CALHM2

Summary

CALHM2 (calcium homeostasis modulator family member 2, HGNC:23493) is a protein-coding gene on chromosome 10q24.33, encoding Calcium homeostasis modulator protein 2 (Q9HA72). Pore-forming subunit of Ca(2+) homeostasis modulator channels.

Predicted to enable monoatomic cation channel activity. Involved in ATP export and positive regulation of apoptotic process. Predicted to be active in plasma membrane.

Source: NCBI Gene 51063 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 67 total
• MANE Select transcript: NM_015916

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:23493
Approved symbol	CALHM2
Name	calcium homeostasis modulator family member 2
Location	10q24.33
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000138172
Ensembl biotype	protein_coding
OMIM	612235
Entrez	51063

Gene structure

Transcript identifiers

Ensembl transcripts: 35 — 30 protein_coding, 5 protein_coding_CDS_not_defined

ENST00000260743, ENST00000369788, ENST00000461631, ENST00000463878, ENST00000474797, ENST00000480642, ENST00000494180, ENST00000882006, ENST00000882007, ENST00000882008, ENST00000882009, ENST00000882010, ENST00000882011, ENST00000882012, ENST00000882013, ENST00000882014, ENST00000882015, ENST00000882016, ENST00000882017, ENST00000882018, ENST00000882019, ENST00000936390, ENST00000936391, ENST00000964393, ENST00000964394, ENST00000964395, ENST00000964396, ENST00000964397, ENST00000964398, ENST00000964399, ENST00000964400, ENST00000964401, ENST00000964402, ENST00000964403, ENST00000964404

RefSeq mRNA: 1 — MANE Select: NM_015916 NM_015916

CCDS: CCDS7549

Canonical transcript exons

ENST00000260743 — 4 exons

Exon	Start	End
ENSE00001092407	103451083	103451285
ENSE00001450897	103449387	103450099
ENSE00001900694	103452156	103452370
ENSE00001924141	103446786	103447568

Expression profiles

Bgee: expression breadth ubiquitous, 264 present calls, max score 96.58.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 23.4749 / max 247.0629, expressed in 1474 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
111231	9.7214	1317
111230	7.3634	1310
111232	5.2499	1261
111228	0.6470	387
111227	0.3618	218
111229	0.1314	55

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	96.58	gold quality
endocervix	UBERON:0000458	96.19	gold quality
body of uterus	UBERON:0009853	96.14	gold quality
right coronary artery	UBERON:0001625	96.13	gold quality
left uterine tube	UBERON:0001303	95.66	gold quality
left ovary	UBERON:0002119	95.03	gold quality
right ovary	UBERON:0002118	94.95	gold quality
left coronary artery	UBERON:0001626	94.84	gold quality
descending thoracic aorta	UBERON:0002345	94.62	gold quality
coronary artery	UBERON:0001621	94.50	gold quality
thoracic aorta	UBERON:0001515	94.01	gold quality
omental fat pad	UBERON:0010414	94.01	gold quality
peritoneum	UBERON:0002358	93.97	gold quality
ascending aorta	UBERON:0001496	93.95	gold quality
aorta	UBERON:0000947	93.88	gold quality
popliteal artery	UBERON:0002250	93.85	gold quality
tibial artery	UBERON:0007610	93.84	gold quality
mucosa of stomach	UBERON:0001199	93.82	gold quality
subcutaneous adipose tissue	UBERON:0002190	93.42	gold quality
adipose tissue of abdominal region	UBERON:0007808	93.39	gold quality
ectocervix	UBERON:0012249	93.20	gold quality
myometrium	UBERON:0001296	93.12	gold quality
leukocyte	CL:0000738	92.83	gold quality
monocyte	CL:0000576	92.65	gold quality
mononuclear cell	CL:0000842	92.55	gold quality
synovial joint	UBERON:0002217	92.17	gold quality
layer of synovial tissue	UBERON:0007616	91.84	gold quality
right atrium auricular region	UBERON:0006631	91.81	gold quality
apex of heart	UBERON:0002098	91.65	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	91.58	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	15.25

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

19 targeting CALHM2, 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-5011-5P	100.00	83.46	5820
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-3913-5P	99.78	67.26	968
HSA-MIR-4328	99.57	71.06	4094
HSA-MIR-3122	99.50	66.33	821
HSA-MIR-217-5P	99.49	69.93	1419
HSA-MIR-410-3P	99.27	69.98	2457
HSA-MIR-6807-3P	99.15	69.23	1275
HSA-MIR-3127-3P	98.94	67.34	1055
HSA-MIR-6756-3P	98.94	66.79	1104
HSA-MIR-1911-5P	98.92	67.53	325
HSA-MIR-4764-5P	98.88	65.53	894
HSA-MIR-374A-3P	98.87	67.82	1531
HSA-MIR-331-3P	98.76	64.91	793
HSA-MIR-1301-3P	98.64	68.27	1071
HSA-MIR-5047	98.64	68.62	1035

Literature-anchored findings (GeneRIF, showing 4)

• This study failed to show an association between theeight SNPs of the CALHM2 genes and alzheimer disease. (PMID:20164573)
• shows that purified CALHM2 channels form both gap junctions and undecameric hemichannels (PMID:31776515)
• Molecular dynamics simulations suggest that lipids can favorably assemble into a bilayer within the larger human CALHM2 pore, but not within chicken CALHM1, demonstrating the potential correlation between pore size, lipid accommodation and channel activity. (PMID:31988524)
• Structural features of heteromeric channels composed of CALHM2 and CALHM4 paralogs. (PMID:38896440)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	calhm2.1	ENSDARG00000039482
danio_rerio	calhm2.2	ENSDARG00000074179
mus_musculus	Calhm2	ENSMUSG00000033033
rattus_norvegicus	Calhm2	ENSRNOG00000020325
caenorhabditis_elegans		WBGENE00016626

Paralogs (5): CALHM4 (ENSG00000164451), CALHM5 (ENSG00000178033), CALHM3 (ENSG00000183128), CALHM1 (ENSG00000185933), CALHM6 (ENSG00000188820)

Protein

Protein identifiers

Calcium homeostasis modulator protein 2 — Q9HA72 (reviewed: Q9HA72)

Alternative names: Protein FAM26B

All UniProt accessions (1): Q9HA72

UniProt curated annotations — full annotation on UniProt →

Function. Pore-forming subunit of Ca(2+) homeostasis modulator channels. Mediates ATP release from astrocytes and ATP-induced Ca(2+) influx in microglia thus regulating neuronal ATP and Ca(2+) homeostasis, synaptic transmission and neuroinflammatory response. May form intercellular gap junctions. The gating mechanism remains unknown.

Subunit / interactions. Homo-undecamer. Two undecameric hemichannels can assemble in a head-to-head manner to form a gap junction.

Subcellular location. Cell membrane.

Tissue specificity. Placenta.

Activity regulation. Inhibited by Ca(2+) and ruthenium red in a voltage-dependent way.

Similarity. Belongs to the CALHM family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q9HA72-1	1	yes
Q9HA72-2	2
Q9HA72-3	3

RefSeq proteins (1): NP_057000* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR029569	CALHM	Family

Pfam: PF14798

Catalyzed reactions (Rhea), 1 shown:

• ATP(in) = ATP(out) (RHEA:75687)

UniProt features (51 total): helix 18, mutagenesis site 7, topological domain 5, splice variant 4, transmembrane region 4, region of interest 3, strand 3, disulfide bond 2, sequence variant 2, chain 1, site 1, turn 1

Structure

Experimental structures (PDB)

12 structures.

PDB	Method	Resolution (Å)
6UIW	ELECTRON MICROSCOPY	2.7
8RMK	ELECTRON MICROSCOPY	3.07
8RMM	ELECTRON MICROSCOPY	3.26
6UIV	ELECTRON MICROSCOPY	3.3
6LMU	ELECTRON MICROSCOPY	3.4
6LMW	ELECTRON MICROSCOPY	3.4
6LMX	ELECTRON MICROSCOPY	3.4
6VAK	ELECTRON MICROSCOPY	3.48
6UIX	ELECTRON MICROSCOPY	3.5
6VAI	ELECTRON MICROSCOPY	3.68
8RML	ELECTRON MICROSCOPY	3.84
6VAL	ELECTRON MICROSCOPY	3.87

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9HA72-F1	81.52	0.37

Antibody-complex structures (SAbDab): 3 — 8RMK, 8RML, 8RMM

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): 168 (not n-glycosylated)

Disulfide bonds (2): 46–130, 48–162

Mutagenesis-validated functional residues (7):

Position	Phenotype
1–52	does not affect intrasubunit interactions.
1–20	markedly reduces the inhibition by ruthenium red. does not affect ca(2+)-dependent inactivation of the channel.
10	markedly reduces the inhibition by ruthenium red at negative membrane potentials. does not affect ca(2+)-dependent inact
37	reduces the inhibition by ruthenium red.
143–146	prevents gap junction formation.
238	decreases intrasubunit interactions.
251	decreases intrasubunit interactions.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 184 (showing top): GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_INFLAMMATORY_RESPONSE, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_UP, GOBP_REGULATION_OF_MACROPHAGE_ACTIVATION, AP2_Q3, GGGTGGRR_PAX4_03, GOBP_NUCLEOTIDE_TRANSPORT, GOBP_MONOATOMIC_CATION_TRANSPORT, GOBP_CELL_CELL_SIGNALING, GOBP_ORGANOPHOSPHATE_ESTER_TRANSPORT, GOBP_REGULATION_OF_SYNAPTIC_PLASTICITY, CREIGHTON_ENDOCRINE_THERAPY_RESISTANCE_1, GOBP_CALCIUM_ION_IMPORT, GOBP_MYELOID_LEUKOCYTE_ACTIVATION

GO Biological Process (8): positive regulation of apoptotic process (GO:0043065), regulation of synaptic plasticity (GO:0048167), calcium ion import (GO:0070509), regulation of microglial cell activation (GO:1903978), ATP export (GO:1904669), monoatomic ion transport (GO:0006811), monoatomic ion transmembrane transport (GO:0034220), monoatomic cation transmembrane transport (GO:0098655)

GO Molecular Function (1): monoatomic cation channel activity (GO:0005261)

GO Cellular Component (2): plasma membrane (GO:0005886), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
apoptotic process	1
regulation of apoptotic process	1
positive regulation of programmed cell death	1
modulation of chemical synaptic transmission	1
regulation of biological quality	1
calcium ion transport	1
microglial cell activation	1
regulation of macrophage activation	1
regulation of neuroinflammatory response	1
ATP transport	1
transport	1
monoatomic ion transport	1
transmembrane transport	1
monoatomic cation transport	1
monoatomic ion transmembrane transport	1
monoatomic ion channel activity	1
monoatomic cation transmembrane transporter activity	1
membrane	1
cell periphery	1
cellular anatomical structure	1

Protein interactions and networks

STRING

538 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CALHM2	TMEM44	Q2T9K0	496
CALHM2	ANKUB1	A6NFN9	443
CALHM2	WBP1L	Q9NX94	440
CALHM2	NIF3L1	Q9GZT8	437
CALHM2	EFCC1	Q9HA90	433
CALHM2	NEURL2	Q9BR09	432
CALHM2	ANO7	Q6IWH7	417
CALHM2	LRRC71	Q8N4P6	400
CALHM2	MCTP1	Q6DN14	396
CALHM2	OR8D1	Q8WZ84	391
CALHM2	ZNF415	Q09FC8	389
CALHM2	ANKRD66	B4E2M5	384
CALHM2	SV2B	Q7L1I2	381
CALHM2	NT5C2	P49902	377
CALHM2	EFCAB11	Q9BUY7	372

IntAct

7 interactions, top by confidence:

A	B	Type	Score
CALHM2	CALHM2	psi-mi:“MI:0407”(direct interaction)	0.360
TGFBR2	TNFRSF10A	psi-mi:“MI:0914”(association)	0.350
INKA1	SDCBP	psi-mi:“MI:0914”(association)	0.350
TMEM59	TNFRSF10B	psi-mi:“MI:0914”(association)	0.350
PRND	ATP1A3	psi-mi:“MI:0914”(association)	0.350

BioGRID (4): CALHM2 (Affinity Capture-MS), CALHM2 (Affinity Capture-MS), CALHM2 (Affinity Capture-MS), CALHM2 (Affinity Capture-MS)

ESM2 similar proteins: A2BD92, A4FV45, A5D7N3, A7S641, B0BN86, D3Z2R5, F1Q930, O76024, O95870, P17152, P97587, Q0IJ20, Q17QW2, Q1JPD2, Q1JPG0, Q2HJ63, Q3B8H3, Q4QQM5, Q5BK13, Q5BLE2, Q5RAS8, Q5RJQ8, Q5SWK7, Q5SYH2, Q5ZLD4, Q66H44, Q6DC66, Q6DF19, Q6GR21, Q6MG55, Q6NRI4, Q6NUQ4, Q6NWH5, Q6ZQE4, Q7L4E1, Q7SZC5, Q7ZW11, Q7ZWF4, Q7ZYA0, Q810L4

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

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	62
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

815 predictions. Top by Δscore:

Variant	Effect	Δscore
10:103447574:C:CT	acceptor_gain	1.0000
10:103452150:CCTTA:C	donor_loss	1.0000
10:103452151:CTTAC:C	donor_loss	1.0000
10:103452152:TTAC:T	donor_loss	1.0000
10:103452153:TACCT:T	donor_loss	1.0000
10:103452154:A:C	donor_loss	1.0000
10:103452155:C:G	donor_loss	1.0000
10:103447564:AAGAG:A	acceptor_gain	0.9900
10:103447565:AGAG:A	acceptor_gain	0.9900
10:103447566:GAG:G	acceptor_gain	0.9900
10:103447566:GAGC:G	acceptor_loss	0.9900
10:103447567:AG:A	acceptor_gain	0.9900
10:103447567:AGCT:A	acceptor_loss	0.9900
10:103447569:C:CC	acceptor_gain	0.9900
10:103447569:CTGGC:C	acceptor_loss	0.9900
10:103447574:C:T	acceptor_gain	0.9900
10:103447575:A:T	acceptor_gain	0.9900
10:103449965:T:TC	acceptor_gain	0.9900
10:103452154:A:AC	donor_gain	0.9900
10:103452155:C:CC	donor_gain	0.9900
10:103449968:C:CT	acceptor_gain	0.9500
10:103449414:G:T	donor_gain	0.9400
10:103449418:T:TA	donor_gain	0.9400
10:103449965:T:C	acceptor_gain	0.9300
10:103449381:CCTTA:C	donor_loss	0.9200
10:103449382:CTTA:C	donor_loss	0.9200
10:103449383:TTA:T	donor_loss	0.9200
10:103449384:TACCT:T	donor_loss	0.9200
10:103451687:T:TA	donor_gain	0.9200
10:103451188:A:T	acceptor_gain	0.9100

AlphaMissense

2092 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
10:103449593:A:G	W117R	0.998
10:103449593:A:T	W117R	0.998
10:103449837:G:C	S35R	0.998
10:103449837:G:T	S35R	0.998
10:103449839:T:G	S35R	0.998
10:103447559:A:G	W189R	0.997
10:103447559:A:T	W189R	0.997
10:103449553:C:G	C130S	0.997
10:103449554:A:T	C130S	0.997
10:103449751:G:T	P64H	0.997
10:103449810:G:C	F44L	0.997
10:103449810:G:T	F44L	0.997
10:103449812:A:G	F44L	0.997
10:103447290:C:A	W278C	0.996
10:103447290:C:G	W278C	0.996
10:103447292:A:G	W278R	0.996
10:103447292:A:T	W278R	0.996
10:103449543:A:C	S133R	0.996
10:103449543:A:T	S133R	0.996
10:103449545:T:G	S133R	0.996
10:103449553:C:T	C130Y	0.996
10:103449554:A:G	C130R	0.996
10:103449751:G:C	P64R	0.996
10:103449772:C:T	G57E	0.996
10:103449773:C:A	G57W	0.996
10:103449783:G:C	N53K	0.996
10:103449783:G:T	N53K	0.996
10:103447421:C:G	A235P	0.995
10:103447561:C:T	G188E	0.995
10:103449391:G:A	S184F	0.995

dbSNP variants (sampled 300 via entrez): RS1000036322 (10:103448308 G>A), RS1000409972 (10:103450555 G>A), RS1000494063 (10:103447957 CAT>C), RS1000905244 (10:103452720 G>T), RS1001108417 (10:103446768 A>G), RS1001256011 (10:103448477 A>G), RS1001445447 (10:103452186 G>A), RS1001813030 (10:103451787 C>G), RS1002399695 (10:103453274 C>G), RS1002430066 (10:103453400 TTC>T), RS1002881870 (10:103453484 A>G), RS1002926589 (10:103449911 A>C), RS1003242395 (10:103449054 T>C), RS1003367996 (10:103454242 G>A), RS1003989355 (10:103450735 T>C)

Disease associations

OMIM: gene MIM:612235 | 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
GCST002149_2	Schizophrenia	4.000000e-13
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

35 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases abundance, increases expression, decreases expression, affects cotreatment	4
Cisplatin	increases expression, decreases expression, affects reaction	3
Air Pollutants	decreases expression, affects expression, increases abundance	2
Arsenic	affects methylation, affects cotreatment, increases abundance, increases expression	2
Benzo(a)pyrene	affects methylation, increases expression, increases methylation	2
aristolochic acid I	increases expression	1
GSK-J4	decreases expression	1
bisphenol A	increases expression	1
manganese chloride	increases abundance, increases expression, affects cotreatment	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression, affects cotreatment, decreases expression	1
di-n-butylphosphoric acid	affects expression	1
pinostrobin	increases expression	1
ICG 001	increases expression	1
abrine	decreases expression	1
(+)-JQ1 compound	decreases expression	1
Temozolomide	decreases expression	1
Air Pollutants, Occupational	decreases expression	1
Azacitidine	increases expression, affects reaction	1
Doxorubicin	affects expression	1
Estradiol	decreases expression	1
Formaldehyde	increases expression	1
Lipopolysaccharides	decreases expression, affects response to substance, increases expression, affects cotreatment	1
Manganese	increases abundance, increases expression, affects cotreatment	1
Nickel	decreases expression	1
Ozone	affects expression, increases abundance	1
Selenium	increases expression	1
Smoke	decreases expression	1
Tobacco Smoke Pollution	increases expression	1
Tretinoin	decreases expression	1
Valproic Acid	affects expression	1

Clinical trials (associated diseases)

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