CACFD1

Summary

CACFD1 (calcium channel flower domain containing 1, HGNC:1365) is a protein-coding gene on chromosome 9q34.2, encoding Calcium channel flower homolog (Q9UGQ2). Transmembrane protein which mediates synaptic endocytosis and fitness-based cell culling.

Predicted to be involved in vesicle-mediated transport. Predicted to be located in several cellular components, including Golgi apparatus; cytoplasmic vesicle; and endoplasmic reticulum membrane.

Source: NCBI Gene 11094 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 60 total
• MANE Select transcript: NM_017586

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1365
Approved symbol	CACFD1
Name	calcium channel flower domain containing 1
Location	9q34.2
Locus type	gene with protein product
Status	Approved
Aliases	D9S2135, flower
Ensembl gene	ENSG00000160325
Ensembl biotype	protein_coding
OMIM	613104
Entrez	11094

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 7 protein_coding, 2 protein_coding_CDS_not_defined

ENST00000291722, ENST00000316948, ENST00000444798, ENST00000474734, ENST00000489519, ENST00000540581, ENST00000542192, ENST00000877841, ENST00000962938

RefSeq mRNA: 4 — MANE Select: NM_017586 NM_001135775, NM_001242369, NM_001242370, NM_017586

CCDS: CCDS48051, CCDS56591, CCDS56592, CCDS6974

Canonical transcript exons

ENST00000316948 — 5 exons

Exon	Start	End
ENSE00001619431	133468563	133470848
ENSE00003486271	133465322	133465447
ENSE00003550281	133459978	133460187
ENSE00003609384	133463483	133463555
ENSE00003785415	133467921	133468028

Expression profiles

Bgee: expression breadth ubiquitous, 137 present calls, max score 93.50.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 9.4513 / max 107.7092, expressed in 1684 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
99277	7.9979	1645
99278	1.4534	723

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
mucosa of transverse colon	UBERON:0004991	93.50	gold quality
right lobe of liver	UBERON:0001114	93.49	gold quality
cortical plate	UBERON:0005343	92.76	gold quality
liver	UBERON:0002107	90.92	gold quality
body of stomach	UBERON:0001161	90.85	gold quality
duodenum	UBERON:0002114	90.62	gold quality
metanephros cortex	UBERON:0010533	89.74	gold quality
adult mammalian kidney	UBERON:0000082	89.46	gold quality
ganglionic eminence	UBERON:0004023	89.21	gold quality
stomach	UBERON:0000945	89.17	gold quality
adenohypophysis	UBERON:0002196	89.15	gold quality
pituitary gland	UBERON:0000007	89.04	gold quality
fundus of stomach	UBERON:0001160	88.72	gold quality
left testis	UBERON:0004533	88.52	gold quality
transverse colon	UBERON:0001157	88.50	gold quality
gall bladder	UBERON:0002110	88.30	gold quality
right testis	UBERON:0004534	88.12	gold quality
apex of heart	UBERON:0002098	88.11	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	87.81	gold quality
right lobe of thyroid gland	UBERON:0001119	87.75	gold quality
left lobe of thyroid gland	UBERON:0001120	87.72	gold quality
thyroid gland	UBERON:0002046	87.51	gold quality
testis	UBERON:0000473	87.46	gold quality
anterior cingulate cortex	UBERON:0009835	87.00	gold quality
right lung	UBERON:0002167	86.86	gold quality
hypothalamus	UBERON:0001898	86.61	gold quality
amygdala	UBERON:0001876	86.60	gold quality
temporal lobe	UBERON:0001871	86.57	gold quality
substantia nigra	UBERON:0002038	86.54	gold quality
right frontal lobe	UBERON:0002810	86.53	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	2.13

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

66 targeting CACFD1, 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-8485	100.00	77.57	4731
HSA-MIR-4673	100.00	66.64	1490
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-4645-5P	99.98	65.81	1284
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-5682	99.89	72.56	1005
HSA-MIR-1343-3P	99.89	66.78	1815
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-MIR-137-3P	99.87	74.74	2401
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-6764-5P	99.75	67.89	2304
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-3714	99.71	70.74	2671
HSA-MIR-6779-5P	99.70	65.76	2363
HSA-MIR-4530	99.69	66.47	1509
HSA-MIR-6883-5P	99.69	68.05	3785
HSA-MIR-1915-3P	99.58	66.79	1988
HSA-MIR-1207-5P	99.49	69.11	2983
HSA-MIR-4441	99.49	66.56	3216
HSA-MIR-6808-5P	99.31	66.23	2150
HSA-MIR-6837-5P	99.25	65.47	1632
HSA-MIR-4685-5P	99.25	65.99	1563
HSA-MIR-6852-5P	99.17	66.69	2073
HSA-MIR-4292	99.16	65.57	1767

Literature-anchored findings (GeneRIF, showing 2)

• Biomarkers for C9orf7-ALS in Symptomatic and Pre-symptomatic Patients: State-of-the-art in the New Era of Clinical Trials. (PMID:34864683)
• Membrane structure and internalization dynamics of human Flower isoforms hFWE3 and hFWE4 indicate a conserved endocytic role for hFWE4. (PMID:37348560)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	cacfd1	ENSDARG00000090818
mus_musculus	Cacfd1	ENSMUSG00000015488
rattus_norvegicus	Cacfd1	ENSRNOG00000005840
drosophila_melanogaster	fwe	FBGN0261722
caenorhabditis_elegans		WBGENE00008973

Protein

Protein identifiers

Calcium channel flower homolog — Q9UGQ2 (reviewed: Q9UGQ2)

Alternative names: Calcium channel flower domain-containing protein 1

All UniProt accessions (2): Q9UGQ2, F6TGH8

UniProt curated annotations — full annotation on UniProt →

Function. Transmembrane protein which mediates synaptic endocytosis and fitness-based cell culling. In response to different stimulus strengths, controls two major modes of synaptic vesicle (SV) retrieval in hippocampal neurons; Clathrin-mediated endocytosis (CME) in response to mild stimulation and activity-dependent bulk endocytosis (ADBE) in response to strong stimulation. In cytotoxic T-lymphocytes (CTLs) facilitates calcium-dependent endocytosis of cytotoxic granules at the immuno synapse. Different isoforms work as fitness fingerprints in ’loser’ and ‘winner’ cells and thereby mediate win/lose decisions as part of the cell competition process. Functions with the other flower isoforms to produce tissue-specific fitness fingerprints that identify unfit or fit cells during cell selection processes in order to maintain tissue health. During cell competition, if levels of this isoform in cells is higher than in the surrounding neighboring cells, the cells are recognized as ‘winner’ cells, and do not undergo elimination via apoptosis. Functions with the other flower isoforms to produce tissue-specific fitness fingerprints that identify unfit or fit cells during cell selection processes in order to maintain tissue health. During cell competition, if levels of this isoform in unfit cells is higher than in the surrounding neighboring cells, the cells are recognized as ’loser’ cells, and undergo elimination via apoptosis to be replaced by the surrounding healthy ‘winner’ cell population. Functions with the other flower isoforms to produce tissue-specific fitness fingerprints that identify unfit or fit cells during cell selection processes in order to maintain tissue health. During cell competition, if levels of this isoform in unfit cells is higher than in the surrounding neighboring cells, the cells are recognized as ’loser’ cells, and undergo elimination via apoptosis to be replaced by the surrounding healthy ‘winner’ cell population. Functions with the other flower isoforms to produce tissue-specific fitness fingerprints that identify unfit or fit cells during cell selection processes in order to maintain tissue health. During cell competition, if levels of this isoform in cells is higher than in the surrounding neighboring cells, the cells are recognized as ‘winner’ cells, and do not undergo elimination via apoptosis.

Subunit / interactions. Interacts with adaptor protein complex 2 (AP-2).

Subcellular location. Cell membrane. Cytoplasmic vesicle. Secretory vesicle. Synaptic vesicle. Golgi apparatus. Vesicle Cell membrane. Early endosome. Recycling endosome Endoplasmic reticulum membrane.

Tissue specificity. Detected in skin cells at low levels of expression (at protein level).

Miscellaneous. In cancer cells, isoforms 1 and 3 isoforms (usually expressed in ‘winner’ cells) are up-regulated in cancer tissue whereas isoforms 2 and 4 isoform (usually expressed in ’loser’ cells) are up-regulated in tissue adjacent to the cancer, suggesting they might be important for tumor growth.

Similarity. Belongs to the calcium channel flower family.

Isoforms (4)

UniProt ID	Names	Canonical?
Q9UGQ2-1	1, FWE4	yes
Q9UGQ2-2	2, FWE3
Q9UGQ2-3	3, FWE1
Q9UGQ2-4	4, FWE2

RefSeq proteins (4): NP_001129247, NP_001229298, NP_001229299, NP_060056* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR019365	TVP18/Ca-channel_flower	Family

Pfam: PF10233

UniProt features (16 total): topological domain 5, transmembrane region 4, splice variant 2, mutagenesis site 2, chain 1, sequence variant 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UGQ2-F1	62.71	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.

Mutagenesis-validated functional residues (2):

Position	Phenotype
25–30	reduces internalization; when associated with 149-a–a-152.
149–152	reduces internalization; when associated with 25-a–a-30.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 89 (showing top): GTCTACC_MIR379, GOBP_VESICLE_MEDIATED_TRANSPORT, GTGCCTT_MIR506, MARTINEZ_RB1_TARGETS_DN, BLALOCK_ALZHEIMERS_DISEASE_UP, POU3F2_02, GOBP_IMPORT_INTO_CELL, GOBP_ENDOCYTOSIS, GOCC_EXOCYTIC_VESICLE, GOCC_SECRETORY_VESICLE, CHARAFE_BREAST_CANCER_LUMINAL_VS_MESENCHYMAL_UP, GOCC_SYNAPSE, GOCC_NUCLEAR_OUTER_MEMBRANE_ENDOPLASMIC_RETICULUM_MEMBRANE_NETWORK, GOCC_PRESYNAPSE, GOCC_RECYCLING_ENDOSOME

GO Biological Process (1): vesicle-mediated transport (GO:0016192)

GO Molecular Function (1): protein binding (GO:0005515)

GO Cellular Component (13): early endosome (GO:0005769), endoplasmic reticulum membrane (GO:0005789), Golgi apparatus (GO:0005794), plasma membrane (GO:0005886), synaptic vesicle (GO:0008021), recycling endosome (GO:0055037), endosome (GO:0005768), endoplasmic reticulum (GO:0005783), endomembrane system (GO:0012505), membrane (GO:0016020), cytoplasmic vesicle (GO:0031410), vesicle (GO:0031982), synapse (GO:0045202)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cytoplasm	3
endomembrane system	3
endosome	2
intracellular membrane-bounded organelle	2
cellular anatomical structure	2
transport	1
cellular process	1
binding	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
membrane	1
cell periphery	1
exocytic vesicle	1
presynapse	1
cytoplasmic vesicle	1
vacuole	1
plasma membrane	1
intracellular vesicle	1
membrane-bounded organelle	1
cell junction	1

Protein interactions and networks

STRING

298 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CACFD1	FAM163B	P0C2L3	493
CACFD1	MRFAP1L1	Q96HT8	427
CACFD1	C1orf35	Q9BU76	416
CACFD1	C9orf72	Q96LT7	415
CACFD1	FAM163A	Q96GL9	408
CACFD1	RETREG3	Q86VR2	404
CACFD1	GOLGA8K	D6RF30	400
CACFD1	C6orf47	O95873	392
CACFD1	SMIM14	Q96QK8	374
CACFD1	LINC03041	A6NGG3	374
CACFD1	GOLGA8T	H3BQL2	367
CACFD1	MINDY2	Q8NBR6	367
CACFD1	KLHDC3	Q9BQ90	364
CACFD1	PRRG1	O14668	362
CACFD1	SIRAL2	Q9NWS6	359

IntAct

28 interactions, top by confidence:

A	B	Type	Score
LDAF1	CACFD1	psi-mi:“MI:0915”(physical association)	0.670
CACFD1	LDAF1	psi-mi:“MI:0915”(physical association)	0.670
CACFD1	PITPNC1	psi-mi:“MI:0915”(physical association)	0.560
RBFA	CACFD1	psi-mi:“MI:0915”(physical association)	0.560
MTERF3	CACFD1	psi-mi:“MI:0915”(physical association)	0.560
HSFX1	CACFD1	psi-mi:“MI:0915”(physical association)	0.560
CACFD1	NDRG4	psi-mi:“MI:0915”(physical association)	0.560
CACFD1	SH3GLB1	psi-mi:“MI:0915”(physical association)	0.560
PNKP	CACFD1	psi-mi:“MI:0915”(physical association)	0.560
CACFD1	CREB3	psi-mi:“MI:0915”(physical association)	0.370
CACFD1	ORC4	psi-mi:“MI:0914”(association)	0.350
PITPNC1	CACFD1	psi-mi:“MI:0915”(physical association)	0.000
RBFA	CACFD1	psi-mi:“MI:0915”(physical association)	0.000
NDRG4	CACFD1	psi-mi:“MI:0915”(physical association)	0.000
MTERF3	CACFD1	psi-mi:“MI:0915”(physical association)	0.000
HSFX1	CACFD1	psi-mi:“MI:0915”(physical association)	0.000
SH3GLB1	CACFD1	psi-mi:“MI:0915”(physical association)	0.000
PNKP	CACFD1	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (22): TMEM159 (Two-hybrid), CACFD1 (Two-hybrid), TMEM159 (Two-hybrid), CACFD1 (Two-hybrid), CACFD1 (Two-hybrid), CACFD1 (Two-hybrid), CACFD1 (Two-hybrid), CACFD1 (Two-hybrid), CACFD1 (Two-hybrid), HSFX1 (Two-hybrid), HSFX2 (Two-hybrid), GPD2 (Affinity Capture-MS), TM9SF3 (Affinity Capture-MS), ORC4 (Affinity Capture-MS), MARCH5 (Affinity Capture-MS)

ESM2 similar proteins: A0JNC1, A2VE61, A6QL84, A7YY49, B2RZ37, O15260, O15431, O57590, O95674, P31064, Q00765, Q06400, Q0VCK9, Q0X0A5, Q3KNM2, Q3T126, Q3ZC24, Q5M7T4, Q5R705, Q5R7B1, Q5R9I4, Q5R9M4, Q5RBJ7, Q5RE33, Q5ZJ41, Q5ZKJ0, Q64310, Q6DD32, Q6GM44, Q6P360, Q6P3N5, Q7SZQ7, Q800K9, Q8BG21, Q8C407, Q8R1Z9, Q91ZQ0, Q940S0, Q96GC9, Q96KA5

Diamond homologs: B3M9W1, B3NDM7, B4GRI8, B4HIJ8, B4J043, B4L0H1, B4LIH0, B4MXW6, B4PD01, B4QLP9, D4A9I3, Q8BG21, Q95T12, Q9UGQ2

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	47
Likely benign	3
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1183 predictions. Top by Δscore:

Variant	Effect	Δscore
9:133460124:G:GT	donor_gain	1.0000
9:133460184:GTCT:G	donor_gain	1.0000
9:133460188:G:GG	donor_gain	1.0000
9:133463480:A:AG	acceptor_gain	1.0000
9:133463481:A:AG	acceptor_gain	1.0000
9:133463482:G:GG	acceptor_gain	1.0000
9:133463552:TGAT:T	donor_gain	1.0000
9:133463552:TGATG:T	donor_loss	1.0000
9:133463553:GAT:G	donor_gain	1.0000
9:133463553:GATG:G	donor_gain	1.0000
9:133463554:ATGT:A	donor_loss	1.0000
9:133463555:TG:T	donor_loss	1.0000
9:133463556:G:GG	donor_gain	1.0000
9:133463556:GT:G	donor_loss	1.0000
9:133463557:T:G	donor_loss	1.0000
9:133465310:T:TA	acceptor_gain	1.0000
9:133465320:A:AG	acceptor_gain	1.0000
9:133465321:G:GG	acceptor_gain	1.0000
9:133465431:G:GT	donor_gain	1.0000
9:133467919:AG:A	acceptor_gain	1.0000
9:133467920:GG:G	acceptor_gain	1.0000
9:133467994:G:GT	donor_gain	1.0000
9:133468029:G:GG	donor_gain	1.0000
9:133468557:CCCCA:C	acceptor_loss	1.0000
9:133468558:CCCA:C	acceptor_loss	1.0000
9:133468560:CAG:C	acceptor_loss	1.0000
9:133468561:A:AG	acceptor_gain	1.0000
9:133468561:AG:A	acceptor_gain	1.0000
9:133468561:AGG:A	acceptor_gain	1.0000
9:133468562:G:A	acceptor_loss	1.0000

AlphaMissense

1109 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
9:133467995:G:A	G132E	0.995
9:133460178:G:A	G38R	0.994
9:133460178:G:C	G38R	0.994
9:133468007:G:A	G136E	0.994
9:133467994:G:A	G132R	0.992
9:133467994:G:C	G132R	0.992
9:133467994:G:T	G132W	0.992
9:133460179:G:A	G38E	0.991
9:133463498:G:A	G46D	0.991
9:133460170:G:A	G35E	0.990
9:133460178:G:T	G38W	0.990
9:133463497:G:C	G46R	0.990
9:133463543:G:A	G61D	0.990
9:133465443:T:C	C106R	0.989
9:133467970:G:C	G124R	0.989
9:133460169:G:T	G35W	0.988
9:133463542:G:C	G61R	0.988
9:133467971:G:A	G124D	0.988
9:133460169:G:A	G35R	0.987
9:133460169:G:C	G35R	0.987
9:133463485:T:C	C42R	0.987
9:133463548:T:A	W63R	0.987
9:133463548:T:C	W63R	0.987
9:133467926:C:A	A109E	0.987
9:133463509:T:C	C50R	0.986
9:133468006:G:A	G136R	0.986
9:133468006:G:C	G136R	0.986
9:133467935:C:G	P112R	0.985
9:133467975:C:A	N125K	0.984
9:133467975:C:G	N125K	0.984

dbSNP variants (sampled 300 via entrez): RS1000332578 (9:133463017 A>G), RS1000579593 (9:133466556 G>A,T), RS1000844428 (9:133470378 G>C), RS1000932541 (9:133461192 A>T), RS1000983463 (9:133461559 C>T), RS1001060426 (9:133466817 G>A), RS1001287779 (9:133467320 G>A), RS1001498921 (9:133461166 G>T), RS1001579988 (9:133465966 A>C,G), RS1001592658 (9:133460556 G>A), RS1001619101 (9:133463980 T>G), RS1001747463 (9:133470943 C>T), RS1001842155 (9:133470007 T>G), RS1001869693 (9:133467540 C>A,T), RS1001873270 (9:133466988 G>T)

Disease associations

OMIM: gene MIM:613104 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST001574_9	Activated partial thromboplastin time	9.000000e-100
GCST003854_49	Gut microbiota (functional units)	3.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0007874	gut microbiome measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

27 total (human), top 27 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases abundance, increases expression	2
Benzo(a)pyrene	decreases expression, increases methylation	2
GSK-J4	decreases expression	1
triphenyl phosphate	affects expression	1
butyraldehyde	decreases expression	1
perfluorooctanoic acid	affects cotreatment, increases expression	1
S-(1,2-dichlorovinyl)cysteine	decreases expression, affects response to substance, increases expression, affects cotreatment	1
perfluorooctane sulfonic acid	increases expression	1
Air Pollutants	decreases expression, increases abundance	1
Air Pollutants, Occupational	affects expression	1
Arsenic	increases abundance, increases expression	1
Cisplatin	decreases expression	1
Cosmetics	affects cotreatment, increases expression	1
Dichlorodiphenyl Dichloroethylene	decreases expression	1
Doxorubicin	affects expression	1
Estradiol	decreases expression	1
Flame Retardants	affects cotreatment, increases expression	1
Gallic Acid	decreases expression	1
Lipopolysaccharides	decreases expression, affects response to substance, increases expression, affects cotreatment	1
Plasticizers	affects cotreatment, increases expression	1
Smoke	decreases expression	1
Tobacco Smoke Pollution	increases expression	1
Urethane	increases expression	1
Valproic Acid	decreases expression, increases methylation	1
Acrylamide	increases expression	1
Phytoestrogens	affects cotreatment, increases expression	1
Particulate Matter	increases abundance, decreases expression	1

Clinical trials (associated diseases)

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