)

GO Cellular Component (3): plasma membrane (GO:0005886), voltage-gated potassium channel complex (GO:0008076), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein metabolic process	1
protein localization to membrane	1
protein localization to cell periphery	1
regulation of potassium ion transport	1
potassium ion transmembrane transport	1
regulation of monoatomic cation transmembrane transport	1
peptidase activity	1
serine hydrolase activity	1
potassium channel activity	1
ion channel regulator activity	1
binding	1
membrane	1
cell periphery	1
potassium channel complex	1
plasma membrane protein complex	1
cellular anatomical structure	1

Protein interactions and networks

STRING

2194 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DPP6	KCND3	Q9UK17	924
DPP6	SCN5A	Q14524	909
DPP6	KCND2	Q9NZV8	888
DPP6	KCNC1	P48547	876
DPP6	IGLON5	A6NGN9	872
DPP6	LGI1	O95970	871
DPP6	CNTNAP2	Q9UHC6	818
DPP6	KCNIP2	Q9NS61	814
DPP6	KCNIP1	Q9NZI2	790
DPP6	PNMA2	Q9UL42	773
DPP6	GRM5	P41594	755
DPP6	AMPH	P49418	720
DPP6	DPYSL5	Q9BPU6	717
DPP6	ZIC4	Q8N9L1	697
DPP6	KCNIP4	Q6PIL6	693

IntAct

9 interactions, top by confidence:

A	B	Type	Score
PLG	DPP6	psi-mi:“MI:0915”(physical association)	0.400
M		psi-mi:“MI:0914”(association)	0.350
GPM6A	KIF2A	psi-mi:“MI:0914”(association)	0.350
DNAAF2	DNM1L	psi-mi:“MI:0914”(association)	0.350
PCDHGA7	SDCBP	psi-mi:“MI:0914”(association)	0.350
DPP6	ATP5MC1	psi-mi:“MI:0914”(association)	0.350
DPP6	PHB1	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (21): DPP6 (Affinity Capture-MS), DPP6 (Affinity Capture-MS), DPP6 (Synthetic Growth Defect), DPP6 (Affinity Capture-MS), DPP6 (Affinity Capture-MS), DPP6 (Affinity Capture-RNA), MYO10 (Affinity Capture-Western), ATP5G1 (Affinity Capture-MS), NUDT9 (Affinity Capture-MS), DPP6 (Affinity Capture-MS), DPP6 (Affinity Capture-MS), ITIH2 (Affinity Capture-MS), APOL2 (Affinity Capture-MS), DPP6 (Affinity Capture-MS), DPP6 (Affinity Capture-MS)

ESM2 similar proteins: A0A0C1E1D0, A0A1L9WUM2, A0A1Q3EPF5, A0A4S8L6U5, A0S5V9, A1CHP1, A1CX29, A5D7B7, A7UKV8, B0Y6C5, B1A4F7, B2D0J4, B6V868, B8N970, C5FJE3, C9K7B8, D4APE2, D4CZ59, E2JFG1, E2JFG2, H2E7Q7, H2E7Q8, O14073, P0DRB8, P14740, P22411, P27487, P28843, P42658, P46101, P78875, P81425, P97321, P9WEN5, Q09541, Q12884, Q2UH35, Q4WAZ0, Q4WPH9, Q5AV79

Diamond homologs: A0S5V9, A1CHP1, A1CJQ1, A1D7R6, A4QYQ5, A5D7B7, A6RBI0, A6SL49, A7EQZ1, A7UKV8, B0XYK8, B0Y6C5, B1A4F7, B2A951, B2D0J4, B2WC36, B6QVW4, B6V868, B8MTH6, B8N076, B8N970, C0NUQ8, C0S7H1, C1FZL3, C1GT79, C5FJE3, C5GVF3, C5JC30, C6HRC7, C7YYG9, D1Z9B4, D4APE2, D4CZ59, D5GM60, E3QKD2, E4UYL6, E9ED72, E9ETL5, F0U7H7, F0XS04

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
DNMT3A	“down-regulates quantity by repression”	DPP6	“transcriptional regulation”
DNMT3B	“down-regulates quantity by repression”	DPP6	“transcriptional regulation”
DPP6	“up-regulates activity”	KCND2	relocalization

Disease & clinical

Clinical variants and AI predictions

ClinVar

314 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	2
Uncertain significance	80
Likely benign	66
Benign	144

Top pathogenic / likely-pathogenic (4)

Variant ID	HGVS	Classification
189389	NM_130797.4(DPP6):c.1153A>C (p.Met385Leu)	Pathogenic
189390	NC_000007.13:g.153649777_153985995del	Pathogenic
4820094	NM_130797.4(DPP6):c.615C>A (p.Tyr205Ter)	Likely pathogenic
545344	NC_000007.14:g.(?153822158)(153968005_?)del	Likely pathogenic

SpliceAI

2607 predictions. Top by Δscore:

Variant	Effect	Δscore
7:154053058:G:GT	donor_gain	1.0000
7:154053064:G:GG	donor_gain	1.0000
7:154053060:GGAC:G	donor_gain	0.9900
7:154053061:G:T	donor_gain	0.9900
7:154053061:GAC:G	donor_gain	0.9900
7:154053061:GACG:G	donor_gain	0.9900
7:154053062:ACGTA:A	donor_loss	0.9900
7:154053063:CGTA:C	donor_loss	0.9900
7:154053064:G:T	donor_loss	0.9900
7:154053065:T:A	donor_loss	0.9900
7:154157401:G:GT	donor_gain	0.9900
7:154157401:G:T	donor_gain	0.9900
7:154287338:A:G	acceptor_gain	0.9900
7:154305420:C:A	acceptor_gain	0.9900
7:154318650:GC:G	donor_gain	0.9900
7:154347021:G:GG	donor_gain	0.9900
7:154305424:T:A	acceptor_gain	0.9800
7:154392503:GTTC:G	donor_gain	0.9800
7:154053059:AGGAC:A	donor_gain	0.9700
7:154053060:GGACG:G	donor_gain	0.9700
7:154053062:AC:A	donor_gain	0.9700
7:154115167:G:GA	donor_gain	0.9700
7:154230269:G:GT	donor_gain	0.9700
7:154249199:A:G	donor_gain	0.9700
7:154305431:T:TA	acceptor_gain	0.9700
7:154318651:C:G	donor_gain	0.9600
7:154053038:C:T	donor_gain	0.9500
7:154053051:TGACG:T	donor_gain	0.9500
7:154053053:ACGAG:A	donor_gain	0.9500
7:154115166:T:TA	donor_gain	0.9500

AlphaMissense

5724 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:154446253:G:A	G95R	1.000
7:154446253:G:C	G95R	1.000
7:154446269:T:C	L100P	1.000
7:154794104:T:A	W388R	1.000
7:154794104:T:C	W388R	1.000
7:154446249:G:C	W93C	0.999
7:154446249:G:T	W93C	0.999
7:154446254:G:A	G95E	0.999
7:154446263:T:A	I98N	0.999
7:154446266:C:A	A99E	0.999
7:154446278:T:A	I103N	0.999
7:154446289:T:C	C107R	0.999
7:154669418:T:A	W247R	0.999
7:154669418:T:C	W247R	0.999
7:154727864:G:A	G287D	0.999
7:154794106:G:C	W388C	0.999
7:154794106:G:T	W388C	0.999
7:154794173:T:C	C411R	0.999
7:154446243:G:C	R91S	0.998
7:154446243:G:T	R91S	0.998
7:154446246:T:A	N92K	0.998
7:154446246:T:G	N92K	0.998
7:154446257:T:A	I96K	0.998
7:154446272:T:C	L101P	0.998
7:154446275:T:A	V102D	0.998
7:154446299:T:A	I110N	0.998
7:154475028:T:A	W150R	0.998
7:154475028:T:C	W150R	0.998
7:154669420:G:C	W247C	0.998
7:154669420:G:T	W247C	0.998

dbSNP variants (sampled 300 via entrez): RS1000001369 (7:154342646 T>G), RS1000002812 (7:154462404 A>G), RS1000003431 (7:154270258 G>A), RS1000004358 (7:154545071 A>G), RS1000006040 (7:154449738 T>G), RS1000006423 (7:154654707 C>T), RS1000007258 (7:154708682 G>A), RS1000008021 (7:154499759 A>G), RS1000009120 (7:154308051 C>G), RS1000011547 (7:154894630 T>C), RS1000012445 (7:154490992 C>T), RS1000017342 (7:154783408 A>G), RS1000020899 (7:154733443 C>A), RS1000022497 (7:154806892 C>T), RS1000023246 (7:154411551 T>C)

Disease associations

OMIM: gene MIM:126141 | disease phenotypes: MIM:616311, MIM:612956, MIM:194200, MIM:181500, MIM:603829

GenCC curated gene-disease

Disease	Classification	Inheritance
paroxysmal familial ventricular fibrillation	Supportive	Autosomal dominant
autosomal dominant primary microcephaly	Supportive	Autosomal dominant
ventricular fibrillation, paroxysmal familial, 2	Limited	Autosomal dominant
intellectual disability, autosomal dominant 33	Limited	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
complex neurodevelopmental disorder	Disputed	AD

Mondo (12): intellectual disability, autosomal dominant 33 (MONDO:0014580), ventricular fibrillation, paroxysmal familial, 2 (MONDO:0013063), ventricular tachycardia (MONDO:0005477), cardiac arrest (MONDO:0000745), dilated cardiomyopathy (MONDO:0005021), long QT syndrome (MONDO:0002442), complex neurodevelopmental disorder (MONDO:0100038), Wolff-Parkinson-White syndrome (MONDO:0008685), schizophrenia (MONDO:0005090), ventricular fibrillation, paroxysmal familial, type 1 (MONDO:0011376), paroxysmal familial ventricular fibrillation (MONDO:0100234), autosomal dominant primary microcephaly (MONDO:0007988)

Orphanet (5): Idiopathic ventricular fibrillation (Orphanet:228140), Dilated cardiomyopathy (Orphanet:217604), Non-specific syndromic intellectual disability (Orphanet:528084), NON RARE IN EUROPE: Wolff-Parkinson-White syndrome (Orphanet:907), NON RARE IN EUROPE: Schizophrenia (Orphanet:3140)

HPO phenotypes

18 total (21 of 18 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000252	Microcephaly
HP:0000411	Protruding ear
HP:0000533	Chorioretinal atrophy
HP:0000646	Amblyopia
HP:0000666	Horizontal nystagmus
HP:0000752	Hyperactivity
HP:0001137	Alternating esotropia
HP:0001249	Intellectual disability
HP:0001645	Sudden cardiac death
HP:0001663	Ventricular fibrillation
HP:0002650	Scoliosis
HP:0002750	Delayed skeletal maturation
HP:0003577	Congenital onset
HP:0004322	Short stature
HP:0004325	Decreased body weight
HP:0006682	Premature ventricular contraction
HP:0009804	Tooth agenesis
HP:0001644	Dilated cardiomyopathy
HP:0001716	Wolff-Parkinson-White syndrome
HP:0100753	Schizophrenia

GWAS associations

27 associations (top):

Study	Trait	p-value
GCST000126_1	Amyotrophic lateral sclerosis	3.000000e-06
GCST000127_1	Amyotrophic lateral sclerosis	5.000000e-08
GCST000260_1	Amyotrophic lateral sclerosis	3.000000e-06
GCST000745_2	Pancreatic cancer	4.000000e-07
GCST001196_1	Tardive dyskinesia	5.000000e-06
GCST001922_3	QT interval	2.000000e-06
GCST002401_3	Post-traumatic stress disorder	4.000000e-06
GCST002415_6	Colorectal cancer (diet interaction)	2.000000e-06
GCST002926_6	Bone mineral accretion in asthma (oral corticosteroid dose interaction)	8.000000e-08
GCST003226_23	Pelvic organ prolapse	7.000000e-06
GCST003226_6	Pelvic organ prolapse	5.000000e-07
GCST003263_11	Post bronchodilator FEV1 in COPD	4.000000e-07
GCST003685_4	Gestational age at birth in premature rupture of membrane-initiated deliveries (maternal effect)	5.000000e-07
GCST004068_3	Venous thromboembolism adjusted for sickle cell variant rs77121243-T	3.000000e-06
GCST006291_116	Spherical equivalent or myopia (age of diagnosis)	1.000000e-15
GCST006921_5	Regular attendance at a pub or social club	4.000000e-15
GCST008153_58	Lean body mass	3.000000e-08
GCST008163_94	Height	6.000000e-06
GCST008522_40	Bitter alcoholic beverage consumption	4.000000e-10
GCST008757_10	Alcohol consumption	6.000000e-14
GCST008811_42	Alcohol consumption (drinks per week)	2.000000e-11
GCST009264_8	Thalamus volume	3.000000e-06
GCST009443_4	Age-related cognitive decline (visuospatial skill) (slope of z-scores)	7.000000e-06
GCST010151_16	Carotid intima media thickness x smoking interaction	2.000000e-06
GCST010546_18	Problematic alcohol use	2.000000e-08
GCST012319_7	LDL levels x SSRI levels (escitalopram or citalopram) interaction in schizophrenia or bipolar disorder	2.000000e-06
GCST90006997_6	Gut microbiota relative abundance (Coprococcus)	3.000000e-06

EFO canonical traits (15, from GWAS)

EFO ID	Trait name
EFO:0004682	QT interval
EFO:0008111	diet measurement
EFO:0007591	bone mineral accretion measurement
EFO:0004314	forced expiratory volume
EFO:0005112	gestational age
EFO:0004847	age at onset
EFO:0009592	social interaction measurement
EFO:0004995	lean body mass
EFO:0010092	bitter alcoholic beverage consumption measurement
EFO:0006935	thalamus volume
EFO:0007710	cognitive decline measurement
EFO:0006527	smoking status measurement
EFO:0009458	alcohol use disorder measurement
EFO:0004611	low density lipoprotein cholesterol measurement
EFO:0007874	gut microbiome measurement

MeSH disease descriptors (8)

Descriptor	Name	Tree numbers
D002311	Cardiomyopathy, Dilated	C14.280.195.160; C14.280.238.070; C16.320.488.750
D006323	Heart Arrest	C14.280.383
D008133	Long QT Syndrome	C14.280.067.565; C14.280.123.625; C16.131.240.400.715; C23.550.073.547
D017180	Tachycardia, Ventricular	C14.280.067.845.940; C14.280.123.875.940; C23.550.073.845.940
D014927	Wolff-Parkinson-White Syndrome	C14.280.067.780.977; C14.280.123.750.977; C16.131.240.400.980
C537323	Microcephaly autosomal dominant (supp.)
C567851	Ventricular Fibrillation, Paroxysmal Familial, 1 (supp.)
C567841	Ventricular Fibrillation, Paroxysmal Familial, 2 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs2533200	Toxicity	3	ethanol	Alcohol abuse

PharmGKB variants

3 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs6977820	DPP6	3	3.00	1	antipsychotics
rs887929	DPP6, UGT1A1		0.00	0
rs2533200	DPP6	3	1.50	1	ethanol

CTD chemical–gene interactions

18 total (human), top 18 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol S	increases methylation, decreases expression, affects cotreatment	2
Valproic Acid	affects expression, increases methylation	2
methylmercuric chloride	decreases expression	1
bisphenol A	decreases methylation	1
trichostatin A	decreases expression	1
sodium arsenite	affects methylation	1
benzo(e)pyrene	decreases methylation	1
CGP 52608	affects binding, increases reaction	1
Resveratrol	affects cotreatment, decreases expression	1
Fulvestrant	affects cotreatment, increases methylation, decreases methylation	1
Arsenic	affects methylation	1
Benzo(a)pyrene	affects methylation, decreases methylation, increases methylation	1
Lead	affects expression	1
Methapyrilene	decreases methylation	1
Nickel	decreases expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Tretinoin	increases expression	1
Aflatoxin B1	decreases methylation	1

Cellosaurus cell lines

6 cell lines: 6 induced pluripotent stem cell

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_E8YZ	VUi063-A	Induced pluripotent stem cell	Male
CVCL_E8Z0	VUi063-B	Induced pluripotent stem cell	Male
CVCL_E8Z1	VUi063-C	Induced pluripotent stem cell	Male
CVCL_E8Z6	VUi064-A	Induced pluripotent stem cell	Female
CVCL_E8Z7	VUi064-B	Induced pluripotent stem cell	Female
CVCL_E8Z8	VUi064-C	Induced pluripotent stem cell	Female

Clinical trials (associated diseases)

486 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT02201914	PHASE4	UNKNOWN	Clomiphene Citrate Plus Gonadotropins and GnRH Antagonist Versus Flexible GnRH Antagonist Protocol Versus Microdose GnRH Agonist Protocol in Poor Responders Undergoing IVF
NCT02651285	PHASE4	UNKNOWN	Use of G-CSF Supplemented IVF Medium in Patients Undergoing IVF
NCT04002635	PHASE4	WITHDRAWN	Letrozole for Frozen Embryo Transfer (FET) in Patients With Polycystic Ovary Syndrome (PCOS)
NCT04385342	PHASE4	UNKNOWN	FSH Followed by HMG vs FSH Plus HMG in IVF
NCT04487925	PHASE4	RECRUITING	Controlled Ovarian Stimulation Versus Modified Natural Cycles in Poor Responders
NCT04654741	PHASE4	UNKNOWN	The Rate of Embryo Euploidy in Progestin-primed Ovarian Stimulation Cycles
NCT04728659	PHASE4	UNKNOWN	Desogestrel Versus GnRH Antagonist in IVF/ICSI
NCT04993924	PHASE4	UNKNOWN	GnRH Antagonist Pre-treatment in the Early Follicular Phase for Resolution of a Baseline Functional Ovarian Cyst
NCT05071339	PHASE4	UNKNOWN	GnRH Antagonist Pre-treatment for the Prevention of Asynchronous Follicular Growth
NCT05321511	PHASE4	UNKNOWN	Comparison of Triggers in Double Ovarian Stimulation (DuoStim).
NCT05954962	PHASE4	COMPLETED	Efficacy of Micronized Natural Progesterone vs GnRH Antagonist in the Prevention of LH Peak During Ovarian Stimulation.
NCT06181305	PHASE4	UNKNOWN	Endometrial Preparation in Frozen Embryo Transfer Cycles
NCT06396390	PHASE4	NOT_YET_RECRUITING	Comparison of Progestin Primed Ovarian Stimulation (PPOS) vs.GnRH Antagonist Methods on IVF Outcomes
NCT07405229	PHASE4	RECRUITING	MEdical Treatment in Idiopathic Ventricular Fibrillation Patients
NCT07499804	PHASE4	RECRUITING	Effect of Tadalafil on Endometrial Thickness and Frozen Embryo Transfer Outcomes
NCT00257959	PHASE4	COMPLETED	Optimal Pharmacological Therapy In Implantable Defibrillator Patients (OPTIC)
NCT00383799	PHASE4	TERMINATED	Iv Amiodarone Versus Iv Procainamide to Treat Haemodynamically Well Tolerated Ventricular Tachycardia
NCT00401466	PHASE4	COMPLETED	Remote Follow-up of Patients Receiving Implantable Cardioverter Defibrillator for Prophylactic Therapy
NCT00412607	PHASE4	COMPLETED	Catheter Evaluation for Endocardial Ablation in Patients With Ventricular Tachycardia
NCT00538356	PHASE4	COMPLETED	Influence of Home Monitoring on the Clinical Status of Heart Failure Patients With an Impaired Left Ventricular Function
NCT00787800	PHASE4	COMPLETED	The Use of Dual Chamber ICD With Special Programmed Features to Lower the Risk of Inappropriate Shock
NCT00851279	PHASE4	COMPLETED	Stereotaxis Study To Obliterate Persistent Ventricular Tachycardia
NCT00905853	PHASE4	COMPLETED	Ventricular Tachycardia (VT) Ablation or Escalated Drug Therapy
NCT01557842	PHASE4	TERMINATED	Early Ablation Therapy for the Treatment of Ischemic Ventricular Tachycardia in Patients With Implantable Cardioverter Defibrillators
NCT01558830	PHASE4	UNKNOWN	Safety of Amiodarone and Ranolazine Together in Patients With Angina
NCT01780311	PHASE4	UNKNOWN	Catheter Ablation Versus Antiarrhythmic Drugs for Outflow Tract Ventricular ARrhythmias
NCT02083016	PHASE4	COMPLETED	Ultra-high Density Mapping With Multielectrode Catheter vs Conventional Point by Point Mapping for Ventricular Tachycardia Substrate Ablation
NCT02114528	PHASE4	TERMINATED	Anti-arrhythmic Therapy vs Catheter Ablation as First Line Treatment for AICD Shock Prevention
NCT02666742	PHASE4	COMPLETED	DOACs for Stroke Prevention Post Ventricular Tachycardia Ablation
NCT02830360	PHASE4	COMPLETED	Antiarrhythmics or Ablation for Ventricular Tachycardia 2
NCT03833089	PHASE4	ACTIVE_NOT_RECRUITING	Targeted Potassium Levels for Prevention of ICD Therapy
NCT03855826	PHASE4	UNKNOWN	Evaluation of the Efficacy and Safety of Nifekalant Hydrochloride (NIF) Injection.
NCT04694079	PHASE4	COMPLETED	Ventricular Tachycardia Ablation and Myocardial Scar Characterization With Magnetic Resonance
NCT00101881	PHASE4	COMPLETED	Transthoracic Incremental Monophasic Versus Biphasic by Emergency Responders (TIMBER)
NCT00127907	PHASE4	COMPLETED	Vasopressin and Epinephrine Versus Epinephrine Alone in Cardiac Arrest
NCT00180362	PHASE4	COMPLETED	Quick ICD Study: Is Extensive Electrophysiological Testing Before, During and After ICD-Implantation Still Necessary ?
NCT00392639	PHASE4	COMPLETED	Clinical and Economical Interest of Endovascular Cooling in the Management of Cardiac Arrest (ICEREA Study)
NCT00644722	PHASE4	COMPLETED	Out-of-Hospital Intubation With Metal Single Use Laryngoscope Blades
NCT00827957	PHASE4	COMPLETED	Comparing Therapeutic Hypothermia Using External and Internal Cooling for Post-Cardiac Arrest Patients
NCT00843297	PHASE4	COMPLETED	COOL-Trial: Outcome With Invasive and Non-invasive Cooling After Cardiac Arrest