CALML4

Summary

CALML4 (calmodulin like 4, HGNC:18445) is a protein-coding gene on chromosome 15q23, encoding Calmodulin-like protein 4 (Q96GE6). As part of the intermicrovillar adhesion complex/IMAC plays a role in epithelial brush border differentiation, controlling microvilli organization and length.

Enables myosin head/neck binding activity. Involved in brush border assembly. Located in microvillus.

Source: NCBI Gene 91860 — RefSeq curated summary.

At a glance

• GWAS associations: 4
• Clinical variants (ClinVar): 36 total
• MANE Select transcript: NM_033429

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:18445
Approved symbol	CALML4
Name	calmodulin like 4
Location	15q23
Locus type	gene with protein product
Status	Approved
Aliases	MGC4809, NY-BR-20
Ensembl gene	ENSG00000129007
Ensembl biotype	protein_coding
OMIM	620520
Entrez	91860

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 6 protein_coding, 1 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000354678, ENST00000395463, ENST00000395465, ENST00000448060, ENST00000467188, ENST00000467889, ENST00000540479, ENST00000852300

RefSeq mRNA: 4 — MANE Select: NM_033429 NM_001031733, NM_001286694, NM_001286695, NM_033429

CCDS: CCDS10226, CCDS42052, CCDS66808, CCDS92031

Canonical transcript exons

ENST00000467889 — 5 exons

Exon	Start	End
ENSE00001521784	68205121	68205151
ENSE00001881450	68205245	68205332
ENSE00001882087	68190705	68194112
ENSE00003549211	68199541	68199681
ENSE00003789486	68197440	68197628

Expression profiles

Bgee: expression breadth ubiquitous, 134 present calls, max score 97.97.

FANTOM5 (CAGE): breadth broad, TPM avg 2.8794 / max 272.9271, expressed in 511 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
150627	1.3558	277
150628	0.7833	218
150629	0.7403	287

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
mucosa of transverse colon	UBERON:0004991	97.97	gold quality
duodenum	UBERON:0002114	97.58	gold quality
rectum	UBERON:0001052	97.53	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	96.54	gold quality
transverse colon	UBERON:0001157	93.12	gold quality
colonic epithelium	UBERON:0000397	92.88	gold quality
small intestine Peyer’s patch	UBERON:0003454	92.22	gold quality
small intestine	UBERON:0002108	92.05	gold quality
right uterine tube	UBERON:0001302	91.63	gold quality
monocyte	CL:0000576	90.40	gold quality
leukocyte	CL:0000738	90.09	gold quality
adult mammalian kidney	UBERON:0000082	89.51	gold quality
gall bladder	UBERON:0002110	89.39	gold quality
intestine	UBERON:0000160	89.08	gold quality
granulocyte	CL:0000094	88.17	gold quality
colon	UBERON:0001155	87.71	gold quality
kidney	UBERON:0002113	87.51	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	87.44	gold quality
lower esophagus muscularis layer	UBERON:0035833	86.83	gold quality
lower esophagus	UBERON:0013473	86.79	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	86.56	gold quality
vermiform appendix	UBERON:0001154	86.10	gold quality
blood	UBERON:0000178	84.83	gold quality
fallopian tube	UBERON:0003889	84.70	gold quality
cortex of kidney	UBERON:0001225	84.69	gold quality
spleen	UBERON:0002106	84.20	gold quality
right lobe of liver	UBERON:0001114	83.95	gold quality
body of pancreas	UBERON:0001150	83.53	gold quality
lower esophagus mucosa	UBERON:0035834	83.44	gold quality
mucosa of stomach	UBERON:0001199	83.37	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-MTAB-8410	yes	16.31
E-ANND-3	yes	9.60
E-MTAB-6386	no	121.33

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

97 targeting CALML4, 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-6833-3P	100.00	70.63	3197
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-574-5P	100.00	66.01	989
HSA-MIR-10401-5P	99.99	65.79	948
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-223-3P	99.99	70.14	1140
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-493-5P	99.96	72.47	2382
HSA-MIR-2110	99.96	66.68	1930
HSA-MIR-6845-3P	99.94	66.88	1439
HSA-MIR-141-3P	99.94	72.79	2421
HSA-MIR-200A-3P	99.94	72.68	2420
HSA-MIR-1236-3P	99.94	68.04	1695
HSA-MIR-6835-3P	99.93	70.49	2904
HSA-MIR-3682-5P	99.93	67.97	1163
HSA-MIR-3119	99.92	71.34	2390
HSA-MIR-205-3P	99.92	69.92	3165
HSA-MIR-3686	99.90	70.53	2432
HSA-MIR-5582-3P	99.86	72.48	4221
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-944	99.82	70.85	3042
HSA-MIR-204-5P	99.79	71.62	2439
HSA-MIR-211-5P	99.79	71.65	2440
HSA-MIR-4713-5P	99.78	67.80	1794
HSA-MIR-4766-5P	99.75	69.23	2662
HSA-MIR-4755-5P	99.71	70.34	2716

Literature-anchored findings (GeneRIF, showing 1)

• The small EF-hand protein CALML4 functions as a critical myosin light chain within the intermicrovillar adhesion complex. (PMID:32209652)

Cross-species orthologs

11 orthologs

Organism	Symbol	Gene ID
danio_rerio	calml4b	ENSDARG00000059347
danio_rerio	calml4a	ENSDARG00000075800
mus_musculus	Calml4	ENSMUSG00000032246
rattus_norvegicus	Calml4	ENSRNOG00000038202
drosophila_melanogaster	CG17272	FBGN0038830
caenorhabditis_elegans		WBGENE00000285
caenorhabditis_elegans		WBGENE00000287
caenorhabditis_elegans	pat-10	WBGENE00003934
caenorhabditis_elegans		WBGENE00008453
caenorhabditis_elegans	F35C12.3	WBGENE00009408
caenorhabditis_elegans		WBGENE00015264

Paralogs (20): CABP7 (ENSG00000100314), CABP5 (ENSG00000105507), CALM2 (ENSG00000143933), CETN2 (ENSG00000147400), CETN3 (ENSG00000153140), CABP1 (ENSG00000157782), CALM3 (ENSG00000160014), CABP2 (ENSG00000167791), CALML6 (ENSG00000169885), EFCAB3 (ENSG00000172421), EFCAB12 (ENSG00000172771), CABP4 (ENSG00000175544), CETN1 (ENSG00000177143), CALML3 (ENSG00000178363), CALML5 (ENSG00000178372), CALN1 (ENSG00000183166), CALM1 (ENSG00000198668), EFCAB2 (ENSG00000203666), EFCAB7 (ENSG00000203965), EFCAB9 (ENSG00000214360)

Protein

Protein identifiers

Calmodulin-like protein 4 — Q96GE6 (reviewed: Q96GE6)

Alternative names: Serologically defined breast cancer antigen NY-BR-20

All UniProt accessions (5): Q96GE6, A0A804D2Q3, A0A804DNR1, H3BM29, H3BS46

UniProt curated annotations — full annotation on UniProt →

Function. As part of the intermicrovillar adhesion complex/IMAC plays a role in epithelial brush border differentiation, controlling microvilli organization and length. Acts as a light chain for MYO7B and is required for efficient targeting of the IMAC to the tips of border brush microvilli.

Subunit / interactions. Interacts with MYO7B; the interaction mediates the association of CALML4 with the IMAC/intermicrovillar adhesion complex. Interacts with MYO7A.

Subcellular location. Cell projection. Microvillus Cell projection. Microvillus.

Tissue specificity. Expressed in the intestinal tract. Dominant transcript in the intestinal tract.

Similarity. Belongs to the calmodulin family.

Isoforms (6)

UniProt ID	Names	Canonical?
Q96GE6-1	1, Long	yes
Q96GE6-2	2
Q96GE6-3	3
Q96GE6-4	4
Q96GE6-5	5
Q96GE6-6	6, Short

RefSeq proteins (4): NP_001026903, NP_001273623, NP_001273624, NP_219501* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002048	EF_hand_dom	Domain
IPR011992	EF-hand-dom_pair	Homologous_superfamily
IPR050230	CALM/Myosin/TropC-like	Family

Pfam: PF13499

UniProt features (19 total): splice variant 6, domain 4, sequence conflict 3, sequence variant 2, compositionally biased region 2, chain 1, region of interest 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96GE6-F1	76.70	0.30

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 183 (showing top): GGGACCA_MIR133A_MIR133B, CHIARADONNA_NEOPLASTIC_TRANSFORMATION_KRAS_DN, AAGCCAT_MIR135A_MIR135B, LUCAS_HNF4A_TARGETS_UP, CEBP_Q2, SHETH_LIVER_CANCER_VS_TXNIP_LOSS_PAM3, BLALOCK_ALZHEIMERS_DISEASE_UP, CAATGCA_MIR33, ATTACAT_MIR3803P, PYEON_CANCER_HEAD_AND_NECK_VS_CERVICAL_UP, DOUGLAS_BMI1_TARGETS_UP, MARIADASON_RESPONSE_TO_BUTYRATE_CURCUMIN_SULINDAC_TSA_8, chr15q23, ACEVEDO_LIVER_CANCER_UP, BURTON_ADIPOGENESIS_PEAK_AT_0HR

GO Biological Process (2): microtubule cytoskeleton organization (GO:0000226), brush border assembly (GO:1904970)

GO Molecular Function (3): calcium ion binding (GO:0005509), enzyme regulator activity (GO:0030234), myosin head/neck binding (GO:0032028)

GO Cellular Component (3): cytoplasm (GO:0005737), microvillus (GO:0005902), cell projection (GO:0042995)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
cytoskeleton organization	1
microtubule-based process	1
cellular component assembly	1
metal ion binding	1
catalytic activity	1
molecular function regulator activity	1
myosin heavy chain binding	1
intracellular anatomical structure	1
actin filament bundle	1
actin-based cell projection	1

Protein interactions and networks

STRING

6718 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CALML4	NOS3	P29474	996
CALML4	CALD1	Q05682	996
CALML4	NOS1	P29475	995
CALML4	MARCKS	P29966	995
CALML4	IQGAP1	P46940	993
CALML4	MYLK	Q15746	993
CALML4	RYR2	Q92736	993
CALML4	MYLK2	Q9H1R3	993
CALML4	CAMK2A	Q9UQM7	993
CALML4	NRGN	Q92686	992
CALML4	CACNA1C	Q13936	990
CALML4	TRPV1	Q8NER1	990
CALML4	RYR1	P21817	989
CALML4	GAP43	P17677	987
CALML4	MBP	P02686	987

IntAct

2 interactions, top by confidence:

A	B	Type	Score
CAMK2G	PSMD12	psi-mi:“MI:0914”(association)	0.350

BioGRID (5): CALML4 (Negative Genetic), CALML4 (Affinity Capture-RNA), CALML4 (Affinity Capture-MS), CALML4 (Negative Genetic), CALML4 (Affinity Capture-RNA)

ESM2 similar proteins: A0A125YHX7, A0A7U2QYM2, A0JNJ5, F1RRT2, F8RP11, O35648, P02600, P02602, P02604, P02605, P02606, P05434, P05976, P05977, P06742, P08590, P09540, P09541, P09542, P10687, P10894, P12829, P14649, P16409, P17209, P22676, P41044, P47728, P54213, P54357, P82159, P82160, P85100, Q06827, Q15147, Q24621, Q24654, Q24756, Q32LE3, Q5R887

Diamond homologs: A0A125YHX7, A0A125YZN2, A2WN93, A2WNH1, A2Y609, A3E3H0, A3E4D8, A3E4F9, A4UHC0, A8CEP3, A8I1Q0, J9W034, O00897, O15182, O23184, O35648, O60041, O74435, O82018, O82659, O94739, O96102, P02597, P02598, P04352, P04353, P04464, P05419, P05434, P05933, P06704, P06787, P07463, P0DH95, P0DH96, P0DH97, P0DH98, P11120, P13868, P15094

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	27
Likely benign	5
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

908 predictions. Top by Δscore:

Variant	Effect	Δscore
15:68197438:ACCTT:A	donor_gain	1.0000
15:68197439:CCTTC:C	donor_gain	1.0000
15:68194109:TCCA:T	acceptor_gain	0.9900
15:68194110:CCA:C	acceptor_gain	0.9900
15:68194110:CCAC:C	acceptor_gain	0.9900
15:68194111:CA:C	acceptor_gain	0.9900
15:68194111:CAC:C	acceptor_gain	0.9900
15:68194113:C:CC	acceptor_gain	0.9900
15:68197434:TGTTA:T	donor_loss	0.9900
15:68197435:GTTA:G	donor_loss	0.9900
15:68197435:GTTAC:G	donor_loss	0.9900
15:68197436:TTACC:T	donor_loss	0.9900
15:68197437:TA:T	donor_loss	0.9900
15:68197438:A:AG	donor_loss	0.9900
15:68197438:A:AT	donor_loss	0.9900
15:68197439:C:CG	donor_loss	0.9900
15:68197442:T:A	donor_gain	0.9900
15:68197625:CCGT:C	acceptor_gain	0.9900
15:68197626:CGTC:C	acceptor_gain	0.9900
15:68197629:C:CC	acceptor_gain	0.9900
15:68197639:C:CT	acceptor_gain	0.9900
15:68197639:C:T	acceptor_gain	0.9900
15:68199678:TACT:T	acceptor_gain	0.9900
15:68199680:CT:C	acceptor_gain	0.9900
15:68199682:C:CC	acceptor_gain	0.9900
15:68199694:C:CT	acceptor_gain	0.9900
15:68199694:C:T	acceptor_gain	0.9900
15:68205240:CTCA:C	donor_loss	0.9900
15:68205241:TCA:T	donor_loss	0.9900
15:68205242:CAC:C	donor_loss	0.9900

AlphaMissense

1301 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
15:68197487:A:G	L149P	0.997
15:68199665:G:C	F60L	0.997
15:68199665:G:T	F60L	0.997
15:68199667:A:G	F60L	0.997
15:68194103:A:G	L168P	0.996
15:68197595:A:G	L113P	0.996
15:68197598:A:G	F112S	0.995
15:68199618:A:G	L76P	0.995
15:68197475:A:G	L153P	0.994
15:68199666:A:G	F60S	0.994
15:68197597:A:C	F112L	0.993
15:68197597:A:T	F112L	0.993
15:68197599:A:G	F112L	0.993
15:68194052:A:G	F185S	0.991
15:68197606:G:C	F109L	0.991
15:68197606:G:T	F109L	0.991
15:68197608:A:G	F109L	0.991
15:68199674:C:A	K57N	0.990
15:68199674:C:G	K57N	0.990
15:68197475:A:T	L153H	0.989
15:68197502:A:T	V144D	0.988
15:68199558:A:G	L96P	0.988
15:68197539:C:G	A132P	0.987
15:68199618:A:T	L76H	0.987
15:68197524:C:G	D137H	0.986
15:68197607:A:G	F109S	0.986
15:68199670:A:G	C59R	0.986
15:68197487:A:T	L149Q	0.985
15:68197463:C:T	G157E	0.984
15:68197523:T:A	D137V	0.984

dbSNP variants (sampled 300 via entrez): RS1000546011 (15:68194403 A>AAAAC), RS1000964826 (15:68194219 G>C,T), RS1001110745 (15:68198374 T>C), RS1001418517 (15:68190807 T>C), RS1001511901 (15:68190533 A>G,T), RS1001767766 (15:68202561 A>G), RS1001820280 (15:68202286 A>G), RS1001852672 (15:68195140 C>A,T), RS1001894734 (15:68198734 C>T), RS1002020260 (15:68195269 G>A), RS1002078294 (15:68196815 C>T), RS1002101412 (15:68201017 G>C), RS1002154108 (15:68200828 C>A,T), RS1002318109 (15:68206459 C>G), RS1002370936 (15:68195497 C>G,T)

Disease associations

OMIM: gene MIM:620520 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST001850_6	Major depressive disorder	3.000000e-07
GCST003670_1	Systolic blood pressure	3.000000e-08
GCST90002381_624	Eosinophil count	1.000000e-13
GCST90002382_239	Eosinophil percentage of white cells	2.000000e-14

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0006335	systolic blood pressure
EFO:0004842	eosinophil count
EFO:0007991	eosinophil percentage of leukocytes

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression, affects expression, increases methylation	8
Cyclosporine	decreases expression	3
sodium arsenite	increases expression	2
entinostat	decreases expression, affects cotreatment	2
belinostat	decreases expression, affects cotreatment	2
Benzo(a)pyrene	affects methylation, decreases expression, decreases methylation	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Smoke	decreases expression, increases abundance, increases expression	2
Tetrachlorodibenzodioxin	affects cotreatment, decreases expression	2
bisphenol F	affects cotreatment, decreases expression	1
dicrotophos	decreases expression	1
methylmercuric chloride	increases expression	1
methyleugenol	decreases expression	1
pirinixic acid	affects binding, decreases expression, increases activity	1
bisphenol A	decreases expression, affects cotreatment	1
beta-lapachone	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
pentabromodiphenyl ether	increases expression	1
perfluoro-n-nonanoic acid	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression, increases expression	1
abrine	decreases expression	1
2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazophenyl)amide	decreases expression, decreases reaction	1
dorsomorphin	affects cotreatment, decreases expression, increases expression	1
NSC 689534	affects binding, decreases expression	1
2,3,5-trichloro-6-phenyl-(1,4)benzoquinone	decreases expression	1
Rosiglitazone	decreases expression	1
Zoledronic Acid	decreases expression	1
Troglitazone	decreases expression	1
Acetaminophen	decreases expression	1
Air Pollutants	increases abundance, increases expression	1

Clinical trials (associated diseases)

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