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 — automated summary from GO annotations (Alliance of Genome Resources).

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 67 total
• GTEx eGene: eQTL in 38 tissues, sQTL in 7 (q < 0.05)
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 1.21 (unconstrained)
• MANE Select transcript: NM_015916
• Notable: 67 clinical variants but no curated precision-oncology (CIViC) evidence yet

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: 49 — 44 protein_coding, 5 protein_coding_CDS_not_defined

MANE Select: ENST00000260743

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 1, TSL 2: 5, TSL 3: 1

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, ENST00000988659, ENST00000988660, ENST00000988661, ENST00000988662, ENST00001033412, ENST00001033413, ENST00001033414, ENST00001033415, ENST00001033416, ENST00001033417, ENST00001033418, ENST00001033419, ENST00001124966, ENST00001136815

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.

Highest expression (Bgee): granulocyte, endocervix, body of uterus, coronary artery, uterine tube.

Genetic regulation across tissues (GTEx eQTL / sQTL)

CALHM2 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 38 tissues and its splicing (sQTL) in 7 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 45 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Cells Cultured fibroblasts	eqtl	1.8e-21	+0.22	10:103441820:C:T
Whole Blood	eqtl	8.6e-20	-0.46	10:103471557:G:A
Nerve Tibial	eqtl	5.7e-17	+0.22	10:103447117:T:C
Skin Sun Exposed Lower leg	eqtl	5.6e-15	+0.13	10:103423979:T:C
Adipose Subcutaneous	eqtl	6.1e-14	+0.18	10:103423979:T:C
Breast Mammary Tissue	eqtl	2.0e-13	+0.19	10:103436140:A:G
Colon Sigmoid	eqtl	8.1e-13	+0.24	10:103441808:G:A
Adipose Visceral Omentum	eqtl	1.8e-10	-0.71	10:103429111:C:T
Brain Frontal Cortex BA9	eqtl	5.5e-10	+0.39	10:103444697:T:C
Esophagus Muscularis	eqtl	1.9e-09	+0.19	10:103432813:A:G
Esophagus Mucosa	eqtl	2.4e-09	+0.14	10:103431585:CTG:C
Testis	eqtl	3.2e-09	-0.54	10:103429111:C:T
Thyroid	eqtl	3.9e-09	-0.63	10:103449599:CAG:C
Artery Tibial	eqtl	8.5e-09	+0.16	10:103447117:T:C
Muscle Skeletal	eqtl	1.0e-08	+0.15	10:103436140:A:G
Brain Cortex	eqtl	5.5e-08	+0.32	10:103444697:T:C
Colon Transverse	eqtl	8.0e-08	+0.14	10:103447117:T:C
Esophagus Gastroesophageal Junction	eqtl	1.5e-07	+0.18	10:103434329:C:T
Skin Not Sun Exposed Suprapubic	eqtl	3.4e-07	+0.11	10:103441808:G:A
Artery Aorta	eqtl	1.5e-06	+0.20	10:103428450:A:ACT

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

showing 100 of 288 tissues 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
cardiac atrium	UBERON:0002081	91.48	gold quality
spleen	UBERON:0002106	91.48	gold quality
tibial nerve	UBERON:0001323	91.41	gold quality
pericardium	UBERON:0002407	91.41	gold quality
gall bladder	UBERON:0002110	91.40	gold quality
ovary	UBERON:0000992	91.07	gold quality
lower esophagus muscularis layer	UBERON:0035833	90.94	gold quality
tendon of biceps brachii	UBERON:0008188	90.86	gold quality
lower esophagus	UBERON:0013473	90.85	gold quality
adipose tissue	UBERON:0001013	90.62	gold quality
stromal cell of endometrium	CL:0002255	90.26	gold quality
connective tissue	UBERON:0002384	90.20	gold quality
decidua	UBERON:0002450	90.19	gold quality
vena cava	UBERON:0004087	89.92	gold quality
right lobe of thyroid gland	UBERON:0001119	89.58	gold quality
periodontal ligament	UBERON:0008266	89.23	gold quality
upper lobe of left lung	UBERON:0008952	89.15	gold quality
smooth muscle tissue	UBERON:0001135	89.12	gold quality
blood	UBERON:0000178	88.74	gold quality
upper lobe of lung	UBERON:0008948	88.74	gold quality
urethra	UBERON:0000057	88.61	gold quality
saphenous vein	UBERON:0007318	88.60	gold quality
vagina	UBERON:0000996	88.41	gold quality
heart	UBERON:0000948	88.14	gold quality
left adrenal gland	UBERON:0001234	87.93	gold quality
superficial temporal artery	UBERON:0001614	87.87	gold quality
skin of hip	UBERON:0001554	87.71	gold quality
left adrenal gland cortex	UBERON:0035825	87.67	gold quality
uterine cervix	UBERON:0000002	87.48	gold quality
left lobe of thyroid gland	UBERON:0001120	87.29	gold quality
right lung	UBERON:0002167	87.26	gold quality
cardiac muscle of right atrium	UBERON:0003379	87.24	gold quality
right uterine tube	UBERON:0001302	87.22	gold quality
right adrenal gland	UBERON:0001233	87.17	gold quality
adrenal cortex	UBERON:0001235	87.13	gold quality
heart left ventricle	UBERON:0002084	87.09	gold quality
cardiac ventricle	UBERON:0002082	86.95	gold quality
diaphragm	UBERON:0001103	86.94	gold quality
muscle layer of sigmoid colon	UBERON:0035805	86.91	gold quality
lymph node	UBERON:0000029	86.89	gold quality
fundus of stomach	UBERON:0001160	86.87	gold quality
skin of leg	UBERON:0001511	86.82	gold quality
right adrenal gland cortex	UBERON:0035827	86.81	gold quality
female reproductive system	UBERON:0000474	86.78	gold quality
penis	UBERON:0000989	86.44	gold quality
mammalian vulva	UBERON:0000997	86.28	gold quality
small intestine Peyer’s patch	UBERON:0003454	86.26	gold quality
thyroid gland	UBERON:0002046	86.19	gold quality
esophagus	UBERON:0001043	86.18	gold quality
thoracic mammary gland	UBERON:0005200	86.09	gold quality
placenta	UBERON:0001987	86.08	gold quality
mammary gland	UBERON:0001911	86.07	gold quality
hair follicle	UBERON:0002073	86.04	silver quality
caecum	UBERON:0001153	85.90	gold quality
urinary bladder	UBERON:0001255	85.88	gold quality
germinal epithelium of ovary	UBERON:0001304	85.85	gold quality
adrenal gland	UBERON:0002369	85.72	gold quality
mammary duct	UBERON:0001765	85.71	gold quality
minor salivary gland	UBERON:0001830	85.68	gold quality
calcaneal tendon	UBERON:0003701	85.18	gold quality
vermiform appendix	UBERON:0001154	85.07	gold quality
lung	UBERON:0002048	84.97	gold quality
skin of abdomen	UBERON:0001416	84.95	gold quality
cardia of stomach	UBERON:0001162	84.86	gold quality
mouth mucosa	UBERON:0003729	84.84	gold quality
zone of skin	UBERON:0000014	84.74	gold quality
tendon	UBERON:0000043	84.74	gold quality
uterus	UBERON:0000995	84.74	gold quality
small intestine	UBERON:0002108	84.44	gold quality
cauda epididymis	UBERON:0004360	84.44	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

HPA expression

RNA tissue specificity: Low tissue specificity

showing 60 of 79 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Ovary	tissue	38.7	low
Vagina	tissue	37.5	medium
Spleen	tissue	20.8	medium
Gallbladder	tissue	20.2	high
Endometrium 1	tissue	18.9	medium
Cervix	tissue	18.0	medium
Adipose tissue	tissue	17.2	high
Fallopian tube	tissue	16.5	high
Smooth muscle	tissue	14.9	low
Urinary bladder	tissue	14.1	medium
Lymph node	tissue	12.8	medium
Heart muscle	tissue	12.4	medium
Appendix	tissue	11.8	medium
Lung	tissue	11.7	high
Adrenal gland	tissue	10.8	high
Tongue	tissue	10.3
Seminal vesicle	tissue	10.0	medium
Placenta	tissue	9.4	high
Choroid plexus	tissue	8.1
Hippocampus	tissue	8.1	medium
Testis	tissue	7.3	medium
Pituitary gland	tissue	7.0
Esophagus	tissue	7.0	medium
Breast	tissue	6.9	low
Prostate	tissue	6.8	medium
Skin 1	tissue	6.4	medium
Salivary gland	tissue	6.2	medium
Duodenum	tissue	6.1	medium
Small intestine	tissue	5.9	high
Spinal cord	tissue	5.7
Tonsil	tissue	5.7	medium
Skeletal muscle	tissue	5.6	low
Colon	tissue	5.6	high
Hypothalamus	tissue	5.6
Substantia nigra	tissue	5.5
Epididymis	tissue	5.2	medium
Thymus	tissue	5.2
Septum	tissue	5.1
Stomach 1	tissue	4.9	high
Nucleus accumbens	tissue	4.9
Corpus callosum	tissue	4.8
Superior colliculi	tissue	4.7
Locus coeruleus	tissue	4.7
Midbrain	tissue	4.5
Pons	tissue	4.4
Medulla oblongata	tissue	4.3
Thalamus	tissue	4.3
Periaqueductal gray	tissue	4.3
Ventral forebrain	tissue	4.2
Postcentral gyrus	tissue	4.1
Rectum	tissue	4.0
Thyroid gland	tissue	3.9	medium
Putamen	tissue	3.6
Amygdala	tissue	3.5
Hippocampal formation	tissue	3.5
Cerebral cortex	tissue	3.4	high
Pancreas	tissue	3.4	medium
Insular cortex	tissue	3.4
Frontal cortex	tissue	3.1
Entorhinal cortex	tissue	3.1

Brain sub-regions (HPA Brain Atlas): detected in 192; highest nTPM — Blood vessel (44.2), Anterior thalamic nucleus, ventral (10.6), Area postrema (10.1), Lateral funiculus (white matter) (10.0), Cervical spinal cord, ventral horn (9.7).

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

Targeting CALHM2 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

19 miRNAs:

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

Functional genomics

gnomAD constraint: pLI 6.27e-06, LOEUF 1.21, missense Z 0.764 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000260743 — one region, missense o/e 0.94.

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)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:1919941) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 14 distinct phenotype terms.

Mouse phenotype (MP)	Records
persistence of hyaloid vascular system	1
reduced long-term potentiation	1
abnormal pancreas morphology	1
behavioral despair	1
abnormal excitatory postsynaptic potential	1
enlarged pancreas	1
abnormal astrocyte physiology	1
anhedonia	1
impaired spatial learning	1
impaired long-term object recognition memory	1
impaired spatial working memory	1
abnormal sucrose solution preference	1
decreased dendritic spine density	1
decreased dendritic spine number	1

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Bos taurus	Q2HJ63	92.8%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
PDCD11	protein-coding	22984
TAF5	protein-coding	6877
PCGF6	protein-coding	84108
ATP5MK	protein-coding	84833
NEURL1-AS1	ncRNA	102724341
CALHM1	protein-coding	255022
NEURL1	protein-coding	9148
CALHM3	protein-coding	119395
MIR1307	ncRNA	100302174
INA	protein-coding	9118

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)

• ATP(in) = ATP(out) (RHEA:75687)

UniProt features (52 total): helix 19, 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 by resolution:

PDB	Title	Method	Resolution (Å)
6UIW	Cryo-EM structure of human CALHM2 in a ruthenium red-bound inhibited state	ELECTRON MICROSCOPY	2.7
8RMK	Cryo-EM structure of human CALHM2 in complex with synthetic nanobody SbC2	ELECTRON MICROSCOPY	3.07
8RMM	Structure of heteromeric CALHM2/4 channel in complex with synthetic nanobodies SbC2 and …	ELECTRON MICROSCOPY	3.26
6UIV	Cryo-EM structure of human CALHM2 in an active/open state	ELECTRON MICROSCOPY	3.3
6LMU	Cryo-EM structure of the human CALHM2	ELECTRON MICROSCOPY	3.4
6LMW	Cryo-EM structure of the CALHM chimeric construct (8-mer)	ELECTRON MICROSCOPY	3.4
6LMX	Cryo-EM structure of the CALHM chimeric construct (9-mer)	ELECTRON MICROSCOPY	3.4
6VAK	Cryo-EM structure of human CALHM2	ELECTRON MICROSCOPY	3.48
6UIX	Cryo-EM structure of human CALHM2 gap junction	ELECTRON MICROSCOPY	3.5
6VAI	Cryo-EM structure of a dimer of undecameric human CALHM2	ELECTRON MICROSCOPY	3.68
8RML	Structure of heteromeric CALHM2/4 channel in complex with synthetic nanobody SbC4	ELECTRON MICROSCOPY	3.84
6VAL	Cryo-EM structure of an undecameric chicken CALHM1 and human CALHM2 chimera	ELECTRON MICROSCOPY	3.87

Predicted structure (AlphaFold)

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

Antibody-complex structures (SAbDab)

3 antibodies co-crystallized with this protein: 8RMK, 8RML, 8RMM

Human Protein Atlas

Protein class: Transporters, Transporter channels and pores, Predicted membrane proteins

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): mitochondria; nucleoplasm; cytosol

Antibody reliability (HPA): IH approved · IF approved

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)

Position	Role
168	not n-glycosylated

Disulfide bonds (2)

Type	Positions
Disulfide bond	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 inactivation of the …
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 curated (TAS) of 0; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

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 (2): monoatomic cation channel activity (GO:0005261), identical protein binding (GO:0042802)

GO Cellular Component (1): plasma membrane (GO:0005886)

GO top-level categories

20 GO namespaces:

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
protein binding	1
membrane	1
cell periphery	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 2 of 11 annotations. The rest are phylogenetic / computational / electronic (IEA).

2 experimentally-supported GO terms:

GO term	NS	Evidence
ATP export	BP	direct assay
positive regulation of apoptotic process	BP	direct assay

Protein interactions and networks

STRING

showing 15 of 476 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CALHM2	TMEM44	Q2T9K0	480
CALHM2	WBP1L	Q9NX94	453
CALHM2	MCTP1	Q6DN14	438
CALHM2	NIF3L1	Q9GZT8	427
CALHM2	LRRC8A	Q8IWT6	421
CALHM2	PKD2L1	Q9P0L9	415
CALHM2	NT5C2	P49902	399
CALHM2	BORCS7	Q96B45	387
CALHM2	FBXW4	P57775	380
CALHM2	ANO7	Q6IWH7	370
CALHM2	SV2B	Q7L1I2	370
CALHM2	PANX1	Q96RD7	364
CALHM2	NEURL2	Q9BR09	363
CALHM2	PKD1L3	Q7Z443	355
CALHM2	EFCC1	Q9HA90	354

IntAct

BioGRID (4 interactions; top human partners by supporting records): FAM212A (Affinity Capture-MS), PRND (Affinity Capture-MS), TGFBR2 (Affinity Capture-MS), TMEM59 (Affinity Capture-MS)

Disease & clinical

Genetic variants

Variant evidence for CALHM2: 67 ClinVar records (0 pathogenic / likely pathogenic); 2 GWAS associations.

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

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 32 predictions of 505):

Position(s)	Effect	Δscore	Sites
10:103452154–103452155	donor_loss	1.0000	5
10:103447569–103447570	acceptor_loss	0.9900	6
10:103447574–103447575	acceptor_gain	0.9900	2
10:103449414	donor_gain	0.9400
10:103449965	acceptor_gain	0.9300
10:103449385–103449386	donor_loss	0.9200	6
10:103451188	acceptor_gain	0.9100
10:103449387	donor_loss	0.8900
10:103449387	donor_loss	0.8800
10:103449398–103449400	donor_loss	0.8800	8

AlphaMissense

747 missense substitutions predicted likely pathogenic (of 2,092 scored), across 205 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
F44	8	0.968	0.997
N53	8	0.968	0.996
F251	8	0.937	0.984
S297	8	0.880	0.994
H238	8	0.862	0.953
D20	8	0.773	0.906
F200	8	0.767	0.894
F16	8	0.752	0.871
C130	7	0.993	0.997
C46	7	0.991	0.995
W278	7	0.984	0.996
W117	7	0.981	0.998
C48	7	0.979	0.989
C162	7	0.965	0.983
F39	7	0.945	0.985
E227	7	0.938	0.974
F250	7	0.937	0.986
W189	7	0.933	0.997
F231	7	0.927	0.983
F135	7	0.926	0.987

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Disease associations

OMIM: gene MIM:612235 | disease phenotypes:

GWAS associations

2 associations:

Study	Trait	p-value
GCST002149_2	Schizophrenia	4e-13
GCST008361_2	Response to cognitive-behavioural therapy in major depressive disorder	2e-6

EFO canonical traits (from GWAS)

1 canonical traits:

EFO ID	Trait name
EFO:0007820	cognitive behavioural therapy

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (CPIC guideline: no)

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, affects cotreatment, increases abundance, increases expression	4
Cisplatin	affects reaction, increases expression, decreases expression	3
Air Pollutants	affects expression, increases abundance, decreases expression	2
Arsenic	increases expression, affects methylation, affects cotreatment, increases abundance	2
Benzo(a)pyrene	increases methylation, affects methylation, increases expression	2
aristolochic acid I	increases expression	1
GSK-J4	decreases expression	1
bisphenol A	increases expression	1
manganese chloride	affects cotreatment, increases abundance, increases expression	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)

Via MONDO — disease-level, not drug-specific.