CALHM4

Summary

CALHM4 (calcium homeostasis modulator family member 4, HGNC:21094) is a protein-coding gene on chromosome 6q22.1, encoding Calcium homeostasis modulator protein 4 (Q5JW98). May assemble to form gap junction channel-like structures involved in intercellular communication.

Predicted to enable monoatomic cation channel activity. Predicted to be involved in ATP export and monoatomic cation transmembrane transport. Predicted to be located in membrane. Predicted to be active in plasma membrane.

Source: NCBI Gene 221301 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 43 total — 2 pathogenic, 1 likely-pathogenic
• MANE Select transcript: NM_001366078

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:21094
Approved symbol	CALHM4
Name	calcium homeostasis modulator family member 4
Location	6q22.1
Locus type	gene with protein product
Status	Approved
Aliases	FLJ32239
Ensembl gene	ENSG00000164451
Ensembl biotype	protein_coding
Entrez	221301

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 5 protein_coding

ENST00000368596, ENST00000368597, ENST00000405399, ENST00000452373, ENST00000628083

RefSeq mRNA: 5 — MANE Select: NM_001366078 NM_001256887, NM_001256888, NM_001256889, NM_001366078, NM_153036

CCDS: CCDS5109, CCDS59031, CCDS59032, CCDS93991

Canonical transcript exons

ENST00000368596 — 2 exons

Exon	Start	End
ENSE00001447518	116553751	116554351
ENSE00003929960	116557825	116561127

Expression profiles

Bgee: expression breadth broad, 53 present calls, max score 88.69.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.0589 / max 20.6405, expressed in 22 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
69430	0.0589	22

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
placenta	UBERON:0001987	88.69	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	82.09	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	71.88	gold quality
right coronary artery	UBERON:0001625	57.91	gold quality
apex of heart	UBERON:0002098	49.40	gold quality
hindlimb stylopod muscle	UBERON:0004252	49.14	gold quality
skeletal muscle tissue	UBERON:0001134	45.75	gold quality
gastrocnemius	UBERON:0001388	44.82	gold quality
heart left ventricle	UBERON:0002084	44.77	gold quality
muscle of leg	UBERON:0001383	44.01	gold quality
colonic epithelium	UBERON:0000397	42.59	gold quality
muscle tissue	UBERON:0002385	41.50	gold quality
heart	UBERON:0000948	41.30	gold quality
kidney	UBERON:0002113	39.52	gold quality
right atrium auricular region	UBERON:0006631	39.36	gold quality
cortex of kidney	UBERON:0001225	38.87	gold quality
adult mammalian kidney	UBERON:0000082	38.78	gold quality
right uterine tube	UBERON:0001302	37.16	silver quality
monocyte	CL:0000576	36.99	silver quality
subcutaneous adipose tissue	UBERON:0002190	36.90	gold quality
adipose tissue	UBERON:0001013	36.49	gold quality
ventricular zone	UBERON:0003053	36.48	gold quality
cortical plate	UBERON:0005343	36.47	gold quality
omental fat pad	UBERON:0010414	36.17	gold quality
bone marrow cell	CL:0002092	36.16	gold quality
leukocyte	CL:0000738	36.15	silver quality
ganglionic eminence	UBERON:0004023	35.49	gold quality
sural nerve	UBERON:0015488	35.29	gold quality
left coronary artery	UBERON:0001626	34.85	gold quality
popliteal artery	UBERON:0002250	34.32	silver quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	2.61

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

121 targeting CALHM4, 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-190A-3P	100.00	80.35	5520
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-96-5P	99.95	72.80	2140
HSA-MIR-3143	99.93	71.96	3104
HSA-MIR-3682-5P	99.93	67.97	1163
HSA-MIR-12133	99.92	71.82	2006
HSA-MIR-1271-5P	99.91	71.99	1972
HSA-MIR-7-1-3P	99.91	71.53	4384
HSA-MIR-7-2-3P	99.91	71.40	4394
HSA-MIR-9902	99.89	69.15	2250
HSA-MIR-548E-5P	99.89	72.73	4486
HSA-MIR-3919	99.87	69.45	2489
HSA-MIR-182-5P	99.87	74.03	2589
HSA-MIR-579-3P	99.86	71.66	3628
HSA-MIR-4503	99.85	71.45	1869
HSA-MIR-4698	99.84	71.41	4303
HSA-MIR-664B-3P	99.84	71.65	3590

Literature-anchored findings (GeneRIF, showing 1)

• Structural features of heteromeric channels composed of CALHM2 and CALHM4 paralogs. (PMID:38896440)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
mus_musculus	Calhm4	ENSMUSG00000039508
rattus_norvegicus	Calhm4	ENSRNOG00000000580
caenorhabditis_elegans		WBGENE00016626

Paralogs (5): CALHM2 (ENSG00000138172), CALHM5 (ENSG00000178033), CALHM3 (ENSG00000183128), CALHM1 (ENSG00000185933), CALHM6 (ENSG00000188820)

Protein

Protein identifiers

Calcium homeostasis modulator protein 4 — Q5JW98 (reviewed: Q5JW98)

Alternative names: Protein FAM26D

All UniProt accessions (2): B0QZ26, Q5JW98

UniProt curated annotations — full annotation on UniProt →

Function. May assemble to form gap junction channel-like structures involved in intercellular communication. Channel gating and ion conductance are likely regulated by membrane lipids rather than by membrane depolarization or extracellular calcium levels.

Subunit / interactions. Oligomerizes to form decameric and undecameric channels. Two hemichannels can assemble in a tail-to-tail manner to form a gap junction.

Subcellular location. Cell membrane.

Tissue specificity. Placenta.

Similarity. Belongs to the CALHM family.

Isoforms (4)

UniProt ID	Names	Canonical?
Q5JW98-1	1	yes
Q5JW98-2	2
Q5JW98-3	3
Q5JW98-4	4

RefSeq proteins (5): NP_001243816, NP_001243817, NP_001243818, NP_001353007, NP_694581 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR029569	CALHM	Family

Pfam: PF14798

UniProt features (30 total): helix 13, topological domain 5, transmembrane region 4, splice variant 3, disulfide bond 2, chain 1, strand 1, turn 1

Structure

Experimental structures (PDB)

7 structures.

PDB	Method	Resolution (Å)
8RMM	ELECTRON MICROSCOPY	3.26
8RMN	ELECTRON MICROSCOPY	3.8
6YTL	ELECTRON MICROSCOPY	3.82
8RML	ELECTRON MICROSCOPY	3.84
6YTQ	ELECTRON MICROSCOPY	4.02
6YTK	ELECTRON MICROSCOPY	4.07
6YTO	ELECTRON MICROSCOPY	4.24

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q5JW98-F1	74.63	0.30

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

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 (2): 41–131, 43–162

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 60 (showing top): GSE37336_LY6C_POS_VS_NEG_NAIVE_CD4_TCELL_DN, GOBP_NUCLEOTIDE_TRANSPORT, GOBP_MONOATOMIC_CATION_TRANSPORT, GOBP_ORGANOPHOSPHATE_ESTER_TRANSPORT, GOBP_NUCLEOBASE_CONTAINING_COMPOUND_TRANSPORT, GOBP_ORGANIC_ANION_TRANSPORT, TGACATY_UNKNOWN, GOBP_PURINE_NUCLEOTIDE_TRANSPORT, YY1_01, GOBP_CARBOHYDRATE_DERIVATIVE_TRANSPORT, GOBP_TRANSMEMBRANE_TRANSPORT, EVI1_04, WGGAATGY_TEF1_Q6, GOMF_PASSIVE_TRANSMEMBRANE_TRANSPORTER_ACTIVITY, GOMF_MONOATOMIC_CATION_TRANSMEMBRANE_TRANSPORTER_ACTIVITY

GO Biological Process (4): 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
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

514 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CALHM4	NT5DC1	Q5TFE4	541
CALHM4	OR2AE1	Q8NHA4	476
CALHM4	OR9G1	Q8NH87	447
CALHM4	BPIFC	Q8NFQ6	400
CALHM4	INKA1	Q96EL1	393
CALHM4	TMED6	Q8WW62	371
CALHM4	PRRG1	O14668	368
CALHM4	EIF1AX	P47813	364
CALHM4	LRRC8A	Q8IWT6	327
CALHM4	REEP3	Q6NUK4	305
CALHM4	SUCO	Q9UBS9	303
CALHM4	CALHM5	Q8N5C1	297
CALHM4	CALHM3	Q86XJ0	297
CALHM4	TRIB2	Q92519	293
CALHM4	RTKN2	Q8IZC4	290

IntAct

56 interactions, top by confidence:

A	B	Type	Score
OAZ3	AZIN1	psi-mi:“MI:0914”(association)	0.800
KIF3A	KIF3C	psi-mi:“MI:0914”(association)	0.730
ANXA9	PPL	psi-mi:“MI:0914”(association)	0.660
RAB11B	SH3BP5	psi-mi:“MI:0914”(association)	0.640
CAPZA2	CNOT1	psi-mi:“MI:0914”(association)	0.640
LACC1	DUSP14	psi-mi:“MI:0914”(association)	0.530
NSMAF	DUSP14	psi-mi:“MI:0914”(association)	0.530
MRPL38	DUSP14	psi-mi:“MI:0914”(association)	0.530
OR51E2	DUSP14	psi-mi:“MI:0914”(association)	0.530
FBXL4	DUSP14	psi-mi:“MI:0914”(association)	0.530
SEMG2	VSIG8	psi-mi:“MI:0914”(association)	0.530
CPLX3	CIAO1	psi-mi:“MI:0914”(association)	0.530
KIF3A	MAP1LC3B2	psi-mi:“MI:0914”(association)	0.350
SGO2	DUSP14	psi-mi:“MI:0914”(association)	0.350
PYHIN1	DUSP14	psi-mi:“MI:0914”(association)	0.350
IL31RA	DUSP14	psi-mi:“MI:0914”(association)	0.350
TEX35	SNAPIN	psi-mi:“MI:0914”(association)	0.350
ZMAT4	VSIG8	psi-mi:“MI:0914”(association)	0.350
PTPN9	VSIG8	psi-mi:“MI:0914”(association)	0.350
PNMA2	TARS3	psi-mi:“MI:0914”(association)	0.350
PTDSS1	IGLL5	psi-mi:“MI:0914”(association)	0.350
SLC6A20	TLCD2	psi-mi:“MI:0914”(association)	0.350
CXorf66	LRP4	psi-mi:“MI:0914”(association)	0.350

BioGRID (56): FAM26D (Affinity Capture-MS), FAM26D (Affinity Capture-MS), FAM26D (Affinity Capture-MS), FAM26D (Affinity Capture-MS), FAM26D (Affinity Capture-MS), FAM26D (Affinity Capture-MS), FAM26D (Affinity Capture-MS), FAM26D (Affinity Capture-MS), FAM26D (Affinity Capture-MS), FAM26D (Affinity Capture-MS), FAM26D (Affinity Capture-MS), FAM26D (Affinity Capture-MS), FAM26D (Affinity Capture-MS), FAM26D (Affinity Capture-MS), FAM26D (Affinity Capture-MS)

ESM2 similar proteins: A0A140LIJ0, A1L3G9, A4IFL1, B9X187, O18968, O70491, P08033, P08034, P28230, P35212, P36380, P51915, P60572, Q02738, Q059Y8, Q0V8E7, Q1LXZ7, Q28FG4, Q29559, Q4QR83, Q5E9Z5, Q5FVF4, Q5FWS4, Q5JW98, Q5R7B4, Q5T197, Q5T1A1, Q60HF7, Q640M6, Q6GMB1, Q6WGK6, Q7SY10, Q7TNJ0, Q8BXV2, Q8C2L6, Q8C9E8, Q8CE93, Q8CEG0, Q8N5C1, Q8NDZ6

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

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	1
Uncertain significance	37
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (3)

Variant ID	HGVS	Classification
563222	GRCh37/hg19 6q21-22.1(chr6:113261042-117842826)x1	Pathogenic
58441	GRCh38/hg38 6q22.1(chr6:115220054-117196371)x1	Pathogenic
146318	GRCh38/hg38 6q22.1-22.2(chr6:115326962-117935240)x1	Likely pathogenic

SpliceAI

520 predictions. Top by Δscore:

Variant	Effect	Δscore
6:116543296:CACTT:C	donor_loss	1.0000
6:116543297:ACTTA:A	donor_loss	1.0000
6:116543298:CTTA:C	donor_loss	1.0000
6:116543299:TTA:T	donor_loss	1.0000
6:116543300:T:TG	donor_loss	1.0000
6:116543301:A:AC	donor_gain	1.0000
6:116543301:ACA:A	donor_loss	1.0000
6:116543302:C:CC	donor_gain	1.0000
6:116543302:CA:C	donor_gain	1.0000
6:116543302:CAT:C	donor_gain	1.0000
6:116543399:TT:T	acceptor_gain	1.0000
6:116543401:C:CC	acceptor_gain	1.0000
6:116545471:A:AC	donor_gain	1.0000
6:116545472:C:CC	donor_gain	1.0000
6:116557810:A:AG	acceptor_gain	1.0000
6:116557813:A:AG	acceptor_gain	1.0000
6:116557813:AAT:A	acceptor_gain	1.0000
6:116557814:A:G	acceptor_gain	1.0000
6:116557815:T:TA	acceptor_gain	1.0000
6:116540460:CCC:C	acceptor_gain	0.9900
6:116540461:CC:C	acceptor_gain	0.9900
6:116540461:CCC:C	acceptor_gain	0.9900
6:116540462:CC:C	acceptor_gain	0.9900
6:116543294:T:TA	donor_gain	0.9900
6:116543295:CCACT:C	donor_loss	0.9900
6:116543302:CATT:C	donor_gain	0.9900
6:116543302:CATTT:C	donor_gain	0.9900
6:116543400:TC:T	acceptor_loss	0.9900
6:116543401:C:CA	acceptor_loss	0.9900
6:116545472:CT:C	donor_gain	0.9900

AlphaMissense

2062 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:116553908:T:C	F39L	0.975
6:116553910:C:A	F39L	0.975
6:116553910:C:G	F39L	0.975
6:116554193:A:C	S134R	0.970
6:116554195:T:A	S134R	0.970
6:116554195:T:G	S134R	0.970
6:116557834:T:A	W190R	0.955
6:116557834:T:C	W190R	0.955
6:116553937:T:A	N48K	0.953
6:116553937:T:G	N48K	0.953
6:116554145:T:A	W118R	0.951
6:116554145:T:C	W118R	0.951
6:116553956:T:C	F55L	0.936
6:116553958:T:A	F55L	0.936
6:116553958:T:G	F55L	0.936
6:116554184:T:A	C131S	0.930
6:116554185:G:C	C131S	0.930
6:116557969:G:C	A235P	0.924
6:116558082:G:C	W272C	0.918
6:116558082:G:T	W272C	0.918
6:116554199:T:C	F136L	0.916
6:116554201:T:A	F136L	0.916
6:116554201:T:G	F136L	0.916
6:116557972:G:C	A236P	0.916
6:116558020:T:C	F252L	0.912
6:116558022:T:A	F252L	0.912
6:116558022:T:G	F252L	0.912
6:116553948:G:A	G52D	0.909
6:116554137:C:G	P115R	0.905
6:116554134:C:A	A114D	0.904

dbSNP variants (sampled 300 via entrez): RS1000057975 (6:116528385 G>A,T), RS1000100044 (6:116554642 T>A), RS1000160627 (6:116553060 C>A,G,T), RS1000213322 (6:116553606 T>C), RS1000388554 (6:116559689 G>A), RS1000403625 (6:116535765 C>G), RS1000409538 (6:116540966 C>T), RS1000461902 (6:116541290 T>C), RS1000493357 (6:116560227 C>A), RS1000545618 (6:116555264 T>A), RS1000627366 (6:116527257 C>T), RS1000641122 (6:116534015 C>A,G,T), RS1000670255 (6:116561436 C>G), RS1000861231 (6:116542408 G>A), RS1000948039 (6:116554924 A>C)

Disease associations

OMIM: gene `` | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST003225_10	Pelvic organ prolapse (moderate/severe)	6.000000e-06

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

5 total (human), top 5 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects cotreatment, decreases methylation	1
fipronil	increases expression, affects cotreatment	1
Fulvestrant	affects cotreatment, decreases methylation, increases methylation	1
DEET	affects cotreatment, increases expression	1
Valproic Acid	decreases methylation	1

Cellosaurus cell lines

1 cell lines: 1 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_YA44	IDG-HEK293T-CALHM4-V5-OE	Transformed cell line	Female

Clinical trials (associated diseases)

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