FUNDC2

Summary

FUNDC2 (FUN14 domain containing 2, HGNC:24925) is a protein-coding gene on chromosome Xq28, encoding FUN14 domain-containing protein 2 (Q9BWH2). Binds directly and specifically 1,2-Diacyl-sn-glycero-3-phospho-(1’-myo-inositol-3’,4’,5’-bisphosphate) (PIP3) leading to the recruitment of PIP3 to mitochondria and may play a role in the regulation of the platelet activation via AKT/GSK3B/cGMP signaling pathways.

Enables phosphatidylinositol-3,4,5-trisphosphate binding activity. Involved in intracellular triglyceride homeostasis. Located in mitochondrion.

Source: NCBI Gene 65991 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 73 total — 1 likely-pathogenic
• MANE Select transcript: NM_023934

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:24925
Approved symbol	FUNDC2
Name	FUN14 domain containing 2
Location	Xq28
Locus type	gene with protein product
Status	Approved
Aliases	HCBP6, DC44
Ensembl gene	ENSG00000165775
Ensembl biotype	protein_coding
OMIM	301042
Entrez	65991

Gene structure

Transcript identifiers

Ensembl transcripts: 11 — 5 protein_coding, 3 retained_intron, 2 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000369498, ENST00000456179, ENST00000471528, ENST00000475165, ENST00000484175, ENST00000485289, ENST00000492303, ENST00000856523, ENST00000856524, ENST00000856525, ENST00000942567

RefSeq mRNA: 1 — MANE Select: NM_023934 NM_023934

CCDS: CCDS14763

Canonical transcript exons

ENST00000369498 — 5 exons

Exon	Start	End
ENSE00001424118	155026844	155027071
ENSE00001885449	155054595	155060304
ENSE00003597716	155051670	155051801
ENSE00003600119	155033403	155033553
ENSE00003600808	155046509	155046584

Expression profiles

Bgee: expression breadth ubiquitous, 192 present calls, max score 99.18.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 16.7640 / max 108.3331, expressed in 1796 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
198213	6.8633	1690
198211	5.7165	1645
198210	3.7935	1494
198212	0.3907	194

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
apex of heart	UBERON:0002098	99.18	gold quality
hindlimb stylopod muscle	UBERON:0004252	99.02	gold quality
gastrocnemius	UBERON:0001388	98.95	gold quality
right atrium auricular region	UBERON:0006631	98.95	gold quality
muscle of leg	UBERON:0001383	98.84	gold quality
body of pancreas	UBERON:0001150	98.70	gold quality
left ovary	UBERON:0002119	98.49	gold quality
right ovary	UBERON:0002118	98.38	gold quality
lower esophagus muscularis layer	UBERON:0035833	98.33	gold quality
lower esophagus	UBERON:0013473	98.31	gold quality
ganglionic eminence	UBERON:0004023	98.26	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	98.23	gold quality
muscle layer of sigmoid colon	UBERON:0035805	98.02	gold quality
left uterine tube	UBERON:0001303	97.97	gold quality
adenohypophysis	UBERON:0002196	97.96	gold quality
left adrenal gland	UBERON:0001234	97.89	gold quality
smooth muscle tissue	UBERON:0001135	97.88	gold quality
endocervix	UBERON:0000458	97.87	gold quality
left coronary artery	UBERON:0001626	97.86	gold quality
popliteal artery	UBERON:0002250	97.86	gold quality
tibial artery	UBERON:0007610	97.86	gold quality
left adrenal gland cortex	UBERON:0035825	97.86	gold quality
right adrenal gland	UBERON:0001233	97.84	gold quality
islet of Langerhans	UBERON:0000006	97.83	gold quality
body of uterus	UBERON:0009853	97.69	gold quality
right adrenal gland cortex	UBERON:0035827	97.57	gold quality
ascending aorta	UBERON:0001496	97.54	gold quality
thoracic aorta	UBERON:0001515	97.54	gold quality
descending thoracic aorta	UBERON:0002345	97.50	gold quality
mucosa of stomach	UBERON:0001199	97.43	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-MTAB-6142	no	289.82
E-HCAD-13	no	2.88
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

99 targeting FUNDC2, 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-6867-5P	100.00	82.21	3464
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-6798-5P	100.00	65.77	699
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-485-3P	99.98	70.68	1585
HSA-MIR-539-3P	99.98	70.74	1616
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-607	99.97	73.62	5593
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-1468-3P	99.96	72.74	3797
HSA-MIR-8082	99.95	67.27	1170
HSA-MIR-545-3P	99.95	70.74	2783
HSA-MIR-10523-5P	99.91	69.22	2038
HSA-MIR-3686	99.90	70.53	2432
HSA-MIR-627-3P	99.90	71.42	3316
HSA-MIR-380-3P	99.89	70.18	1978
HSA-MIR-10395-5P	99.86	67.35	676
HSA-MIR-202-3P	99.84	71.41	1290
HSA-MIR-548AZ-5P	99.83	69.94	3230
HSA-MIR-548T-5P	99.83	69.91	3220
HSA-MIR-2052	99.79	69.37	2031

Literature-anchored findings (GeneRIF, showing 6)

• our results provide new evidence that miR-122-regulated HCBP6 functions as a sensor protein to maintain intrahepatocyte Triglyceride levels. (PMID:25855506)
• These results indicate that HCBP6 upregulates human SREBP1c expression by binding to the C/EBPbeta-binding site in the SREBP1c promoter. (PMID:29187281)
• This data indicate that FUNDC2 directly and selectively binds to PIP3 via its PB motif. Fractionation assays with HeLa cell lysates biochemically confirmed the localization of endogenous FUNDC2 to mitochondria. (PMID:29786068)
• Methylation of the HCBP6 promoter is associated with primary biliary cholangitis pathogenesis. (PMID:35468421)
• FUNDC2 promotes liver tumorigenesis by inhibiting MFN1-mediated mitochondrial fusion. (PMID:35710796)
• FUNDC2, a mitochondrial outer membrane protein, mediates triple-negative breast cancer progression via the AKT/GSK3beta/GLI1 pathway. (PMID:37700593)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	fundc2	ENSDARG00000103740
mus_musculus	Fundc2	ENSMUSG00000031198
mus_musculus	Fundc2b	ENSMUSG00000074619
rattus_norvegicus	Fundc2b	ENSRNOG00000061390
caenorhabditis_elegans		WBGENE00011528

Paralogs (1): FUNDC1 (ENSG00000069509)

Protein

Protein identifiers

FUN14 domain-containing protein 2 — Q9BWH2 (reviewed: Q9BWH2)

Alternative names: Cervical cancer proto-oncogene 3 protein, Hepatitis C virus core-binding protein 6

All UniProt accessions (2): Q9BWH2, H7C0K8

UniProt curated annotations — full annotation on UniProt →

Function. Binds directly and specifically 1,2-Diacyl-sn-glycero-3-phospho-(1’-myo-inositol-3’,4’,5’-bisphosphate) (PIP3) leading to the recruitment of PIP3 to mitochondria and may play a role in the regulation of the platelet activation via AKT/GSK3B/cGMP signaling pathways. May act as transcription factor that regulates SREBP1 (isoform SREBP-1C) expression in order to modulate triglyceride (TG) homeostasis in hepatocytes.

Subcellular location. Mitochondrion outer membrane. Nucleus.

Tissue specificity. Highly expressed in platelets (at protein level).

Similarity. Belongs to the FUN14 family.

RefSeq proteins (1): NP_076423* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR007014	FUN14	Family

Pfam: PF04930

UniProt features (11 total): topological domain 4, modified residue 3, transmembrane region 3, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9BWH2-F1	66.04	0.01

Functional residue map

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

Post-translational modifications (3): 151, 10, 53

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 95 (showing top): GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_ACYLGLYCEROL_HOMEOSTASIS, GOBP_PLATELET_ACTIVATION, GOBP_LIPID_HOMEOSTASIS, GOBP_WOUND_HEALING, GOCC_MITOCHONDRIAL_ENVELOPE, YAMASHITA_METHYLATED_IN_PROSTATE_CANCER, GOBP_HEMOSTASIS, GOBP_REGULATION_OF_PLATELET_ACTIVATION, VIETOR_IFRD1_TARGETS, MODULE_277, ACEVEDO_METHYLATED_IN_LIVER_CANCER_DN, GOBP_REGULATION_OF_BODY_FLUID_LEVELS, GOBP_HOMEOSTATIC_PROCESS, GOBP_CHEMICAL_HOMEOSTASIS

GO Biological Process (3): autophagy of mitochondrion (GO:0000422), regulation of platelet activation (GO:0010543), intracellular triglyceride homeostasis (GO:0035356)

GO Molecular Function (2): phosphatidylinositol-3,4,5-trisphosphate binding (GO:0005547), protein binding (GO:0005515)

GO Cellular Component (4): nucleus (GO:0005634), mitochondrion (GO:0005739), mitochondrial outer membrane (GO:0005741), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
intracellular membrane-bounded organelle	2
autophagy	1
platelet activation	1
regulation of cell activation	1
intracellular chemical homeostasis	1
triglyceride homeostasis	1
anion binding	1
phosphatidylinositol phosphate binding	1
binding	1
cytoplasm	1
mitochondrial membrane	1
organelle outer membrane	1
cellular anatomical structure	1

Protein interactions and networks

STRING

982 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FUNDC2	CMC4	P56277	594
FUNDC2	VBP1	P61758	505
FUNDC2	ZNG1E	Q5RIA9	431
FUNDC2	CLIC2	O15247	420
FUNDC2	FAM162A	Q96A26	416
FUNDC2	ZAN	Q9Y493	414
FUNDC2	PHTF2	Q8N3S3	411
FUNDC2	STEEP1	Q9H5V9	407
FUNDC2	HNRNPA1L2	Q32P51	393
FUNDC2	ESR1	P03372	392
FUNDC2	MSANTD4	Q8NCY6	391
FUNDC2	IQGAP1	P46940	389
FUNDC2	FKBP8	Q14318	389
FUNDC2	PGAM5	Q96HS1	386
FUNDC2	RAB39B	Q96DA2	380

IntAct

136 interactions, top by confidence:

A	B	Type	Score
CYB5R3	FUNDC2	psi-mi:“MI:0915”(physical association)	0.670
DNAJC7	PLD2	psi-mi:“MI:0914”(association)	0.640
FAF2	UBB	psi-mi:“MI:0914”(association)	0.640
ARL4C	RGS12	psi-mi:“MI:0914”(association)	0.640
FUNDC2		psi-mi:“MI:0915”(physical association)	0.560
FUNDC2	CIDEB	psi-mi:“MI:0915”(physical association)	0.560
FUNDC2	TMX2	psi-mi:“MI:0915”(physical association)	0.560
MFSD14B	FUNDC2	psi-mi:“MI:0915”(physical association)	0.560
KIR2DL3	FUNDC2	psi-mi:“MI:0915”(physical association)	0.560
AQP6	FUNDC2	psi-mi:“MI:0915”(physical association)	0.560
SLC16A10	FUNDC2	psi-mi:“MI:0915”(physical association)	0.560
	FUNDC2	psi-mi:“MI:0915”(physical association)	0.560
MGST3	FUNDC2	psi-mi:“MI:0915”(physical association)	0.560
FGF14	FUNDC2	psi-mi:“MI:0915”(physical association)	0.560
RETREG3	FUNDC2	psi-mi:“MI:0915”(physical association)	0.560
CRB3	FUNDC2	psi-mi:“MI:0915”(physical association)	0.560
ARL13B	FUNDC2	psi-mi:“MI:0915”(physical association)	0.560
KCNJ6	FUNDC2	psi-mi:“MI:0915”(physical association)	0.560
FUNDC2	REEP4	psi-mi:“MI:0915”(physical association)	0.560
SDR16C5	FUNDC2	psi-mi:“MI:0915”(physical association)	0.560
SLC66A2	FUNDC2	psi-mi:“MI:0915”(physical association)	0.560
COX20	FUNDC2	psi-mi:“MI:0915”(physical association)	0.560
CD79A	FUNDC2	psi-mi:“MI:0915”(physical association)	0.560
EVI2B	FUNDC2	psi-mi:“MI:0915”(physical association)	0.560
SLC10A6	FUNDC2	psi-mi:“MI:0915”(physical association)	0.560
SYT2	FUNDC2	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (126): FUNDC2 (Two-hybrid), FUNDC2 (Affinity Capture-RNA), FUNDC2 (Affinity Capture-RNA), FUNDC2 (Affinity Capture-RNA), SEC62 (Affinity Capture-MS), FAF2 (Affinity Capture-MS), FUNDC1 (Affinity Capture-MS), FUNDC2 (Affinity Capture-MS), FUNDC2 (Affinity Capture-MS), FUNDC2 (Affinity Capture-MS), FUNDC2 (Affinity Capture-MS), FUNDC2 (Affinity Capture-MS), FUNDC2 (Affinity Capture-MS), FAF2 (Affinity Capture-MS), FUNDC2 (Affinity Capture-MS)

ESM2 similar proteins: A4IFL0, B1H3B1, D3ZLY0, D3ZXD8, E1BD52, E1BWM5, F1N5S9, O14925, O35093, O35094, O43615, P00130, Q08DM5, Q0VCK9, Q28851, Q2KHV4, Q3B8P0, Q4RY26, Q58EA0, Q5BJS4, Q5R5H4, Q5R9K4, Q5RDD0, Q5RI15, Q5SRD1, Q5XH94, Q5XIA8, Q5XJY4, Q68EQ9, Q6DFJ3, Q6DH87, Q6INE8, Q6INU6, Q6NYY9, Q6P4H8, Q7YRC0, Q864V5, Q8IVP5, Q8MJN0, Q91ZQ0

Diamond homologs: B1H3B1, E1BWM5, F1N5S9, Q22252, Q4RY26, Q58EA0, Q5BJS4, Q6DFJ3, Q6DH87, Q7YRC0, Q864V5, Q8IVP5, Q8MJN0, Q9BWH2, Q9D6K8, Q9DB70

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	1
Uncertain significance	16
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
268063	GRCh37/hg19 Xq28(chrX:154256858-154297348)x0	Likely pathogenic

SpliceAI

627 predictions. Top by Δscore:

Variant	Effect	Δscore
X:155027070:AGGTA:A	donor_loss	1.0000
X:155027071:GGTAA:G	donor_loss	1.0000
X:155027072:GTAA:G	donor_loss	1.0000
X:155027073:T:G	donor_loss	1.0000
X:155033400:TAG:T	acceptor_loss	1.0000
X:155033401:A:AG	acceptor_gain	1.0000
X:155033401:AG:A	acceptor_gain	1.0000
X:155033401:AGGA:A	acceptor_loss	1.0000
X:155033402:G:GA	acceptor_gain	1.0000
X:155033402:GG:G	acceptor_gain	1.0000
X:155033402:GGA:G	acceptor_gain	1.0000
X:155033402:GGAA:G	acceptor_gain	1.0000
X:155033402:GGAAA:G	acceptor_gain	1.0000
X:155033549:GGATG:G	donor_gain	1.0000
X:155033550:GATG:G	donor_gain	1.0000
X:155033550:GATGG:G	donor_gain	1.0000
X:155033551:ATG:A	donor_gain	1.0000
X:155033552:TG:T	donor_gain	1.0000
X:155033553:GG:G	donor_gain	1.0000
X:155033554:G:GG	donor_gain	1.0000
X:155033554:GT:G	donor_loss	1.0000
X:155033555:TAAG:T	donor_loss	1.0000
X:155051654:A:AG	acceptor_gain	1.0000
X:155051656:T:A	acceptor_gain	1.0000
X:155051659:T:A	acceptor_gain	1.0000
X:155051665:TGTA:T	acceptor_loss	1.0000
X:155051666:GTAGC:G	acceptor_loss	1.0000
X:155051667:TAGCT:T	acceptor_loss	1.0000
X:155051668:A:AG	acceptor_gain	1.0000
X:155051668:A:AT	acceptor_loss	1.0000

AlphaMissense

1218 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:155046547:C:A	A108D	1.000
X:155046556:C:A	A111D	1.000
X:155033550:G:A	G94E	0.999
X:155046510:T:C	C96R	0.999
X:155046517:G:A	G98D	0.999
X:155046550:C:A	A109E	0.999
X:155046555:G:C	A111P	0.999
X:155046564:G:C	G114R	0.999
X:155046565:G:A	G114D	0.999
X:155046567:G:A	G115R	0.999
X:155046567:G:C	G115R	0.999
X:155046568:G:A	G115E	0.999
X:155054644:G:A	G181E	0.999
X:155033538:G:A	G90E	0.998
X:155033541:G:A	G91D	0.998
X:155033549:G:A	G94R	0.998
X:155033549:G:C	G94R	0.998
X:155033552:T:A	W95R	0.998
X:155033552:T:C	W95R	0.998
X:155046516:G:C	G98R	0.998
X:155046523:T:A	I100K	0.998
X:155046562:G:A	G113E	0.998
X:155051674:C:A	A122E	0.998
X:155051692:T:A	I128N	0.998
X:155054635:G:A	G178E	0.998
X:155054646:G:C	G182R	0.998
X:155054647:G:A	G182D	0.998
X:155054658:G:C	G186R	0.998
X:155033540:G:C	G91R	0.997
X:155033550:G:T	G94V	0.997

dbSNP variants (sampled 300 via entrez): RS1000031718 (X:155041659 A>G), RS1000044273 (X:155030321 A>C), RS1000325240 (X:155053069 G>A), RS1000437386 (X:155059190 G>T), RS1000815481 (X:155044221 T>C), RS1000930558 (X:155055364 T>C), RS1001022412 (X:155033316 T>C), RS1001361875 (X:155054970 C>G), RS1001453466 (X:155032904 C>T), RS1001480906 (X:155038429 A>T), RS1001694673 (X:155028465 G>C), RS1001700047 (X:155039079 C>G,T), RS1001726565 (X:155029021 A>G), RS1002132692 (X:155057736 G>C), RS1002324662 (X:155031359 C>T)

Disease associations

OMIM: gene MIM:301042 | 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

21 total (human), top 21 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
FR900359	decreases phosphorylation	1
bisphenol F	increases expression	1
bisphenol A	increases expression	1
potassium chromate(VI)	decreases expression	1
nickel sulfate	decreases expression	1
CGP 52608	affects binding, increases reaction	1
corosolic acid	increases expression	1
bisphenol S	increases expression	1
bisphenol AF	increases expression	1
Acetaminophen	affects expression	1
Air Pollutants	increases abundance, increases expression	1
Amiodarone	increases expression	1
Atrazine	increases expression	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Doxorubicin	decreases expression	1
Smoke	decreases expression	1
Valproic Acid	decreases expression	1
Aflatoxin B1	decreases methylation	1
Copper Sulfate	decreases expression	1
Permethrin	decreases expression	1
Particulate Matter	increases abundance, increases expression	1

Cellosaurus cell lines

5 cell lines: 5 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_SP01	HAP1 FUNDC2 (-) 1	Cancer cell line	Male
CVCL_XN95	HAP1 FUNDC2 (-) 2	Cancer cell line	Male
CVCL_XN96	HAP1 FUNDC2 (-) 3	Cancer cell line	Male
CVCL_XN97	HAP1 FUNDC2 (-) 4	Cancer cell line	Male
CVCL_XN98	HAP1 FUNDC2 (-) 5	Cancer cell line	Male

Clinical trials (associated diseases)

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