CALHM6

Summary

CALHM6 (calcium homeostasis modulator family member 6, HGNC:33391) is a protein-coding gene on chromosome 6q22.1, encoding Calcium homeostasis modulator protein 6 (Q5R3K3). Pore-forming subunit of an ATP-permeable channel.

Predicted to enable monoatomic cation channel activity. Predicted to be involved in ATP export; monoatomic cation transmembrane transport; and regulation of natural killer cell cytokine production. Predicted to be located in immunological synapse. Predicted to be active in plasma membrane.

Source: NCBI Gene 441168 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 52 total
• MANE Select transcript: NM_001010919

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:33391
Approved symbol	CALHM6
Name	calcium homeostasis modulator family member 6
Location	6q22.1
Locus type	gene with protein product
Status	Approved
Aliases	RP1-93H18.5, OTTHUMP00000017061, OTTHUMP00000017062, dJ93H18.5, INAM
Ensembl gene	ENSG00000188820
Ensembl biotype	protein_coding
OMIM	617305
Entrez	441168

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 4 protein_coding

ENST00000368604, ENST00000368605, ENST00000368606, ENST00000859968

RefSeq mRNA: 2 — MANE Select: NM_001010919 NM_001010919, NM_001276460

CCDS: CCDS34519, CCDS64506

Canonical transcript exons

ENST00000368605 — 3 exons

Exon	Start	End
ENSE00001381941	116463283	116463771
ENSE00001447540	116461872	116462454
ENSE00001905887	116461375	116461429

Expression profiles

Bgee: expression breadth ubiquitous, 133 present calls, max score 98.02.

FANTOM5 (CAGE): breadth broad, TPM avg 6.5122 / max 356.2437, expressed in 851 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
69425	4.1719	789
69423	1.2070	205
69424	0.6104	107
204172	0.1513	44
204171	0.1387	31
69420	0.1082	31
69422	0.0728	33
69421	0.0520	30

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
spleen	UBERON:0002106	98.02	gold quality
thymus	UBERON:0002370	97.82	silver quality
granulocyte	CL:0000094	97.39	gold quality
monocyte	CL:0000576	97.15	gold quality
leukocyte	CL:0000738	97.13	gold quality
vermiform appendix	UBERON:0001154	95.77	gold quality
lymph node	UBERON:0000029	94.79	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	89.12	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	87.45	gold quality
blood	UBERON:0000178	85.17	gold quality
bone marrow	UBERON:0002371	84.56	gold quality
placenta	UBERON:0001987	84.21	gold quality
small intestine Peyer’s patch	UBERON:0003454	83.14	gold quality
duodenum	UBERON:0002114	82.81	gold quality
small intestine	UBERON:0002108	80.97	gold quality
nucleus accumbens	UBERON:0001882	80.27	gold quality
bone marrow cell	CL:0002092	79.06	gold quality
smooth muscle tissue	UBERON:0001135	78.62	gold quality
right coronary artery	UBERON:0001625	78.18	gold quality
omental fat pad	UBERON:0010414	77.93	gold quality
right lung	UBERON:0002167	77.73	gold quality
mucosa of transverse colon	UBERON:0004991	77.02	gold quality
spinal cord	UBERON:0002240	76.82	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	76.77	gold quality
right adrenal gland cortex	UBERON:0035827	76.75	gold quality
caudate nucleus	UBERON:0001873	76.69	gold quality
left adrenal gland cortex	UBERON:0035825	76.63	gold quality
left adrenal gland	UBERON:0001234	76.52	gold quality
putamen	UBERON:0001874	76.20	gold quality
descending thoracic aorta	UBERON:0002345	76.20	gold quality

Single-cell (SCXA)

Detected in 12 experiment(s), a significant marker in 11.

Experiment	Marker?	Max mean expression
E-HCAD-1	yes	61.51
E-HCAD-4	yes	50.10
E-HCAD-6	yes	48.32
E-CURD-46	yes	45.19
E-MTAB-10553	yes	41.25
E-MTAB-6701	yes	22.19
E-MTAB-9467	yes	21.40
E-CURD-88	yes	19.37
E-HCAD-9	yes	16.99
E-MTAB-8410	yes	12.68
E-ANND-3	yes	8.34
E-GEOD-110499	no	62.13

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 5)

• FAM26Fwas found to be consistently and significantly overexpressed in ulcerative colitis patients. (PMID:25082827)
• FAM26F: An Enigmatic Protein Having a Complex Role in the Immune System. (PMID:27645024)
• FAM26F is a conserved, signal peptide deprived transmembrane protein that is secreted through non-classical pathway.FAM26F has an immunoglobulin-like fold which emphasizes its role in immune responses. (PMID:27784631)
• CALHM6 is implicated in regulating the immune response to infection and may have a role in typical triggering of Steroid-Sensitive Nephrotic Syndrome (SSNS) onset by infections (PMID:31263063)
• Effect of oxidative stress and calcium deregulation on FAM26F (CALHM6) expression during hepatitis B virus infection. (PMID:33639860)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
mus_musculus	Calhm6	ENSMUSG00000046031
rattus_norvegicus	Calhm6	ENSRNOG00000037757
caenorhabditis_elegans		WBGENE00016626

Paralogs (5): CALHM2 (ENSG00000138172), CALHM4 (ENSG00000164451), CALHM5 (ENSG00000178033), CALHM3 (ENSG00000183128), CALHM1 (ENSG00000185933)

Protein

Protein identifiers

Calcium homeostasis modulator protein 6 — Q5R3K3 (reviewed: Q5R3K3)

Alternative names: Protein FAM26F

All UniProt accessions (2): Q5R3K2, Q5R3K3

UniProt curated annotations — full annotation on UniProt →

Function. Pore-forming subunit of an ATP-permeable channel. In response to pathogen-derived and proinflammatory stimuli, relocates from intracellular compartments to NK-dendritic cell and NK-macrophage immune synapses where it mediates ATP efflux and NK cell activation involved in antimicrobial and antitumor responses. May assemble to form gap junction channel-like structures with gating and ion conductance likely regulated by membrane lipids and voltage rather than by extracellular calcium levels.

Subunit / interactions. Oligomerizes to form decameric and undecameric channels.

Subcellular location. Cell membrane.

Tissue specificity. Placenta.

Post-translational modifications. N-glycosylated.

Similarity. Belongs to the CALHM family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q5R3K3-1	1	yes
Q5R3K3-2	2

RefSeq proteins (2): NP_001010919, NP_001263389 (=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 (18 total): topological domain 5, transmembrane region 4, disulfide bond 3, sequence variant 3, splice variant 2, chain 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
6YTV	ELECTRON MICROSCOPY	4.39
6YTX	ELECTRON MICROSCOPY	6.23

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q5R3K3-F1	84.83	0.41

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 (3): 41–126, 43–155, 139–146

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 215 (showing top): GSE45365_NK_CELL_VS_CD11B_DC_DN, GSE18804_SPLEEN_MACROPHAGE_VS_COLON_TUMORAL_MACROPHAGE_UP, XU_GH1_AUTOCRINE_TARGETS_UP, GOBP_LEUKOCYTE_MEDIATED_IMMUNITY, GOBP_NUCLEOTIDE_TRANSPORT, GOBP_MONOATOMIC_CATION_TRANSPORT, GOBP_ORGANOPHOSPHATE_ESTER_TRANSPORT, GOBP_REGULATION_OF_IMMUNE_RESPONSE, GOBP_DEFENSE_RESPONSE_TO_OTHER_ORGANISM, GOBP_LYMPHOCYTE_MEDIATED_IMMUNITY, GOBP_CYTOKINE_PRODUCTION, GOBP_REGULATION_OF_RESPONSE_TO_STRESS, GOBP_NUCLEOBASE_CONTAINING_COMPOUND_TRANSPORT, GOBP_ORGANIC_ANION_TRANSPORT, GOBP_REGULATION_OF_LYMPHOCYTE_MEDIATED_IMMUNITY

GO Biological Process (5): regulation of natural killer cell cytokine production (GO:0002727), ATP export (GO:1904669), monoatomic ion transport (GO:0006811), monoatomic ion transmembrane transport (GO:0034220), monoatomic cation transmembrane transport (GO:0098655)

GO Molecular Function (3): monoatomic cation channel activity (GO:0005261), voltage-gated channel activity (GO:0022832), protein binding (GO:0005515)

GO Cellular Component (3): immunological synapse (GO:0001772), plasma membrane (GO:0005886), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
natural killer cell cytokine production	1
regulation of natural killer cell mediated immunity	1
regulation of cytokine production involved in immune 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
gated channel activity	1
binding	1
plasma membrane	1
membrane	1
cell periphery	1

Protein interactions and networks

STRING

682 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CALHM6	CD4	P01730	434
CALHM6	TSPAN13	O95857	422
CALHM6	CD180	Q99467	404
CALHM6	PPP2R5C	Q13362	401
CALHM6	CD8A	P01732	398
CALHM6	NT5DC1	Q5TFE4	395
CALHM6	SLC8B1	Q6J4K2	388
CALHM6	PHF20L1	A8MW92	382
CALHM6	NMT1	P30419	378
CALHM6	LMAN2L	Q9H0V9	373
CALHM6	PDE8A	O60658	350
CALHM6	USP25	Q9UHP3	343
CALHM6	ANKMY2	Q8IV38	336
CALHM6	GBP6	Q6ZN66	332
CALHM6	LCP2	Q13094	313

IntAct

10 interactions, top by confidence:

A	B	Type	Score
CALHM6	HSD17B13	psi-mi:“MI:0915”(physical association)	0.560
CALHM6	JAGN1	psi-mi:“MI:0915”(physical association)	0.560
CALHM6	CBARP	psi-mi:“MI:0915”(physical association)	0.560
CALHM6	CBARP	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (3): FAM26F (Two-hybrid), FAM26F (Two-hybrid), FAM26F (Two-hybrid)

ESM2 similar proteins: A2A8U2, A2SXS5, D3Z291, E9Q6C8, J3QMI4, O00255, O02718, O88559, P51811, P56726, P60570, P85299, P97260, P97698, Q0P5I0, Q0VF94, Q12770, Q14714, Q17RQ9, Q2HJ63, Q49LS5, Q49LS8, Q5GH57, Q5GH64, Q5GH73, Q5MNU5, Q5R3K3, Q5REE3, Q5RJQ8, Q5SNT2, Q5XI52, Q69Z89, Q6AXN4, Q6AXR8, Q6DVA0, Q6P8G8, Q7RTS5, Q86XJ0, Q8C190, Q8C561

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

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	47
Likely benign	2
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

329 predictions. Top by Δscore:

Variant	Effect	Δscore
6:116462443:GC:G	donor_gain	1.0000
6:116462434:G:GT	donor_gain	0.9900
6:116462444:C:G	donor_gain	0.9900
6:116463279:TAAG:T	acceptor_loss	0.9900
6:116463281:A:AT	acceptor_loss	0.9900
6:116463281:A:G	acceptor_gain	0.9900
6:116463282:G:GT	acceptor_loss	0.9900
6:116463282:GGT:G	acceptor_gain	0.9800
6:116462449:TCGC:T	donor_gain	0.9700
6:116462422:G:GT	donor_gain	0.9600
6:116462413:G:GT	donor_gain	0.9500
6:116462450:CGCAG:C	donor_loss	0.9400
6:116462451:GCAG:G	donor_loss	0.9400
6:116462452:CAG:C	donor_loss	0.9400
6:116462453:AGGTC:A	donor_loss	0.9400
6:116462454:G:C	donor_loss	0.9400
6:116462455:G:A	donor_loss	0.9400
6:116462456:T:A	donor_loss	0.9400
6:116463280:A:AG	acceptor_gain	0.9300
6:116463282:G:GG	acceptor_gain	0.9300
6:116462654:T:TA	donor_gain	0.9200
6:116462655:A:AA	donor_gain	0.9200
6:116461430:G:GG	donor_gain	0.9100
6:116463337:T:G	acceptor_gain	0.9100
6:116462430:G:GT	donor_gain	0.9000
6:116462439:G:GT	donor_gain	0.9000
6:116463280:AAGGT:A	acceptor_gain	0.9000
6:116462540:C:G	donor_gain	0.8900
6:116462449:TCGCA:T	donor_loss	0.8800
6:116463280:AAG:A	acceptor_gain	0.8800

AlphaMissense

2027 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:116462044:T:C	F39L	0.994
6:116462046:C:A	F39L	0.994
6:116462046:C:G	F39L	0.994
6:116463292:T:A	W179R	0.991
6:116463292:T:C	W179R	0.991
6:116462266:T:A	W113R	0.990
6:116462266:T:C	W113R	0.990
6:116462092:T:C	F55L	0.989
6:116462094:C:A	F55L	0.989
6:116462094:C:G	F55L	0.989
6:116463382:T:C	F209L	0.988
6:116463384:C:A	F209L	0.988
6:116463384:C:G	F209L	0.988
6:116462045:T:G	F39C	0.987
6:116462105:C:A	P59Q	0.987
6:116462296:T:C	F123L	0.985
6:116462298:T:A	F123L	0.985
6:116462298:T:G	F123L	0.985
6:116462305:T:A	C126S	0.984
6:116462306:G:C	C126S	0.984
6:116463526:T:A	W257R	0.984
6:116463526:T:C	W257R	0.984
6:116462105:C:G	P59R	0.982
6:116463442:G:C	A229P	0.982
6:116462305:T:C	C126R	0.981
6:116463577:A:C	S274R	0.981
6:116463579:C:A	S274R	0.981
6:116463579:C:G	S274R	0.981
6:116462050:T:A	C41S	0.980
6:116462051:G:C	C41S	0.980

dbSNP variants (sampled 300 via entrez): RS1000611244 (6:116463212 T>C), RS1000937351 (6:116460701 T>G), RS1000955888 (6:116463462 G>A,C), RS1001389699 (6:116461087 T>A), RS1001442558 (6:116462463 C>T), RS1002445122 (6:116461184 T>C), RS1002497357 (6:116461555 G>A,C), RS1003114656 (6:116463783 CT>C,CTT), RS1003151983 (6:116460168 G>A), RS1003166865 (6:116464031 C>T), RS1003202712 (6:116461812 C>A,T), RS1003275525 (6:116460430 T>C), RS1003893286 (6:116461500 T>C,G), RS1004324127 (6:116459951 T>C), RS1004358686 (6:116461583 G>A,C)

Disease associations

OMIM: gene MIM:617305 | 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
GCST002548_1	Ulcerative colitis	8.000000e-10
GCST004133_46	Ulcerative colitis	9.000000e-06
GCST008456_7	Childhood steroid-sensitive nephrotic syndrome	1.000000e-17

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

19 total (human), top 19 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases expression, increases expression, increases methylation	4
Nickel	increases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
triphenyl phosphate	affects expression	1
hydroquinone	decreases expression	1
avobenzone	increases expression	1
2-palmitoylglycerol	increases expression	1
entinostat	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	increases expression, affects cotreatment	1
belinostat	decreases expression	1
dorsomorphin	affects cotreatment, increases expression	1
(+)-JQ1 compound	decreases expression	1
Formaldehyde	decreases expression	1
Oxygen	increases expression	1
Progesterone	increases expression	1
Silicon Dioxide	increases expression	1
Tobacco Smoke Pollution	decreases expression	1
Antirheumatic Agents	decreases expression	1
Lactic Acid	increases expression	1

Clinical trials (associated diseases)

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