CALML5

Summary

CALML5 (calmodulin like 5, HGNC:18180) is a protein-coding gene on chromosome 10p15.1, encoding Calmodulin-like protein 5 (Q9NZT1). Binds calcium.

This gene encodes a novel calcium binding protein expressed in the epidermis and related to the calmodulin family of calcium binding proteins. Functional studies with recombinant protein demonstrate it does bind calcium and undergoes a conformational change when it does so. Abundant expression is detected only in reconstructed epidermis and is restricted to differentiating keratinocytes. In addition, it can associate with transglutaminase 3, shown to be a key enzyme in the terminal differentiation of keratinocytes.

Source: NCBI Gene 51806 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 19 total
• MANE Select transcript: NM_017422

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:18180
Approved symbol	CALML5
Name	calmodulin like 5
Location	10p15.1
Locus type	gene with protein product
Status	Approved
Aliases	CLSP
Ensembl gene	ENSG00000178372
Ensembl biotype	protein_coding
OMIM	605183
Entrez	51806

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000380332

RefSeq mRNA: 1 — MANE Select: NM_017422 NM_017422

CCDS: CCDS7068

Canonical transcript exons

ENST00000380332 — 1 exons

Exon	Start	End
ENSE00001484579	5498697	5499570

Expression profiles

Bgee: expression breadth ubiquitous, 149 present calls, max score 99.56.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 3.8732 / max 2817.6586, expressed in 157 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
108092	3.2092	153
108091	0.4210	118
108090	0.1759	68
108093	0.0671	32

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
skin of abdomen	UBERON:0001416	99.56	gold quality
mammalian vulva	UBERON:0000997	99.43	gold quality
skin of leg	UBERON:0001511	99.41	gold quality
penis	UBERON:0000989	99.23	gold quality
upper leg skin	UBERON:0004262	99.21	gold quality
zone of skin	UBERON:0000014	98.87	gold quality
skin of hip	UBERON:0001554	98.35	gold quality
upper arm skin	UBERON:0004263	97.97	gold quality
nipple	UBERON:0002030	97.35	gold quality
minor salivary gland	UBERON:0001830	95.81	gold quality
saliva-secreting gland	UBERON:0001044	95.14	gold quality
mouth mucosa	UBERON:0003729	94.86	gold quality
lower esophagus mucosa	UBERON:0035834	94.81	gold quality
esophagus mucosa	UBERON:0002469	88.12	gold quality
parotid gland	UBERON:0001831	87.88	gold quality
gingiva	UBERON:0001828	87.00	gold quality
gingival epithelium	UBERON:0001949	85.06	gold quality
oral cavity	UBERON:0000167	81.61	gold quality
vagina	UBERON:0000996	81.60	gold quality
pancreatic ductal cell	CL:0002079	79.82	silver quality
tonsil	UBERON:0002372	76.34	gold quality
squamous epithelium	UBERON:0006914	75.88	gold quality
cervix epithelium	UBERON:0004801	75.24	silver quality
esophagus squamous epithelium	UBERON:0006920	74.63	gold quality
epithelium of esophagus	UBERON:0001976	74.19	gold quality
esophagus	UBERON:0001043	73.50	gold quality
palpebral conjunctiva	UBERON:0001812	69.69	gold quality
cervix squamous epithelium	UBERON:0006922	69.40	silver quality
apex of heart	UBERON:0002098	67.24	gold quality
gastrocnemius	UBERON:0001388	66.75	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.24

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): KDM5B

miRNA regulators (miRDB)

12 targeting CALML5, 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-6132	99.60	65.83	1554
HSA-MIR-6836-5P	99.60	65.62	1538
HSA-MIR-3612	99.45	66.02	1333
HSA-MIR-650	99.45	65.77	1309
HSA-MIR-423-5P	98.69	67.48	1522
HSA-MIR-3184-5P	98.56	67.13	1491
HSA-MIR-6509-3P	98.32	67.33	1343
HSA-MIR-1291	96.28	65.89	1224
HSA-MIR-6775-3P	95.76	65.91	982
HSA-MIR-744-5P	93.78	65.29	230
HSA-MIR-10396A-5P	93.49	65.54	172
HSA-MIR-6763-3P	90.80	64.32	80

Literature-anchored findings (GeneRIF, showing 11)

• An investigation of the cation-binding properties of CLSP and the ensuing conformational changes finds that, with its high- and low-affinity Ca+2+-binding sites and a pronounced effect of Mg2+, CLSP is more similar to troponin C than to calmodulin. (PMID:11969404)
• abnormal elevated levels of CLSP, characteristic of psoriatic epidermis, were probably not due to an overexpression of the protein, but most likely the result of its non-degradation (PMID:16689864)
• The structure and dynamics of human calmodulin-like skin protein (CLSP) have been characterized by NMR spectroscopy. (PMID:16765896)
• CLSP is a physiological heterotrimeric humanin receptor agonist. (PMID:23519124)
• Ubiquitination of CALML5 in the nucleus is involved in the carcinogenesis of breast cancer in premenopausal women. (PMID:24146193)
• CLSP is increased in the upper epidermis in exacerbated atopic dermatitis as compared to non-exacerbated atopic dermatitis and normal skin, revealing a role in re-establishing the epidermal barrier (PMID:24279918)
• CALML5 interacts with SFN in suprabasal epidermis, cocontrols 13% of late differentiation genes, and modulates interaction of SFN to some of its binding partners. (PMID:26545810)
• The authors results suggest that CLSP may function as a senescence-suppressing factor in keratinocytes. (PMID:31038250)
• Identification of calmodulin-like protein 5 as tumor-suppressor gene silenced during early stage of carcinogenesis in squamous cell carcinoma of uterine cervix. (PMID:33997976)
• CALML5 is a novel diagnostic marker for differentiating thymic squamous cell carcinoma from type B3 thymoma. (PMID:36924358)
• Identification of lactylation gene CALML5 and its correlated lncRNAs in cutaneous melanoma by machine learning. (PMID:38013352)

Cross-species orthologs

18 orthologs

Organism	Symbol	Gene ID
danio_rerio	cabp2a	ENSDARG00000052016
danio_rerio	cabp2b	ENSDARG00000052277
mus_musculus	Calm4	ENSMUSG00000033765
mus_musculus	Calm5	ENSMUSG00000099269
rattus_norvegicus	Calml5	ENSRNOG00000091280
drosophila_melanogaster	TpnC4	FBGN0033027
drosophila_melanogaster	CG13526	FBGN0034774
drosophila_melanogaster	CG5024	FBGN0039373
drosophila_melanogaster	CG17770	FBGN0039374
drosophila_melanogaster	CG30378	FBGN0050378
caenorhabditis_elegans		WBGENE00000285
caenorhabditis_elegans		WBGENE00000287
caenorhabditis_elegans	pat-10	WBGENE00003934
caenorhabditis_elegans		WBGENE00006583
caenorhabditis_elegans		WBGENE00008453
caenorhabditis_elegans	F35C12.3	WBGENE00009408
caenorhabditis_elegans		WBGENE00015264
caenorhabditis_elegans		WBGENE00019352

Paralogs (20): CABP7 (ENSG00000100314), CABP5 (ENSG00000105507), CALML4 (ENSG00000129007), CALM2 (ENSG00000143933), CETN2 (ENSG00000147400), CETN3 (ENSG00000153140), CABP1 (ENSG00000157782), CALM3 (ENSG00000160014), CABP2 (ENSG00000167791), CALML6 (ENSG00000169885), EFCAB3 (ENSG00000172421), EFCAB12 (ENSG00000172771), CABP4 (ENSG00000175544), CETN1 (ENSG00000177143), CALML3 (ENSG00000178363), CALN1 (ENSG00000183166), CALM1 (ENSG00000198668), EFCAB2 (ENSG00000203666), EFCAB7 (ENSG00000203965), EFCAB9 (ENSG00000214360)

Protein

Protein identifiers

Calmodulin-like protein 5 — Q9NZT1 (reviewed: Q9NZT1)

Alternative names: Calmodulin-like skin protein

All UniProt accessions (1): Q9NZT1

UniProt curated annotations — full annotation on UniProt →

Function. Binds calcium. May be involved in terminal differentiation of keratinocytes.

Subunit / interactions. Associates with transglutaminase 3.

Tissue specificity. Particularly abundant in the epidermis where its expression is directly related to keratinocyte differentiation. Very low expression in lung.

RefSeq proteins (1): NP_059118* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002048	EF_hand_dom	Domain
IPR011992	EF-hand-dom_pair	Homologous_superfamily
IPR018247	EF_Hand_1_Ca_BS	Binding_site
IPR050230	CALM/Myosin/TropC-like	Family

Pfam: PF13499

UniProt features (36 total): binding site 20, helix 5, domain 4, sequence variant 2, strand 2, initiator methionine 1, chain 1, modified residue 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
2B1U	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NZT1-F1	81.24	0.00

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (20): 32; 57; 59; 61; 63; 68; 91; 93; 95; 97; 102; 127 …

Post-translational modifications (1): 2

Function

Pathways and Gene Ontology

Reactome pathways

6 pathways

ID	Pathway
R-HSA-6798695	Neutrophil degranulation
R-HSA-9725554	Differentiation of Keratinocytes in Interfollicular Epidermis in Mammalian Skin
R-HSA-1266738	Developmental Biology
R-HSA-168249	Innate Immune System
R-HSA-168256	Immune System
R-HSA-9734767	Developmental Cell Lineages

MSigDB gene sets: 98 (showing top): REACTOME_INNATE_IMMUNE_SYSTEM, JAEGER_METASTASIS_DN, GOCC_SECRETORY_GRANULE, DARWICHE_SKIN_TUMOR_PROMOTER_DN, DARWICHE_PAPILLOMA_RISK_LOW_UP, DARWICHE_PAPILLOMA_RISK_HIGH_UP, DARWICHE_SQUAMOUS_CELL_CARCINOMA_DN, GGGTGGRR_PAX4_03, HOWLIN_PUBERTAL_MAMMARY_GLAND, CREIGHTON_ENDOCRINE_THERAPY_RESISTANCE_5, GOBP_EPIDERMIS_DEVELOPMENT, KEGG_OLFACTORY_TRANSDUCTION, LIU_CMYB_TARGETS_UP, CHESLER_BRAIN_D6MIT150_QTL_TRANS, KEGG_ALZHEIMERS_DISEASE

GO Biological Process (3): microtubule cytoskeleton organization (GO:0000226), signal transduction (GO:0007165), epidermis development (GO:0008544)

GO Molecular Function (4): calcium ion binding (GO:0005509), enzyme regulator activity (GO:0030234), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (3): extracellular region (GO:0005576), cytoplasm (GO:0005737), ficolin-1-rich granule lumen (GO:1904813)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Innate Immune System	1
Developmental Cell Lineages of the Integumentary System	1
Immune System	1
Developmental Biology	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
cytoskeleton organization	1
microtubule-based process	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
tissue development	1
metal ion binding	1
catalytic activity	1
molecular function regulator activity	1
binding	1
cation binding	1
intracellular anatomical structure	1
intracellular organelle lumen	1
ficolin-1-rich granule	1

Protein interactions and networks

STRING

7302 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CALML5	NOS3	P29474	996
CALML5	CALD1	Q05682	996
CALML5	NOS1	P29475	995
CALML5	MARCKS	P29966	995
CALML5	IQGAP1	P46940	994
CALML5	MYLK2	Q9H1R3	994
CALML5	CAMK2A	Q9UQM7	994
CALML5	MYLK	Q15746	993
CALML5	RYR2	Q92736	993
CALML5	NRGN	Q92686	992
CALML5	CACNA1C	Q13936	991
CALML5	RYR1	P21817	990
CALML5	TRPV1	Q8NER1	990
CALML5	CAMK4	Q16566	987
CALML5	MBP	P02686	987
CALML5	GAP43	P17677	987

IntAct

153 interactions, top by confidence:

A	B	Type	Score
POC5	CETN3	psi-mi:“MI:0914”(association)	0.920
POC5	CETN3	psi-mi:“MI:0914”(association)	0.770
JADE1	KAT7	psi-mi:“MI:0914”(association)	0.720
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
SINHCAF	TNRC18	psi-mi:“MI:0914”(association)	0.640
ASF1A	HAT1	psi-mi:“MI:0914”(association)	0.640
NCBP2	KPNA3	psi-mi:“MI:0914”(association)	0.640
CCNC	MED19	psi-mi:“MI:0914”(association)	0.640
CAPZA2	CNOT1	psi-mi:“MI:0914”(association)	0.640
CFAP298	PEX7	psi-mi:“MI:0914”(association)	0.620
LRRN3	CALML5	psi-mi:“MI:0915”(physical association)	0.560
KSR2	POLR3A	psi-mi:“MI:0914”(association)	0.530
FTH1	A2ML1	psi-mi:“MI:0914”(association)	0.530
FRMD1	A2ML1	psi-mi:“MI:0914”(association)	0.530
UGT1A10	A2ML1	psi-mi:“MI:0914”(association)	0.530
TBC1D22B	A2ML1	psi-mi:“MI:0914”(association)	0.530
RBM24	PPL	psi-mi:“MI:0914”(association)	0.530
KIR3DS1	PPL	psi-mi:“MI:0914”(association)	0.530
GDF5	SERPINB7	psi-mi:“MI:0914”(association)	0.530
ARAF	BAG2	psi-mi:“MI:0914”(association)	0.530
RYK	PCDH7	psi-mi:“MI:0914”(association)	0.530

BioGRID (234): CALML5 (Affinity Capture-MS), CALML5 (Affinity Capture-MS), CALML5 (Affinity Capture-MS), CALML5 (Affinity Capture-MS), CALML5 (Affinity Capture-MS), CALML5 (Affinity Capture-MS), CALML5 (Affinity Capture-MS), CALML5 (Affinity Capture-MS), CALML5 (Affinity Capture-MS), CALML5 (Affinity Capture-MS), CALML5 (Affinity Capture-MS), CALML5 (Affinity Capture-MS), CALML5 (Affinity Capture-MS), CALML5 (Affinity Capture-MS), CALML5 (Affinity Capture-MS)

ESM2 similar proteins: O23320, O60041, P02585, P02586, P02587, P02588, P02589, P02591, P02597, P05933, P06787, P08053, P09860, P10246, P14533, P19123, P20801, P23286, P24044, P27163, P27482, P41040, P41041, P41210, P49258, P53440, P54357, P60204, P60205, P60206, P61859, P61860, P61861, P62203, P63315, P63316, P63317, P81660, Q09665, Q0IQB6

Diamond homologs: A2WN93, A2WNH1, A2Y609, A3E3H0, A3E4D8, A3E4F9, A4UHC0, A8CEP3, A8I1Q0, O02367, O16305, O82018, O94739, O96081, O96102, O97341, P02594, P02595, P02598, P04352, P04353, P04464, P04630, P07463, P0DH95, P0DH96, P0DP23, P0DP24, P0DP25, P0DP26, P0DP27, P0DP28, P0DP29, P0DP30, P0DP31, P0DP33, P0DP34, P0DP35, P11118, P11120

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	17
Likely benign	2
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

111 predictions. Top by Δscore:

Variant	Effect	Δscore
10:5499294:G:C	donor_gain	0.7600
10:5499000:ACT:A	donor_gain	0.6400
10:5499001:CTC:C	donor_gain	0.6400
10:5499316:G:A	donor_gain	0.6400
10:5499161:T:TA	donor_gain	0.6300
10:5499275:T:TG	acceptor_gain	0.6300
10:5499184:G:GT	donor_gain	0.6200
10:5499382:C:CT	acceptor_gain	0.6000
10:5499288:T:TA	donor_gain	0.5800
10:5499000:A:AC	donor_gain	0.5600
10:5499001:C:CC	donor_gain	0.5600
10:5499271:A:AT	donor_gain	0.5400
10:5499236:T:TA	donor_gain	0.5300
10:5499047:T:TA	donor_gain	0.5000
10:5499015:T:TA	donor_gain	0.4800
10:5499042:G:A	donor_gain	0.4600
10:5499425:AG:A	donor_gain	0.4600
10:5499027:C:CA	donor_gain	0.4400
10:5499237:C:CA	donor_gain	0.4400
10:5499132:G:C	donor_gain	0.4300
10:5499216:T:TA	donor_gain	0.4300
10:5499003:C:CA	donor_gain	0.4200
10:5499137:T:TA	donor_gain	0.4200
10:5499002:T:TA	donor_gain	0.4100
10:5499126:G:A	donor_gain	0.4100
10:5499212:G:A	donor_gain	0.4100
10:5499001:CT:C	donor_gain	0.4000
10:5499035:T:C	donor_gain	0.3900
10:5499276:C:A	acceptor_gain	0.3800
10:5498788:T:TA	donor_gain	0.3700

AlphaMissense

962 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
10:5499178:G:C	F87L	0.994
10:5499178:G:T	F87L	0.994
10:5499180:A:G	F87L	0.994
10:5499388:G:C	F17L	0.993
10:5499388:G:T	F17L	0.993
10:5499390:A:G	F17L	0.993
10:5499146:A:G	I98T	0.988
10:5499179:A:G	F87S	0.985
10:5499232:G:C	F69L	0.985
10:5499232:G:T	F69L	0.985
10:5499234:A:G	F69L	0.985
10:5499356:A:T	I28N	0.984
10:5499022:G:C	F139L	0.983
10:5499022:G:T	F139L	0.983
10:5499024:A:G	F139L	0.983
10:5499131:A:G	L103P	0.983
10:5499146:A:T	I98N	0.983
10:5499233:A:G	F69S	0.983
10:5499389:A:G	F17S	0.983
10:5499146:A:C	I98S	0.982
10:5499270:C:G	D57H	0.982
10:5499378:C:G	D21H	0.980
10:5499060:C:G	D127H	0.978
10:5499356:A:C	I28S	0.978
10:5499167:T:G	D91A	0.977
10:5499131:A:T	L103H	0.976
10:5499169:G:C	F90L	0.976
10:5499169:G:T	F90L	0.976
10:5499171:A:G	F90L	0.976
10:5499063:C:G	A126P	0.975

dbSNP variants (sampled 300 via entrez): RS1000383189 (10:5498229 T>C), RS1002547499 (10:5501370 G>A), RS1003393037 (10:5500504 G>A,T), RS1005882780 (10:5501322 A>G), RS1007454349 (10:5500423 G>C), RS1007595149 (10:5500982 C>T), RS1007899042 (10:5500737 C>G), RS1008866162 (10:5499272 A>G), RS1009810387 (10:5501403 T>A,C), RS1010766814 (10:5500685 G>A), RS1011151163 (10:5500367 T>C,G), RS1011379278 (10:5500232 G>A), RS1011431556 (10:5500460 C>T), RS1012658837 (10:5500040 G>A), RS1013520862 (10:5498772 C>G)

Disease associations

OMIM: gene MIM:605183 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

16 total (human), top 16 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression	2
Air Pollutants	decreases expression, increases abundance, increases expression	2
Benzo(a)pyrene	affects expression, increases methylation	2
Estradiol	decreases expression, affects cotreatment	2
Particulate Matter	decreases expression, increases abundance, increases expression	2
sodium arsenate	increases abundance, decreases expression	1
avobenzone	decreases expression	1
Acetylglucosamine	increases expression	1
Antimony Potassium Tartrate	decreases expression	1
Arsenic	decreases expression, increases abundance	1
Cadmium	affects binding	1
Lead	affects binding	1
Ouabain	affects expression	1
Ribonucleotides	affects binding	1
Tobacco Smoke Pollution	decreases expression	1
Valproic Acid	increases methylation	1

Clinical trials (associated diseases)

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