HVCN1

Summary

HVCN1 (hydrogen voltage gated channel 1, HGNC:28240) is a protein-coding gene on chromosome 12q24.11, encoding Voltage-gated hydrogen channel 1 (Q96D96). Voltage-gated proton-selective channel that conducts outward proton currents in response to intracellular acidification.

This gene encodes a voltage-gated protein channel protein expressed more highly in certain cells of the immune system. Phagocytic cells produce superoxide anions which require this channel protein, and in B cells this same process facilitates antibody production. This same channel protein, however, can also regulate functions in other cells including spermatozoa. Multiple transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 84329 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 35 total
• Druggable target: yes
• MANE Select transcript: NM_032369

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:28240
Approved symbol	HVCN1
Name	hydrogen voltage gated channel 1
Location	12q24.11
Locus type	gene with protein product
Status	Approved
Aliases	MGC15619, Hv1, VSOP
Ensembl gene	ENSG00000122986
Ensembl biotype	protein_coding
OMIM	611227
Entrez	84329

Gene structure

Transcript identifiers

Ensembl transcripts: 34 — 32 protein_coding, 1 retained_intron, 1 nonsense_mediated_decay

ENST00000242607, ENST00000356742, ENST00000439744, ENST00000546425, ENST00000546713, ENST00000547887, ENST00000548312, ENST00000549442, ENST00000620084, ENST00000888560, ENST00000888561, ENST00000888562, ENST00000888563, ENST00000888564, ENST00000888565, ENST00000888566, ENST00000888567, ENST00000888568, ENST00000888569, ENST00000888570, ENST00000933894, ENST00000933895, ENST00000933896, ENST00000933897, ENST00000933898, ENST00000948645, ENST00000948646, ENST00000948647, ENST00000948648, ENST00000948649, ENST00000948650, ENST00000948651, ENST00000948652, ENST00000948653

RefSeq mRNA: 3 — MANE Select: NM_032369 NM_001040107, NM_001256413, NM_032369

CCDS: CCDS31900, CCDS58278

Canonical transcript exons

ENST00000242607 — 8 exons

Exon	Start	End
ENSE00000834816	110650168	110650280
ENSE00000834817	110651217	110651448
ENSE00001209633	110683225	110683264
ENSE00002274116	110688625	110688708
ENSE00002372321	110689080	110689115
ENSE00003504338	110661164	110661448
ENSE00003519335	110655234	110655338
ENSE00003719031	110648686	110649475

Expression profiles

Bgee: expression breadth ubiquitous, 231 present calls, max score 96.56.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 9.8780 / max 645.9601, expressed in 1047 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
133255	7.3014	720
133260	1.8267	740
133256	0.6142	236
133259	0.0814	31
133257	0.0411	16
133262	0.0099	3
133258	0.0034	2

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
leukocyte	CL:0000738	96.56	gold quality
monocyte	CL:0000576	96.55	gold quality
granulocyte	CL:0000094	95.51	gold quality
lymph node	UBERON:0000029	94.27	gold quality
ileal mucosa	UBERON:0000331	93.17	silver quality
blood	UBERON:0000178	92.94	gold quality
left testis	UBERON:0004533	92.34	gold quality
spleen	UBERON:0002106	91.74	gold quality
right testis	UBERON:0004534	91.72	gold quality
vermiform appendix	UBERON:0001154	91.49	gold quality
testis	UBERON:0000473	90.69	gold quality
secondary oocyte	CL:0000655	89.56	gold quality
substantia nigra	UBERON:0002038	89.14	gold quality
caecum	UBERON:0001153	88.89	gold quality
upper arm skin	UBERON:0004263	88.26	silver quality
epithelium of nasopharynx	UBERON:0001951	88.09	gold quality
midbrain	UBERON:0001891	88.08	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	87.97	gold quality
lateral globus pallidus	UBERON:0002476	87.18	gold quality
oocyte	CL:0000023	86.41	gold quality
adult organism	UBERON:0007023	86.01	gold quality
sperm	CL:0000019	85.66	gold quality
bone marrow cell	CL:0002092	85.36	gold quality
superficial temporal artery	UBERON:0001614	85.29	gold quality
bone marrow	UBERON:0002371	85.23	gold quality
heart left ventricle	UBERON:0002084	84.94	gold quality
apex of heart	UBERON:0002098	84.92	gold quality
hypothalamus	UBERON:0001898	84.89	gold quality
globus pallidus	UBERON:0001875	84.76	gold quality
cardiac ventricle	UBERON:0002082	84.71	gold quality

Single-cell (SCXA)

Detected in 6 experiment(s), a significant marker in 6.

Experiment	Marker?	Max mean expression
E-MTAB-6075	yes	326.17
E-HCAD-4	yes	101.30
E-CURD-122	yes	84.29
E-CURD-88	yes	48.07
E-CURD-112	yes	9.97
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

48 targeting HVCN1, 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-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-2110	99.96	66.68	1930
HSA-MIR-493-5P	99.96	72.47	2382
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-101-3P	99.94	75.03	2230
HSA-MIR-144-3P	99.94	73.98	2698
HSA-LET-7A-2-3P	99.87	70.53	1921
HSA-MIR-4779	99.86	66.50	1583
HSA-LET-7G-3P	99.85	70.43	1929
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-199A-3P	99.75	70.48	929
HSA-MIR-199B-3P	99.75	70.48	929
HSA-MIR-3129-5P	99.75	70.46	914
HSA-MIR-4255	99.72	67.70	1541
HSA-MIR-4524A-3P	99.72	66.85	2406
HSA-MIR-6766-5P	99.68	67.70	2325
HSA-MIR-6740-3P	99.48	68.49	1392
HSA-MIR-1224-5P	99.48	65.59	803
HSA-MIR-3915	99.45	68.49	1905
HSA-MIR-584-3P	99.35	67.69	1082
HSA-MIR-6868-5P	99.06	65.69	1284
HSA-MIR-4711-5P	98.89	68.00	965

Literature-anchored findings (GeneRIF, showing 40)

• data presented here identify H(v)1 as a long-sought voltage-gated H+ channel and establish H(v)1 as the founding member of a family of mammalian VSD proteins (PMID:16554753)
• We cloned a new B cell-specific tetraspanning (BTS) membrane molecule (PMID:17948262)
• Hv1 forms a dimer in the membrane;its regions that are close to the dimer interface were defined. (PMID:18509058)
• The Hv1 channel voltage sensor domain by itself supports H(+) flux. (PMID:19233200)
• The C-terminal domain of the human voltage-gated proton channel Hv1 (C-Hv1) was overexpressed in Escherichia coli, purified and crystallized using the hanging-drop vapour-diffusion method. (PMID:19255483)
• Hv1 channels truncated just downstream of R2 in the S4 segment retain most channel properties. (PMID:20018719)
• Identification of Thr29 as a critical phosphorylation site that activates the human proton channel Hvcn1 in leukocytes (PMID:20037153)
• Since Hv1 specifically mediates proton efflux, it is likely to be the long-sought molecule that controls male fertility by mediating intracellular alkalinization of human sperm (PMID:20144758)
• In the 2.0 A structure of the C-terminal domain, the two monomers form a dimer via a parallel alpha-helical coiled-coil, in which one chloride ion binds with the Neta atom of Arg(264). (PMID:20147290)
• Molecular dynamics simulations revealed water molecules in the central crevice of Hv1 model structures but not in homologous voltage-sensor domain (VSD) structures. (PMID:20543828)
• The HVCN1 H(+) channel mediates pH-regulated acid secretion by the airway epithelium. Apical HVCN1 represents a mechanism to acidify an alkaline airway surface liquid. (PMID:20548053)
• Report on the interaction of HV1 proton channel protomers during ion channel gating. (PMID:20676047)
• HVCN1 not only modulates signaling from the B-cell receptor following B-cell activation and histamine release from basophils, but also mediates pH-dependent activation of spermatozoa, as well as acid secretion by tracheal epithelium. [Review] (PMID:20961760)
• Data demonstrated that a massive reduction in H(v)1 expression can limit the Nox2 mediated superoxide production of PLB-985 granulocytes. (PMID:21124855)
• these results strongly suggest that Hv1 regulates breast cancer intracellular pH and exacerbates the migratory ability of metastatic cells. (PMID:21821008)
• Interactions with two of the S4 arginines and the formation of a well defined hydrophobic gap in the center of the Hv1 are key to the formation of a robust water wire. (PMID:21843503)
• identification of aspartate 112 as a crucial component of the selectivity filter of H(V)1 (PMID:22020278)
• Hv1 channels maintain a physiological membrane potential during the respiratory burst of neutrophils by providing a compensating charge for the electrons transferred by NOX2 from NADPH to superoxide. (PMID:22056415)
• inhibition of Hv1 function via knockdown of Hv1 expression can effectively retard cancer growth (PMID:22367212)
• Hv1-dependent reactive oxygen species production is responsible for a substantial fraction of brain damage at early time points after ischemic stroke. (PMID:22388960)
• In the Hv1 voltage-gated channel a highly conserved phenylalanine is found in the charge transfer center. (PMID:23352164)
• Two conformational changes are detected in Hv1 channels that are involved in channel opening. (PMID:23352165)
• inhibition of Hv1 activity via Zn(2+) ions can effectively retard the cancer growth and suppress the cancer metastasis by the decrease of proton extrusion and the down-regulation of gelatinase activity (PMID:23891691)
• Results suggest that Hv1 may be used as a potential biomarker for diagnosis and prognosis of colorectal carcinoma, and a potential target for anticancer drugs in colorectal cancer therapy. (PMID:23940591)
• Salt bridge networks and the hydrophobic plug function as the gate in Hv1 channels; outward movement of the fourth transmembrane segment leads to the opening of this gate. (PMID:24379371)
• Divalent metal binding causes a conformational change in human the Hv1 c-terminal domain. (PMID:24867409)
• Hv1 activity displays hysteresis (PMID:25296308)
• A shorter isoform of HVCN1 with enhanced gating is specifically enriched in malignant B cells. (PMID:25425665)
• analysis of of the C-terminal domain of voltage-gated proton channel HV1 and the thermodynamic characteristics of Zn(2) binding to this domain (PMID:25446125)
• The main properties of the voltage-gated proton channel (HV1) are described in this review, along with what is known about how the channel protein structure accomplishes its functions. [review] (PMID:25964989)
• Trp207 is crucial for slow channel opening, highly temperature-dependent gating kinetics, proton selectivity, and DeltapH-dependent gating. (PMID:26458876)
• Our data demonstrated that the expression of Hv1 in pancreatic islet beta-cells regulates insulin secretion through regulating Ca(2+) homeostasis. (PMID:26559003)
• The authors now report that R1H mutation is sufficient to reconstitute resting-state H(+) ‘shuttle’ conductance in Hv1 without abrogating the intrinsic ‘aqueous’ H(+) conductance. (PMID:27572256)
• We suggest that cleavage and heterodimerization of Hv1 represents an adaptation to the specific requirements of pH control in sperm. (PMID:27859356)
• Inhibition of Hv1 channels by Zn(2+). (PMID:28013412)
• CREBBP mutations were associated with inferior progression-free survival (PFS), whereas mutations in previously unreported HVCN1, a voltage-gated proton channel-encoding gene and B-cell receptor signaling modulator, were associated with improved PFS. (PMID:28064239)
• His168 is essential for DeltapH-dependent gating of NV1. (PMID:29743300)
• Gating Currents in the Hv1 Proton Channel (PMID:29925021)
• A voltage-gated proton channel (Hv1) is the main pathway for H(+) efflux that allows capacitation in sperm and permits sustained reactive oxygen species production in white blood cells. A designed peptide inhibitor C6 was identified by a phage-display strategy whereby approximately 1 million novel peptides were fabricated on an inhibitor cysteine knot scaffold and sorted on purified Hv1 protein. (PMID:30478045)
• The hydrophobic gasket (HG) of the human voltage-gated proton channel, hHV1 plays a critical and exclusive role in preventing H(+) influx through closed channels. Mutation of HG residues produces gating pore currents reminiscent of several channelopathies. (PMID:31462498)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	hvcn1	ENSDARG00000040338
mus_musculus	Hvcn1	ENSMUSG00000064267
rattus_norvegicus	Hvcn1	ENSRNOG00000001270

Paralogs (6): TNS1 (ENSG00000079308), TPTE2 (ENSG00000132958), TNS3 (ENSG00000136205), TMEM266 (ENSG00000169758), PTEN (ENSG00000171862), TPTE (ENSG00000274391)

Protein

Protein identifiers

Voltage-gated hydrogen channel 1 — Q96D96 (reviewed: Q96D96)

Alternative names: Hydrogen voltage-gated channel 1, Voltage sensor domain-only protein

All UniProt accessions (4): Q96D96, F8VPF7, F8VS40, F8W0B3

UniProt curated annotations — full annotation on UniProt →

Function. Voltage-gated proton-selective channel that conducts outward proton currents in response to intracellular acidification. Lacks a canonical ion-channel pore domain and mediates proton permeability via its voltage sensor domain. Appears to play a dominant role in regulation of CO2/HCO3(-)/H(+) equilibrium in sperm flagellum. Prevents the acidification resulting from HCO3(-) synthesis and thus sustains high HCO3(-) levels inside sperm for capacitation. Provides for proton efflux that compensates for electron charge generated by NADPH oxidase activity either in the extracellular or phagosomal compartments, thus enabling the production of high levels of bactericidal reactive oxygen species during the respiratory burst. Opens when the pH of airway surface liquid exceeds 7 and contributes to respiratory epithelial acid secretion to maintain pH in the mucosa.

Subunit / interactions. Homodimer; each protomer forms its own proton conduction pathway.

Subcellular location. Cell membrane. Apical cell membrane. Cytoplasmic vesicle. Phagosome membrane. Cell projection. Cilium. Flagellum membrane.

Tissue specificity. Enriched in immune tissues, such as lymph nodes, B-lymphocytes, monocytes and spleen. Expressed in spermatozoa. Expressed in respiratory epithelial cells.

Post-translational modifications. Proteolytically cleaved in sperm. The cleaved protomer forms homodimers and heterodimers with the full-length protomer. It confers reduced dependence to intracellular pH changes. Phosphorylated in vitro by PRKCD. Phosphorylation may enhance channel gating.

Activity regulation. The channel gating depends on both the membrane potential and the transmembrane pH gradient. The dimers display cooperative channel gating. The channel activity is inhibited by zinc ions and by toxins, and activated by endocannabinoid anandamide and fatty acids.

Domain organisation. The voltage sensor domain (VSD, segments S1-S4) conducts both gating and ion permeation. The segment S4 is probably the voltage-sensor and is characterized by a series of positively charged amino acids at every third position. Unlike other voltage-gated ion channels it lacks the pore domain. The C-terminal coiled coil region mediates homodimerization and cooperative channel gating. It is essential for normal subcellular localization.

Polymorphism. Genetic variation in HVCN1 may alter the likelyhood of channel opening.

Similarity. Belongs to the voltage-gated proton channel (VPC) (TC 1.A.51) family.

Isoforms (4)

UniProt ID	Names	Canonical?
Q96D96-1	1	yes
Q96D96-2	2
Q96D96-3	3
Q96D96-4	4

RefSeq proteins (3): NP_001035196, NP_001243342, NP_115745* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR005821	Ion_trans_dom	Domain
IPR027359	Volt_channel_dom_sf	Homologous_superfamily
IPR031844	VGPC1_C	Domain
IPR031846	Hvcn1	Family

Pfam: PF00520, PF16799

Catalyzed reactions (Rhea), 1 shown:

• H(+)(in) = H(+)(out) (RHEA:34979)

UniProt features (39 total): mutagenesis site 10, helix 6, topological domain 5, transmembrane region 4, splice variant 3, modified residue 2, strand 2, chain 1, region of interest 1, coiled-coil region 1, compositionally biased region 1, site 1, sequence variant 1, sequence conflict 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
3A2A	X-RAY DIFFRACTION	2
5OQK	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96D96-F1	70.27	0.14

Functional residue map

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

Catalytic / active sites (1): 68–69 (cleavage; by a serine protease)

Post-translational modifications (2): 29, 97

Mutagenesis-validated functional residues (10):

Position	Phenotype
29	loss of a phosphorylation site. reduces phosphorylation.
97	loss of a phosphorylation site. strongly reduces phosphorylation.
112	alters channel selectivity. converts the proton channel to an anion channel.
112	no effect on channel activity and proton selectivity.
112	abolishes channel activity.
140	exhibits selectivity to protons but sensitivity to zinc ions is abolished; when associated with a-193.
193	exhibits selectivity to protons but sensitivity to zinc ions is abolished; when associated with a-140.
205	faster channel activation and deactivation kinetics.
208	faster channel activation and deactivation kinetics.
211	faster channel deactivation kinetics.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-1222556	ROS and RNS production in phagocytes
R-HSA-1300642	Sperm Motility And Taxes
R-HSA-6798695	Neutrophil degranulation

MSigDB gene sets: 236 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_UP, GOBP_SINGLE_FERTILIZATION, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_RESPONSE_TO_ZINC_ION, GOCC_SECRETORY_GRANULE, IVANOVA_HEMATOPOIESIS_LATE_PROGENITOR, GOBP_MONOATOMIC_CATION_TRANSPORT, GOBP_RESPONSE_TO_METAL_ION, GOBP_REACTIVE_OXYGEN_SPECIES_BIOSYNTHETIC_PROCESS, GOBP_DEFENSE_RESPONSE_TO_OTHER_ORGANISM, GOBP_CELL_REDOX_HOMEOSTASIS, MODULE_171, MODULE_301, GOBP_REGULATION_OF_REACTIVE_OXYGEN_SPECIES_METABOLIC_PROCESS, GOBP_REGULATION_OF_REPRODUCTIVE_PROCESS

GO Biological Process (15): single fertilization (GO:0007338), response to pH (GO:0009268), response to zinc ion (GO:0010043), innate immune response (GO:0045087), cell redox homeostasis (GO:0045454), regulation of intracellular pH (GO:0051453), regulation of acrosome reaction (GO:0060046), cellular response to zinc ion (GO:0071294), cellular response to pH (GO:0071467), proton transmembrane transport (GO:1902600), regulation of reactive oxygen species biosynthetic process (GO:1903426), immune system process (GO:0002376), monoatomic ion transport (GO:0006811), monoatomic ion transmembrane transport (GO:0034220), transmembrane transport (GO:0055085)

GO Molecular Function (5): voltage-gated monoatomic cation channel activity (GO:0022843), voltage-gated proton channel activity (GO:0030171), identical protein binding (GO:0042802), protein homodimerization activity (GO:0042803), monoatomic ion channel activity (GO:0005216)

GO Cellular Component (12): plasma membrane (GO:0005886), membrane (GO:0016020), apical plasma membrane (GO:0016324), secretory granule membrane (GO:0030667), phagocytic vesicle membrane (GO:0030670), monoatomic ion channel complex (GO:0034702), specific granule membrane (GO:0035579), sperm flagellum (GO:0036126), cilium (GO:0005929), cytoplasmic vesicle (GO:0031410), motile cilium (GO:0031514), cell projection (GO:0042995)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Innate Immune System	2
Fertilization	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
transport	2
cellular anatomical structure	2
fertilization	1
response to abiotic stimulus	1
response to metal ion	1
immune response	1
defense response to symbiont	1
cellular homeostasis	1
regulation of pH	1
intracellular monoatomic cation homeostasis	1
regulation of biological quality	1
acrosome reaction	1
regulation of reproductive process	1
response to zinc ion	1
cellular response to metal ion	1
response to pH	1
cellular response to abiotic stimulus	1
monoatomic cation transmembrane transport	1
regulation of biosynthetic process	1
reactive oxygen species biosynthetic process	1
regulation of reactive oxygen species metabolic process	1
biological_process	1
monoatomic ion transport	1
transmembrane transport	1
cellular process	1
voltage-gated monoatomic ion channel activity	1
monoatomic cation channel activity	1
proton channel activity	1
voltage-gated monoatomic cation channel activity	1
protein binding	1
identical protein binding	1
protein dimerization activity	1
monoatomic ion transmembrane transporter activity	1
channel activity	1
membrane	1
cell periphery	1
apical part of cell	1
plasma membrane region	1
secretory granule	1
cytoplasmic vesicle membrane	1

Protein interactions and networks

STRING

1184 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HVCN1	IGHV4-38-2	P0DP08	662
HVCN1	KCNU1	A8MYU2	622
HVCN1	KCNA2	P16389	583
HVCN1	SLC9C1	Q4G0N8	581
HVCN1	NOX5	Q96PH1	557
HVCN1	CATSPER1	Q8NEC5	507
HVCN1	CEACAM5	P06731	480
HVCN1	CYBB	P04839	460
HVCN1	CATSPER2	Q96P56	453
HVCN1	A6NFB4	A6NFB4	447
HVCN1	OTOP1	Q7RTM1	440
HVCN1	CATSPER3	Q86XQ3	433
HVCN1	CLCN3	P51790	431
HVCN1	SLC9A1	P19634	430
HVCN1	CATSPER4	Q7RTX7	430

IntAct

10 interactions, top by confidence:

A	B	Type	Score
HVCN1	HVCN1	psi-mi:“MI:0407”(direct interaction)	0.560
HVCN1	FUS	psi-mi:“MI:0915”(physical association)	0.400
HVCN1	DOK2	psi-mi:“MI:0914”(association)	0.350
ATG16L1		psi-mi:“MI:0914”(association)	0.350
TTYH1	TMEM223	psi-mi:“MI:0914”(association)	0.350
HVCN1	CHEK1	psi-mi:“MI:0914”(association)	0.350
SLC7A1	ESYT2	psi-mi:“MI:0914”(association)	0.350

BioGRID (38): MUCL1 (Affinity Capture-MS), PIGR (Affinity Capture-MS), OXLD1 (Affinity Capture-MS), CST1 (Affinity Capture-MS), CST2 (Affinity Capture-MS), DOK2 (Affinity Capture-MS), HVCN1 (Two-hybrid), OXLD1 (Affinity Capture-MS), CST1 (Affinity Capture-MS), DOK2 (Affinity Capture-MS), IGJ (Affinity Capture-MS), PIGR (Affinity Capture-MS), MUCL1 (Affinity Capture-MS), HVCN1 (Affinity Capture-MS), HVCN1 (Proximity Label-MS)

ESM2 similar proteins: A0JMD4, B7ZC96, F6RG56, O65718, O73606, P17971, P17972, P70259, P97557, Q00195, Q03041, Q05973, Q0P583, Q16280, Q16281, Q24278, Q28718, Q29441, Q3U2S8, Q3UW12, Q5F4C0, Q5R5V8, Q5RC10, Q60565, Q62398, Q64359, Q6PIU1, Q6Q760, Q6R6I7, Q8AYS8, Q8BWC0, Q8BXR5, Q8BZN2, Q8IV77, Q8IZF0, Q8IZK6, Q8K595, Q8TDD5, Q90980, Q94AS9

Diamond homologs: G5EE01, O08586, O14976, O54857, O75061, O94526, P56180, P60483, P60484, P97874, Q27974, Q4R6N0, Q54JL7, Q5T6R2, Q6XPS3, Q80TZ3, Q8H106, Q96D96, Q99KY4, Q9FLZ5, Q9LT75, Q9PUT6, Q1JV40, Q2M3C6, Q3U2S8, Q5F4C0, Q5M7E9, Q5M8L8, Q6DHQ1, Q9N0B5, E9Q0S6, Q04205, Q5SSZ5, Q63HR2, Q68CZ2, Q8CGB6, Q8T9S7, Q9GLM4, Q9HBL0, Q9P7H1

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
PRKCD	“up-regulates activity”	HVCN1	phosphorylation

Disease & clinical

Cancer significance

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	19
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

2891 predictions. Top by Δscore:

Variant	Effect	Δscore
12:110628796:GAA:G	acceptor_gain	1.0000
12:110628916:GAGGT:G	donor_loss	1.0000
12:110628917:AGGTG:A	donor_loss	1.0000
12:110632470:A:AG	acceptor_gain	1.0000
12:110632470:AGTAT:A	acceptor_gain	1.0000
12:110632471:G:GG	acceptor_gain	1.0000
12:110632471:GTAT:G	acceptor_gain	1.0000
12:110632471:GTATG:G	acceptor_gain	1.0000
12:110634649:G:A	acceptor_gain	1.0000
12:110645127:A:T	donor_gain	1.0000
12:110647301:G:GG	donor_gain	1.0000
12:110647894:G:GG	donor_gain	1.0000
12:110649475:CCTAT:C	acceptor_gain	1.0000
12:110649479:T:TC	acceptor_gain	1.0000
12:110650278:TCC:T	acceptor_gain	1.0000
12:110650279:CC:C	acceptor_gain	1.0000
12:110650279:CCC:C	acceptor_gain	1.0000
12:110650280:CC:C	acceptor_gain	1.0000
12:110650281:CTG:C	acceptor_loss	1.0000
12:110650282:T:G	acceptor_loss	1.0000
12:110651212:CGTA:C	donor_loss	1.0000
12:110651213:GTA:G	donor_loss	1.0000
12:110651215:A:AC	donor_gain	1.0000
12:110651215:AC:A	donor_gain	1.0000
12:110651216:C:CT	donor_gain	1.0000
12:110651216:CC:C	donor_gain	1.0000
12:110651216:CCA:C	donor_gain	1.0000
12:110651216:CCAT:C	donor_gain	1.0000
12:110651448:CCTGA:C	acceptor_loss	1.0000
12:110651449:CT:C	acceptor_loss	1.0000

AlphaMissense

1807 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:110651241:A:G	W207R	0.998
12:110651241:A:T	W207R	0.998
12:110649456:A:G	L259P	0.996
12:110650190:A:G	L245P	0.996
12:110651338:A:C	D174E	0.996
12:110651338:A:T	D174E	0.996
12:110651339:T:C	D174G	0.996
12:110651339:T:G	D174A	0.996
12:110655286:A:G	L120P	0.996
12:110651339:T:A	D174V	0.995
12:110651228:C:G	R211P	0.994
12:110651231:G:T	A210D	0.994
12:110651237:C:G	R208P	0.994
12:110651340:C:G	D174H	0.994
12:110651431:G:C	S143R	0.994
12:110651431:G:T	S143R	0.994
12:110651433:T:G	S143R	0.994
12:110651340:C:T	D174N	0.993
12:110651217:C:G	G215R	0.992
12:110651217:C:T	G215R	0.992
12:110651239:C:A	W207C	0.992
12:110651239:C:G	W207C	0.992
12:110651249:A:T	L204H	0.992
12:110651247:G:C	R205G	0.991
12:110651243:A:G	L206P	0.990
12:110651330:A:T	V177E	0.990
12:110651340:C:A	D174Y	0.989
12:110655326:A:G	C107R	0.989
12:110651225:A:G	I212T	0.988
12:110651238:G:C	R208G	0.988

dbSNP variants (sampled 300 via entrez): RS1000095775 (12:110668414 A>C), RS1000208336 (12:110702006 C>A,T), RS1000245191 (12:110706483 A>T), RS1000332917 (12:110682112 T>C), RS1000422694 (12:110688608 A>T), RS1000479248 (12:110673244 C>T), RS1000540756 (12:110700448 C>T), RS1000603988 (12:110656094 C>T), RS1000734154 (12:110703677 T>C), RS1000743230 (12:110649028 TTTTC>T,TTTTCTTTC), RS1000750276 (12:110694934 T>C), RS1000760708 (12:110687461 G>A), RS1000770438 (12:110694712 A>G), RS1000824185 (12:110680032 G>A,T), RS1000841825 (12:110676756 T>C)

Disease associations

OMIM: gene MIM:611227 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST008572_9	Composite immunoglobulin trait (IgA/IgG)	1.000000e-09
GCST90002403_457	Red blood cell count	2.000000e-11

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004305	erythrocyte count

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6067294 (SINGLE PROTEIN)

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

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: vgic — Voltage-gated proton channel (H_v1)

Most potent curated ligand interactions (2 total), top 2:

Ligand	Action	Affinity	Parameter
Zn2+	Channel blocker	6.3	pIC50
Cd2+	Channel blocker	5.0	pIC50

CTD chemical–gene interactions

23 total (human), top 23 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects methylation, increases expression	2
triphenyl phosphate	affects expression	1
CGP 52608	affects binding, increases reaction	1
abrine	decreases expression	1
Decitabine	increases expression	1
Acetaminophen	increases expression	1
Air Pollutants, Occupational	decreases expression	1
Benzo(a)pyrene	increases methylation	1
Cisplatin	increases expression	1
Diethylhexyl Phthalate	decreases expression	1
Ethyl Methanesulfonate	decreases expression	1
Formaldehyde	decreases expression	1
Methyl Methanesulfonate	decreases expression	1
Nickel	decreases expression	1
Niclosamide	increases expression	1
Testosterone	decreases expression	1
Tetrachlorodibenzodioxin	affects expression	1
Tretinoin	decreases expression	1
Triclosan	increases expression	1
Valproic Acid	increases methylation	1
Cadmium Chloride	decreases expression	1
Okadaic Acid	increases expression	1
Particulate Matter	increases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5651604	Binding	Binding affinity to human HVCN1 incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Clinical trials (associated diseases)

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