CALHM3

Summary

CALHM3 (calcium homeostasis modulator 3, HGNC:23458) is a protein-coding gene on chromosome 10q24.33, encoding Calcium homeostasis modulator protein 3 (Q86XJ0). Pore-forming subunit of gustatory voltage-gated ion channels required for sensory perception of sweet, bitter and umami tastes.

Predicted to enable monoatomic cation channel activity and voltage-gated monoatomic ion channel activity. Predicted to be involved in ATP transport; protein heterooligomerization; and sensory perception of taste. Predicted to be located in basolateral plasma membrane. Predicted to be active in plasma membrane.

Source: NCBI Gene 119395 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 69 total
• MANE Select transcript: NM_001129742

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:23458
Approved symbol	CALHM3
Name	calcium homeostasis modulator 3
Location	10q24.33
Locus type	gene with protein product
Status	Approved
Aliases	bA225H22.7
Ensembl gene	ENSG00000183128
Ensembl biotype	protein_coding
OMIM	618263
Entrez	119395

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000369783

RefSeq mRNA: 1 — MANE Select: NM_001129742 NM_001129742

CCDS: CCDS44476

Canonical transcript exons

ENST00000369783 — 3 exons

Exon	Start	End
ENSE00001311617	103476294	103476549
ENSE00001450876	103472804	103473704
ENSE00001450877	103478746	103479240

Expression profiles

Bgee: expression breadth broad, 31 present calls, max score 78.50.

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	78.50	gold quality
myocardium	UBERON:0002349	77.30	gold quality
endothelial cell	CL:0000115	64.11	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	60.22	gold quality
cartilage tissue	UBERON:0002418	57.50	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	56.61	gold quality
vena cava	UBERON:0004087	52.79	gold quality
mucosa of sigmoid colon	UBERON:0004993	52.02	gold quality
colonic mucosa	UBERON:0000317	48.44	gold quality
body of pancreas	UBERON:0001150	47.53	gold quality
placenta	UBERON:0001987	47.04	gold quality
mammalian vulva	UBERON:0000997	46.35	gold quality
synovial joint	UBERON:0002217	45.78	gold quality
nipple	UBERON:0002030	45.57	gold quality
vastus lateralis	UBERON:0001379	45.39	gold quality
quadriceps femoris	UBERON:0001377	45.27	gold quality
saphenous vein	UBERON:0007318	44.87	gold quality
prefrontal cortex	UBERON:0000451	44.52	gold quality
gingiva	UBERON:0001828	43.94	gold quality
trachea	UBERON:0003126	43.07	gold quality
superior surface of tongue	UBERON:0007371	42.87	gold quality
pylorus	UBERON:0001166	42.85	gold quality
jejunum	UBERON:0002115	42.63	gold quality
secondary oocyte	CL:0000655	42.57	gold quality
pancreas	UBERON:0001264	42.40	gold quality
frontal cortex	UBERON:0001870	41.92	silver quality
middle temporal gyrus	UBERON:0002771	41.78	gold quality
layer of synovial tissue	UBERON:0007616	41.71	gold quality
superficial temporal artery	UBERON:0001614	41.33	gold quality
ventral tegmental area	UBERON:0002691	41.29	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.47

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 1)

• This study failed to show an association between theeight SNPs of the CALHM3 genes and alzheimer disease. (PMID:20164573)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	calhm3	ENSDARG00000079602
mus_musculus	Calhm3	ENSMUSG00000094219
rattus_norvegicus	Calhm3	ENSRNOG00000026086
caenorhabditis_elegans		WBGENE00016626

Paralogs (5): CALHM2 (ENSG00000138172), CALHM4 (ENSG00000164451), CALHM5 (ENSG00000178033), CALHM1 (ENSG00000185933), CALHM6 (ENSG00000188820)

Protein

Protein identifiers

Calcium homeostasis modulator protein 3 — Q86XJ0 (reviewed: Q86XJ0)

Alternative names: Protein A

All UniProt accessions (1): Q86XJ0

UniProt curated annotations — full annotation on UniProt →

Function. Pore-forming subunit of gustatory voltage-gated ion channels required for sensory perception of sweet, bitter and umami tastes. With CALHM1 forms a fast-activating voltage-gated ATP-release channel in type II taste bud cells, ATP acting as a neurotransmitter to activate afferent neural gustatory pathways. Acts both as a voltage-gated and calcium-activated ion channel: mediates neuronal excitability in response to membrane depolarization and low extracellular Ca(2+) concentration. Has poor ion selectivity and forms a wide pore (around 14 Angstroms) that mediates permeation of small ions including Ca(2+), Na(+), K(+) and Cl(-), as well as larger ions such as ATP(4-).

Subunit / interactions. Associates with CALHM1 as a pore-forming subunit in a hetero-hexameric channel complex.

Subcellular location. Basolateral cell membrane.

Tissue specificity. Specifically expressed in circumvallate taste bud cells.

Post-translational modifications. N-glycosylated. Palmitoylated by ZDHHC3 and ZDHHC15. Palmitoylation positively regulates CALHM1:CALHM3 channel conductance.

Similarity. Belongs to the CALHM family.

RefSeq proteins (1): NP_001123214* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR029569	CALHM	Family

Pfam: PF14798

Catalyzed reactions (Rhea), 5 shown:

• K(+)(in) = K(+)(out) (RHEA:29463)
• Ca(2+)(in) = Ca(2+)(out) (RHEA:29671)
• chloride(in) = chloride(out) (RHEA:29823)
• Na(+)(in) = Na(+)(out) (RHEA:34963)
• ATP(in) = ATP(out) (RHEA:75687)

UniProt features (18 total): topological domain 5, transmembrane region 4, lipid moiety-binding region 3, disulfide bond 2, chain 1, region of interest 1, glycosylation site 1, sequence variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q86XJ0-F1	79.99	0.46

Functional residue map

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

Post-translational modifications (3): 99, 200, 204

Disulfide bonds (2): 41–126, 43–157

Glycosylation sites (1): 142

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-9717207	Sensory perception of sweet, bitter, and umami (glutamate) taste
R-HSA-9730628	Sensory perception of salty taste
R-HSA-9709957	Sensory Perception
R-HSA-9717189	Sensory perception of taste

MSigDB gene sets: 54 (showing top): GOBP_SENSORY_PERCEPTION_OF_CHEMICAL_STIMULUS, GOBP_NUCLEOTIDE_TRANSPORT, GOBP_MONOATOMIC_CATION_TRANSPORT, GOBP_ORGANOPHOSPHATE_ESTER_TRANSPORT, GOBP_SENSORY_PERCEPTION_OF_TASTE, GOBP_NUCLEOBASE_CONTAINING_COMPOUND_TRANSPORT, GOBP_ORGANIC_ANION_TRANSPORT, GOBP_PURINE_NUCLEOTIDE_TRANSPORT, GOBP_SENSORY_PERCEPTION, AML1_01, GOBP_CALCIUM_ION_TRANSMEMBRANE_TRANSPORT, GOBP_CARBOHYDRATE_DERIVATIVE_TRANSPORT, GOBP_TRANSMEMBRANE_TRANSPORT, GOBP_PROTEIN_HETEROOLIGOMERIZATION, GOCC_PLASMA_MEMBRANE_REGION

GO Biological Process (8): ATP transport (GO:0015867), sensory perception of taste (GO:0050909), protein heterooligomerization (GO:0051291), ATP export (GO:1904669), monoatomic ion transport (GO:0006811), calcium ion transport (GO:0006816), monoatomic ion transmembrane transport (GO:0034220), calcium ion transmembrane transport (GO:0070588)

GO Molecular Function (5): voltage-gated monoatomic ion channel activity (GO:0005244), monoatomic cation channel activity (GO:0005261), calcium channel activity (GO:0005262), protein binding (GO:0005515), voltage-gated channel activity (GO:0022832)

GO Cellular Component (3): plasma membrane (GO:0005886), basolateral plasma membrane (GO:0016323), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Sensory perception of taste	2
Sensory Perception	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
monoatomic ion channel activity	2
purine ribonucleotide transport	1
adenine nucleotide transport	1
sensory perception of chemical stimulus	1
protein complex oligomerization	1
ATP transport	1
transport	1
metal ion transport	1
monoatomic ion transport	1
transmembrane transport	1
calcium ion transport	1
monoatomic cation transmembrane transport	1
voltage-gated channel activity	1
monoatomic cation transmembrane transporter activity	1
monoatomic cation channel activity	1
calcium ion transmembrane transporter activity	1
binding	1
gated channel activity	1
membrane	1
cell periphery	1
basal plasma membrane	1
plasma membrane region	1
cellular anatomical structure	1

Protein interactions and networks

STRING

382 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CALHM3	OTOP1	Q7RTM1	626
CALHM3	TRPM5	Q9NZQ8	579
CALHM3	PLCB2	Q00722	543
CALHM3	TAS1R2	Q8TE23	516
CALHM3	TAS1R1	Q7RTX1	485
CALHM3	GCSAML	Q5JQS6	477
CALHM3	TAS1R3	Q7RTX0	474
CALHM3	GNAT3	A8MTJ3	473
CALHM3	OR7G1	Q8NGA0	473
CALHM3	TRPM4	Q8TD43	456
CALHM3	CALHM1	Q8IU99	452
CALHM3	PKD2L1	Q9P0L9	448
CALHM3	EFCC1	Q9HA90	445
CALHM3	PANX1	Q96RD7	429
CALHM3	P2RX2	Q9UBL9	417

IntAct

10 interactions, top by confidence:

A	B	Type	Score
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
DLG1	CALHM3	psi-mi:“MI:0407”(direct interaction)	0.440
CFTR	MYH7B	psi-mi:“MI:0914”(association)	0.350

BioGRID (1): CALHM3 (Affinity Capture-MS)

ESM2 similar proteins: A3KN95, A4IFG4, A7E2I7, E2RDP2, J3QMI4, O94810, O95382, P0C5W1, P23677, P82350, Q15628, Q16586, Q1RMX3, Q24JP5, Q28686, Q29RH2, Q3T904, Q3U0S6, Q45T69, Q49LS1, Q5FWU3, Q5RCS0, Q5U651, Q64255, Q674R7, Q684M2, Q68FE2, Q68FE7, Q6EBV9, Q6GQT5, Q6NY19, Q6P9Q4, Q6PEY1, Q7Z3C6, Q80WF4, Q80XF7, Q86TL0, Q86XJ0, Q8C052, Q8C152

Diamond homologs: D3Z291, H2MCM1, J3QMI4, Q5R3K3, Q5RJQ8, Q86XJ0, Q8IU99, Q8VEC4, Q9HA72, Q2HJ63, Q561R8, Q5JW98, Q8C9E8, Q8CE93, Q8N5C1, Q8R100, A4FUN9, Q5FWS4

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	64
Likely benign	4
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

343 predictions. Top by Δscore:

Variant	Effect	Δscore
10:103473700:ATGGC:A	acceptor_gain	1.0000
10:103473701:TGGC:T	acceptor_gain	1.0000
10:103473702:GGC:G	acceptor_gain	1.0000
10:103473702:GGCC:G	acceptor_loss	1.0000
10:103473703:GC:G	acceptor_gain	1.0000
10:103473703:GCC:G	acceptor_loss	1.0000
10:103473704:CC:C	acceptor_gain	1.0000
10:103473705:C:CC	acceptor_gain	1.0000
10:103473705:C:CG	acceptor_loss	1.0000
10:103473708:C:CT	acceptor_gain	1.0000
10:103473712:G:C	acceptor_gain	1.0000
10:103476289:GTTAC:G	donor_loss	1.0000
10:103476290:TTAC:T	donor_loss	1.0000
10:103476291:TAC:T	donor_loss	1.0000
10:103476293:C:A	donor_loss	1.0000
10:103478765:T:TA	donor_gain	1.0000
10:103473705:C:T	acceptor_gain	0.9900
10:103473706:T:A	acceptor_loss	0.9900
10:103473709:A:T	acceptor_gain	0.9900
10:103473712:G:GC	acceptor_gain	0.9900
10:103476547:TACCT:T	acceptor_loss	0.9900
10:103476548:ACC:A	acceptor_loss	0.9900
10:103476549:CCT:C	acceptor_loss	0.9900
10:103476550:C:T	acceptor_loss	0.9900
10:103476551:T:G	acceptor_loss	0.9900
10:103476555:A:T	acceptor_gain	0.9900
10:103478740:CCGCA:C	donor_loss	0.9900
10:103478741:CGCA:C	donor_loss	0.9900
10:103478742:GCA:G	donor_loss	0.9900
10:103478743:CAC:C	donor_loss	0.9900

AlphaMissense

2223 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
10:103476450:G:C	S129R	0.986
10:103476450:G:T	S129R	0.986
10:103476452:T:G	S129R	0.986
10:103473510:G:C	F246L	0.979
10:103473510:G:T	F246L	0.979
10:103473512:A:G	F246L	0.979
10:103473580:T:A	E223V	0.979
10:103473579:C:A	E223D	0.978
10:103473579:C:G	E223D	0.978
10:103473534:G:C	F238L	0.976
10:103473534:G:T	F238L	0.976
10:103473536:A:G	F238L	0.976
10:103476500:A:G	W113R	0.975
10:103476500:A:T	W113R	0.975
10:103473567:G:C	F227L	0.973
10:103473567:G:T	F227L	0.973
10:103473568:A:C	F227C	0.973
10:103473569:A:G	F227L	0.973
10:103473695:A:G	W185R	0.973
10:103473695:A:T	W185R	0.973
10:103473321:C:A	K309N	0.972
10:103473321:C:G	K309N	0.972
10:103473568:A:G	F227S	0.965
10:103473545:C:G	A235P	0.963
10:103473535:A:G	F238S	0.961
10:103473532:G:T	A239E	0.959
10:103473335:A:G	W305R	0.958
10:103473335:A:T	W305R	0.958
10:103473333:C:A	W305C	0.955
10:103473333:C:G	W305C	0.955

dbSNP variants (sampled 300 via entrez): RS1000954462 (10:103479210 G>A,C), RS1001008224 (10:103479607 C>G), RS1001562961 (10:103473378 G>A,T), RS1001953464 (10:103480818 C>G,T), RS1002002759 (10:103481068 G>A,C), RS1002047198 (10:103477391 T>C), RS1002282738 (10:103474893 G>A), RS1003569328 (10:103476149 A>G), RS1004357524 (10:103474579 C>T), RS1004468315 (10:103480490 C>T), RS1004574263 (10:103473190 C>A,T), RS1004626844 (10:103472815 C>T), RS1004807340 (10:103479317 C>T), RS1004907553 (10:103475830 T>C), RS1005642755 (10:103476265 A>C)

Disease associations

OMIM: gene MIM:618263 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST002149_2	Schizophrenia	4.000000e-13
GCST007059_12	Response to antidepressants (symptom improvement)	4.000000e-06
GCST008361_2	Response to cognitive-behavioural therapy in major depressive disorder	2.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0007820	cognitive behavioural therapy

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

13 total (human), top 13 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects response to substance, increases expression, decreases methylation	2
propionaldehyde	increases expression	1
bisphenol A	decreases methylation	1
butyraldehyde	increases expression	1
pentanal	increases expression	1
clothianidin	increases expression	1
abrine	decreases expression	1
Aldehydes	increases expression	1
Arsenic	affects methylation	1
Phenobarbital	decreases expression	1
Valproic Acid	increases methylation	1
Okadaic Acid	increases expression	1
Magnetite Nanoparticles	decreases expression	1

Clinical trials (associated diseases)

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