TCAF1

Summary

TCAF1 (TRPM8 channel associated factor 1, HGNC:22201) is a protein-coding gene on chromosome 7q35, encoding TRPM8 channel-associated factor 1 (Q9Y4C2). Positively regulates the plasma membrane cation channel TRPM8 activity.

Enables transmembrane transporter binding activity. Involved in negative regulation of cell migration; positive regulation of anion channel activity; and positive regulation of protein targeting to membrane. Located in plasma membrane.

Source: NCBI Gene 9747 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 55 total
• MANE Select transcript: NM_014719

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:22201
Approved symbol	TCAF1
Name	TRPM8 channel associated factor 1
Location	7q35
Locus type	gene with protein product
Status	Approved
Aliases	KIAA0738, GATD9A
Ensembl gene	ENSG00000198420
Ensembl biotype	protein_coding
OMIM	616251
Entrez	9747

Gene structure

Transcript identifiers

Ensembl transcripts: 12 — 11 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000355951, ENST00000392900, ENST00000460532, ENST00000478172, ENST00000479870, ENST00000485416, ENST00000491908, ENST00000872784, ENST00000872785, ENST00000872786, ENST00000872787, ENST00000963297

RefSeq mRNA: 3 — MANE Select: NM_014719 NM_001206938, NM_001206941, NM_014719

CCDS: CCDS56514, CCDS5886

Canonical transcript exons

ENST00000479870 — 9 exons

Exon	Start	End
ENSE00001420825	143901961	143902176
ENSE00001432828	143851375	143854142
ENSE00001433460	143875989	143876622
ENSE00003485436	143862416	143862513
ENSE00003571458	143860208	143860447
ENSE00003604295	143861095	143861308
ENSE00003611967	143862802	143863796
ENSE00003659850	143857100	143857350
ENSE00003689209	143858824	143859161

Expression profiles

Bgee: expression breadth ubiquitous, 295 present calls, max score 97.64.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 24.0006 / max 214.7140, expressed in 1786 samples.

FANTOM5 promoters (9 alternative TSS)

Promoter ID	TPM avg	Samples expressed
86687	16.6491	1785
86679	3.5821	982
86685	2.5171	875
86686	0.7309	389
86680	0.3159	181
86681	0.0656	25
86684	0.0546	24
86682	0.0496	24
86683	0.0357	14

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
adrenal tissue	UBERON:0018303	97.64	gold quality
ganglionic eminence	UBERON:0004023	97.39	gold quality
cortical plate	UBERON:0005343	97.26	gold quality
Brodmann (1909) area 23	UBERON:0013554	96.90	gold quality
lateral nuclear group of thalamus	UBERON:0002736	96.46	gold quality
parietal pleura	UBERON:0002400	96.08	gold quality
lateral globus pallidus	UBERON:0002476	96.01	gold quality
placenta	UBERON:0001987	95.98	gold quality
germinal epithelium of ovary	UBERON:0001304	95.78	gold quality
decidua	UBERON:0002450	95.73	gold quality
entorhinal cortex	UBERON:0002728	95.73	gold quality
substantia nigra pars compacta	UBERON:0001965	95.65	gold quality
ventricular zone	UBERON:0003053	95.48	gold quality
pleura	UBERON:0000977	95.22	gold quality
cardia of stomach	UBERON:0001162	95.12	gold quality
superior frontal gyrus	UBERON:0002661	95.12	gold quality
postcentral gyrus	UBERON:0002581	95.02	gold quality
parietal lobe	UBERON:0001872	94.97	gold quality
secondary oocyte	CL:0000655	94.91	gold quality
primary visual cortex	UBERON:0002436	94.78	gold quality
substantia nigra pars reticulata	UBERON:0001966	94.73	gold quality
visceral pleura	UBERON:0002401	94.73	gold quality
ventral tegmental area	UBERON:0002691	94.68	gold quality
tibia	UBERON:0000979	94.61	gold quality
occipital lobe	UBERON:0002021	94.47	gold quality
pons	UBERON:0000988	94.46	gold quality
superior vestibular nucleus	UBERON:0007227	94.32	gold quality
trigeminal ganglion	UBERON:0001675	94.29	gold quality
right adrenal gland cortex	UBERON:0035827	94.19	gold quality
islet of Langerhans	UBERON:0000006	94.17	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-GEOD-100618	yes	200.98
E-MTAB-6701	yes	116.74
E-ANND-3	yes	2.95
E-GEOD-124858	no	292.18

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): FOXO1

miRNA regulators (miRDB)

112 targeting TCAF1, 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-7110-3P	100.00	73.18	2486
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-3646	100.00	73.56	5283
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-1236-3P	99.94	68.04	1695
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-4778-3P	99.93	70.40	1818
HSA-MIR-338-5P	99.92	72.34	2951
HSA-MIR-1305	99.91	71.43	3443
HSA-MIR-219A-5P	99.91	73.36	735
HSA-MIR-4753-3P	99.90	71.03	3786
HSA-MIR-9902	99.89	69.15	2250
HSA-MIR-605-3P	99.88	69.22	1833
HSA-MIR-4782-3P	99.88	73.31	735
HSA-MIR-6766-3P	99.88	73.38	732
HSA-LET-7A-2-3P	99.87	70.53	1921
HSA-LET-7G-3P	99.85	70.43	1929
HSA-MIR-130B-5P	99.83	68.50	1888

Literature-anchored findings (GeneRIF, showing 4)

• Report novel TRP channel-associated factors that modulate TRPM8 activity. (PMID:25559186)
• TCAF1 binds to and promotes trafficking of the TRPM8 cold sensor channel to the cell surface, it contains a PI3K homology domain in its C-terminal tail that modifies TRPM8 gating properties and seems to facilitate channel opening, as assessed by menthol-induced response. Overexpression leads to a reduction in both the speed and directionality of migration of prostate cancer cells. (PMID:25559186)
• Evidence for opposing selective forces operating on human-specific duplicated TCAF genes in Neanderthals and humans. (PMID:34433829)
• TCAF1 promotes TRPV2-mediated Ca[2+] release in response to cytosolic DNA to protect stressed replication forks. (PMID:38816425)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	si:ch211-210b2.2	ENSDARG00000009402
danio_rerio	si:ch211-210b2.4	ENSDARG00000095212
danio_rerio	si:ch211-210b2.3	ENSDARG00000096927
danio_rerio	zgc:162193	ENSDARG00000098171
mus_musculus	Tcaf1	ENSMUSG00000036667
rattus_norvegicus	Tcaf1	ENSRNOG00000017911

Paralogs (2): TCAF2 (ENSG00000170379), TCAF2C (ENSG00000283528)

Protein

Protein identifiers

TRPM8 channel-associated factor 1 — Q9Y4C2 (reviewed: Q9Y4C2)

Alternative names: TRP channel-associated factor 1

All UniProt accessions (5): C9J648, C9J9F4, C9JD13, C9K0E7, Q9Y4C2

UniProt curated annotations — full annotation on UniProt →

Function. Positively regulates the plasma membrane cation channel TRPM8 activity. Involved in the recruitment of TRPM8 to the cell surface. Promotes prostate cancer cell migration inhibition in a TRPM8-dependent manner.

Subunit / interactions. Interacts with TRPM8 (via N-terminus and C-terminus domains); the interaction inhibits TRPM8 channel activity. Interacts with TRPV6.

Subcellular location. Cell membrane.

Tissue specificity. Isoform 2 is expressed in the prostate and strongly expressed in cancerous prostate samples.

Domain organisation. The C-terminal region is necessary for the channel activity stimulation.

Similarity. Belongs to the TCAF family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9Y4C2-1	1	yes
Q9Y4C2-2	2

RefSeq proteins (3): NP_001193867, NP_001193870, NP_055534* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR029062	Class_I_gatase-like	Homologous_superfamily
IPR031161	Peptidase_M60_dom	Domain
IPR035423	M60-like_N	Domain
IPR042279	Pep_M60_3	Homologous_superfamily
IPR051244	TCAF	Family

Pfam: PF13402, PF17291

UniProt features (4 total): chain 1, domain 1, splice variant 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y4C2-F1	92.77	0.83

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 158 (showing top): GSE45365_CTRL_VS_MCMV_INFECTION_NK_CELL_UP, GOBP_POSITIVE_REGULATION_OF_TRANSPORTER_ACTIVITY, GAUSSMANN_MLL_AF4_FUSION_TARGETS_A_UP, GOBP_PROTEIN_TARGETING, GOBP_REGULATION_OF_PROTEIN_TARGETING_TO_MEMBRANE, GOBP_POSITIVE_REGULATION_OF_TRANSMEMBRANE_TRANSPORT, MARTORIATI_MDM4_TARGETS_NEUROEPITHELIUM_DN, GOBP_PROTEIN_TARGETING_TO_MEMBRANE, GOBP_POSITIVE_REGULATION_OF_MOLECULAR_FUNCTION, CREIGHTON_ENDOCRINE_THERAPY_RESISTANCE_1, DEURIG_T_CELL_PROLYMPHOCYTIC_LEUKEMIA_DN, HUTTMANN_B_CLL_POOR_SURVIVAL_DN, GOBP_POSITIVE_REGULATION_OF_MONOATOMIC_ION_TRANSPORT, DOANE_RESPONSE_TO_ANDROGEN_DN, GOBP_REGULATION_OF_CELLULAR_LOCALIZATION

GO Biological Process (3): negative regulation of cell migration (GO:0030336), positive regulation of protein targeting to membrane (GO:0090314), positive regulation of anion channel activity (GO:1901529)

GO Molecular Function (2): transmembrane transporter binding (GO:0044325), protein binding (GO:0005515)

GO Cellular Component (2): plasma membrane (GO:0005886), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cell migration	1
regulation of cell migration	1
negative regulation of cell motility	1
protein targeting to membrane	1
positive regulation of cellular process	1
regulation of protein targeting to membrane	1
positive regulation of establishment of protein localization	1
monoatomic anion channel activity	1
positive regulation of ion transmembrane transporter activity	1
positive regulation of anion transmembrane transport	1
protein binding	1
binding	1
membrane	1
cell periphery	1
cellular anatomical structure	1

Protein interactions and networks

STRING

450 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TCAF1	TRPM8	Q7Z2W7	667
TCAF1	OR2F2	O95006	577
TCAF1	PTPN20	Q4JDL3	532
TCAF1	PEG10	Q86TG7	515
TCAF1	CTAGE6	Q86UF2	506
TCAF1	ARHGAP11B	Q3KRB8	478
TCAF1	ARHGEF5	Q12774	476
TCAF1	DUSP22	Q9NRW4	475
TCAF1	GPRIN2	O60269	462
TCAF1	NPY4R2	P0DQD5	462
TCAF1	GTF2H2C	Q6P1K8	461
TCAF1	GTF2H2	Q13888	443
TCAF1	ARHGEF35	A5YM69	433
TCAF1	SCGB1C1	Q8TD33	412
TCAF1	SCGB1C2	P0DMR2	412

IntAct

127 interactions, top by confidence:

A	B	Type	Score
RPA2	RPA1	psi-mi:“MI:0914”(association)	0.960
MAPK6	HERC2	psi-mi:“MI:0914”(association)	0.840
GET4	GET3	psi-mi:“MI:0914”(association)	0.800
SF3B4	TCAF1	psi-mi:“MI:0915”(physical association)	0.740
TCAF1	IKZF3	psi-mi:“MI:0915”(physical association)	0.740
TCAF1	SF3B4	psi-mi:“MI:0915”(physical association)	0.740
IKZF3	TCAF1	psi-mi:“MI:0915”(physical association)	0.740
ZNF398	ZNF282	psi-mi:“MI:0914”(association)	0.710
PEG10	RTL8C	psi-mi:“MI:0914”(association)	0.700
TCAF1	ZNF398	psi-mi:“MI:0915”(physical association)	0.670
EXOSC5	ZFC3H1	psi-mi:“MI:0914”(association)	0.640
VWCE	HSPA5	psi-mi:“MI:0914”(association)	0.640
ZNF397	ZNF213	psi-mi:“MI:0914”(association)	0.640
ZNF263	TCAF1	psi-mi:“MI:0915”(physical association)	0.560
TCAF1	SPRY2	psi-mi:“MI:0915”(physical association)	0.560
TCF3	TCAF1	psi-mi:“MI:0915”(physical association)	0.560
ZNF24	TCAF1	psi-mi:“MI:0915”(physical association)	0.560
TRIP6	TCAF1	psi-mi:“MI:0915”(physical association)	0.560
ZNF592	TCAF1	psi-mi:“MI:0915”(physical association)	0.560
TFIP11	TCAF1	psi-mi:“MI:0915”(physical association)	0.560
TCAF1	ZNF263	psi-mi:“MI:0915”(physical association)	0.560
SPRY2	TCAF1	psi-mi:“MI:0915”(physical association)	0.560
TCAF1	TCF3	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (160): FAM115A (Two-hybrid), FAM115A (Two-hybrid), FAM115A (Two-hybrid), FAM115A (Two-hybrid), ZNF263 (Two-hybrid), SPRY2 (Two-hybrid), SF3B4 (Two-hybrid), IKZF3 (Two-hybrid), TFIP11 (Two-hybrid), FAM115A (Affinity Capture-MS), EFEMP2 (Two-hybrid), SF3B4 (Two-hybrid), FAM115A (Affinity Capture-MS), FAM115A (Two-hybrid), FAM115A (Two-hybrid)

ESM2 similar proteins: A0A0R4IMY7, A0A0R4IY06, A0JPF9, A2AP18, A5PJN5, C0IN03, D2KX21, E1BVR9, E9PYK3, F1ND48, O00534, O75038, O94952, O95237, P0C1Q3, P53817, Q1LWG4, Q1LZ50, Q32PY6, Q4R3W5, Q4R6L3, Q5M7X9, Q5R5S1, Q5RJG7, Q5S6T3, Q5T8I9, Q6DC39, Q75WE7, Q7Z5M8, Q7ZU92, Q8BYI6, Q8C0L6, Q8CAE2, Q8CAS9, Q8K3R3, Q8NHH9, Q8SPR7, Q8VDH1, Q90678, Q93V51

Diamond homologs: A4IG42, A5PJN5, A6NFQ2, A6QLU7, Q5R8R3, Q5XHI4, Q6P6V7, Q6QR59, Q8BNE1, Q921K8, Q9Y4C2

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 151 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Regulation of PTEN stability and activity	6	11.1×	6e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	49
Likely benign	4
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1365 predictions. Top by Δscore:

Variant	Effect	Δscore
7:143857098:A:AC	donor_gain	1.0000
7:143857099:C:CC	donor_gain	1.0000
7:143857099:CAT:C	donor_gain	1.0000
7:143857133:T:TA	donor_gain	1.0000
7:143857137:T:A	donor_gain	1.0000
7:143857138:C:A	donor_gain	1.0000
7:143857172:T:TA	donor_gain	1.0000
7:143857173:C:A	donor_gain	1.0000
7:143857346:TGGAG:T	acceptor_gain	1.0000
7:143857347:GGAG:G	acceptor_gain	1.0000
7:143857348:GAG:G	acceptor_gain	1.0000
7:143857349:AG:A	acceptor_gain	1.0000
7:143857350:GCTGG:G	acceptor_loss	1.0000
7:143857351:C:CC	acceptor_gain	1.0000
7:143858821:TACC:T	donor_loss	1.0000
7:143858822:A:AT	donor_loss	1.0000
7:143858823:C:T	donor_loss	1.0000
7:143859157:CCAGC:C	acceptor_gain	1.0000
7:143859158:CAGC:C	acceptor_gain	1.0000
7:143859158:CAGCC:C	acceptor_gain	1.0000
7:143859159:AGC:A	acceptor_gain	1.0000
7:143859159:AGCCT:A	acceptor_loss	1.0000
7:143859160:GC:G	acceptor_gain	1.0000
7:143859160:GCC:G	acceptor_loss	1.0000
7:143859161:CC:C	acceptor_gain	1.0000
7:143859161:CCTG:C	acceptor_loss	1.0000
7:143859162:C:CC	acceptor_gain	1.0000
7:143859162:C:G	acceptor_loss	1.0000
7:143859163:T:C	acceptor_loss	1.0000
7:143859169:A:AC	acceptor_gain	1.0000

AlphaMissense

5987 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:143863244:G:C	S391R	0.998
7:143863244:G:T	S391R	0.998
7:143863246:T:G	S391R	0.998
7:143863611:A:T	V269D	0.998
7:143863641:G:T	A259E	0.997
7:143863710:G:A	S236F	0.997
7:143863419:A:T	V333D	0.996
7:143857251:A:G	W869R	0.995
7:143857251:A:T	W869R	0.995
7:143863271:G:C	N382K	0.995
7:143863271:G:T	N382K	0.995
7:143863543:A:G	W292R	0.995
7:143863543:A:T	W292R	0.995
7:143863710:G:T	S236Y	0.995
7:143857140:A:G	W906R	0.994
7:143857140:A:T	W906R	0.994
7:143859027:A:G	W768R	0.994
7:143859027:A:T	W768R	0.994
7:143860304:A:G	W691R	0.994
7:143860304:A:T	W691R	0.994
7:143863155:A:G	F421S	0.994
7:143863539:A:G	L293P	0.994
7:143863541:C:A	W292C	0.994
7:143863541:C:G	W292C	0.994
7:143863551:G:T	A289D	0.994
7:143863552:C:G	A289P	0.994
7:143863638:G:T	A260D	0.994
7:143863761:A:T	L219H	0.994
7:143857194:A:G	W888R	0.993
7:143857194:A:T	W888R	0.993

dbSNP variants (sampled 300 via entrez): RS1000019819 (7:143853500 A>G), RS1000065056 (7:143881913 G>A), RS1000093960 (7:143898217 A>G), RS1000190689 (7:143879048 C>T), RS1000374824 (7:143890980 A>G,T), RS1000392253 (7:143856994 A>G), RS1000529141 (7:143876767 G>A), RS1000709123 (7:143889509 AT>A), RS1000919222 (7:143895989 AAAT>A), RS1000919437 (7:143877312 G>A,C), RS1000926692 (7:143883510 T>C), RS1000957604 (7:143883795 A>G), RS1000988751 (7:143884308 G>C), RS1001041357 (7:143883417 AAAT>A), RS1001109010 (7:143902166 A>C,G)

Disease associations

OMIM: gene MIM:616251 | 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
GCST005588_37	Idiopathic dilated cardiomyopathy	5.000000e-06
GCST010136_23	Fruit consumption	5.000000e-08
GCST010136_24	Fruit consumption	1.000000e-48

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0009094	idiopathic dilated cardiomyopathy
EFO:0008111	diet measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
trichostatin A	affects cotreatment, increases expression	3
Valproic Acid	decreases expression, decreases methylation, increases expression	3
chloropicrin	increases expression	2
entinostat	decreases expression, affects cotreatment	2
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	increases expression, decreases expression, affects cotreatment	2
Estradiol	decreases expression	2
Tobacco Smoke Pollution	decreases expression	2
Tretinoin	decreases expression, increases expression	2
Cadmium Chloride	decreases expression, increases abundance, increases expression	2
Particulate Matter	affects cotreatment, increases expression, decreases expression, increases abundance	2
aristolochic acid I	decreases expression	1
tremortin	decreases expression	1
urushiol	increases expression	1
2,4,6-tribromophenol	decreases expression	1
testosterone enanthate	affects expression	1
triphenyl phosphate	affects expression	1
methylparaben	increases expression	1
ciglitazone	affects binding, increases expression	1
perfluorooctane sulfonic acid	decreases expression	1
K 7174	increases expression	1
torcetrapib	increases expression	1
ICG 001	increases expression	1
14-deoxy-11,12-didehydroandrographolide	decreases expression	1
Grape Seed Proanthocyanidins	affects cotreatment, decreases expression	1
dorsomorphin	affects cotreatment, decreases expression, increases expression	1
bisphenol S	increases methylation	1
LDN 193189	affects cotreatment, increases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	increases expression	1
Resveratrol	increases expression, affects cotreatment	1
Sunitinib	decreases expression	1

Clinical trials (associated diseases)

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