ANKRD6

Summary

ANKRD6 (ankyrin repeat domain 6, HGNC:17280) is a protein-coding gene on chromosome 6q15, encoding Ankyrin repeat domain-containing protein 6 (Q9Y2G4). Recruits CKI-epsilon to the beta-catenin degradation complex that consists of AXN1 or AXN2 and GSK3-beta and allows efficient phosphorylation of beta-catenin, thereby inhibiting beta-catenin/Tcf signals.

Predicted to be involved in negative regulation of canonical Wnt signaling pathway; positive regulation of JNK cascade; and protein targeting to chloroplast. Predicted to act upstream of or within positive regulation of Wnt signaling pathway, planar cell polarity pathway. Located in intracellular membrane-bounded organelle.

Source: NCBI Gene 22881 — RefSeq curated summary.

At a glance

• GWAS associations: 7
• Clinical variants (ClinVar): 172 total
• MANE Select transcript: NM_001242809

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:17280
Approved symbol	ANKRD6
Name	ankyrin repeat domain 6
Location	6q15
Locus type	gene with protein product
Status	Approved
Aliases	KIAA0957
Ensembl gene	ENSG00000135299
Ensembl biotype	protein_coding
OMIM	610583
Entrez	22881

Gene structure

Transcript identifiers

Ensembl transcripts: 71 — 63 protein_coding, 5 retained_intron, 2 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000339746, ENST00000369408, ENST00000415924, ENST00000447838, ENST00000465722, ENST00000479572, ENST00000483473, ENST00000485637, ENST00000492158, ENST00000518150, ENST00000518253, ENST00000520458, ENST00000520793, ENST00000520839, ENST00000520886, ENST00000521004, ENST00000521240, ENST00000522441, ENST00000522705, ENST00000522779, ENST00000523798, ENST00000524056, ENST00000710308, ENST00000862687, ENST00000862688, ENST00000862689, ENST00000862690, ENST00000862691, ENST00000862692, ENST00000862693, ENST00000862694, ENST00000862695, ENST00000862696, ENST00000862697, ENST00000862698, ENST00000862699, ENST00000862700, ENST00000862701, ENST00000913464, ENST00000913465, ENST00000913466, ENST00000913467, ENST00000913468, ENST00000913469, ENST00000913470, ENST00000913471, ENST00000913472, ENST00000913473, ENST00000913474, ENST00000913475, ENST00000913476, ENST00000913477, ENST00000960497, ENST00000960498, ENST00000960499, ENST00000960500, ENST00000960501, ENST00000960502, ENST00000960503, ENST00000960504, ENST00000960505, ENST00000960506, ENST00000960507, ENST00000960508, ENST00000960509, ENST00000960510, ENST00000960511, ENST00000960512, ENST00000960513, ENST00000960514, ENST00000960515

RefSeq mRNA: 5 — MANE Select: NM_001242809 NM_001242809, NM_001242811, NM_001242813, NM_001242814, NM_014942

CCDS: CCDS47460, CCDS56441, CCDS56442, CCDS56443

Canonical transcript exons

ENST00000339746 — 16 exons

Exon	Start	End
ENSE00002096307	89433152	89433375
ENSE00002099418	89630433	89633821
ENSE00003475828	89621922	89622026
ENSE00003482900	89606007	89606105
ENSE00003516044	89613792	89613890
ENSE00003528743	89612272	89612370
ENSE00003530798	89624539	89624691
ENSE00003569908	89629112	89629238
ENSE00003588487	89617954	89618031
ENSE00003596909	89623410	89623544
ENSE00003650083	89623872	89624057
ENSE00003657071	89627583	89627696
ENSE00003692774	89616559	89616657
ENSE00003694574	89603029	89603127
ENSE00004011353	89566834	89567096
ENSE00004011354	89595916	89596014

Expression profiles

Bgee: expression breadth ubiquitous, 272 present calls, max score 95.82.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 4.5187 / max 157.3573, expressed in 1152 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
68880	2.3321	770
68879	1.5412	825
68885	0.1811	67
68883	0.1474	69
68884	0.1233	55
68881	0.0834	37
68887	0.0819	45
68886	0.0284	16

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
blood vessel layer	UBERON:0004797	95.82	gold quality
right hemisphere of cerebellum	UBERON:0014890	94.67	gold quality
right uterine tube	UBERON:0001302	94.66	gold quality
cerebellar hemisphere	UBERON:0002245	94.31	gold quality
cerebellar cortex	UBERON:0002129	94.22	gold quality
cerebellum	UBERON:0002037	93.08	gold quality
secondary oocyte	CL:0000655	91.21	gold quality
ascending aorta	UBERON:0001496	91.08	gold quality
thoracic aorta	UBERON:0001515	91.01	gold quality
parotid gland	UBERON:0001831	90.90	gold quality
right coronary artery	UBERON:0001625	90.67	gold quality
oocyte	CL:0000023	90.60	gold quality
descending thoracic aorta	UBERON:0002345	90.50	gold quality
left ovary	UBERON:0002119	89.57	gold quality
aorta	UBERON:0000947	89.22	gold quality
visceral pleura	UBERON:0002401	88.43	gold quality
tibial artery	UBERON:0007610	87.94	gold quality
popliteal artery	UBERON:0002250	87.93	gold quality
ovary	UBERON:0000992	87.75	gold quality
right ovary	UBERON:0002118	87.45	gold quality
sural nerve	UBERON:0015488	87.43	gold quality
left coronary artery	UBERON:0001626	87.28	gold quality
coronary artery	UBERON:0001621	87.08	gold quality
ventricular zone	UBERON:0003053	85.91	gold quality
pleura	UBERON:0000977	85.79	gold quality
parietal pleura	UBERON:0002400	85.44	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	85.06	gold quality
pigmented layer of retina	UBERON:0001782	84.87	gold quality
prefrontal cortex	UBERON:0000451	84.57	gold quality
saliva-secreting gland	UBERON:0001044	84.19	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.86

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

131 targeting ANKRD6, 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-9-5P	100.00	72.28	2361
HSA-MIR-3613-3P	100.00	76.36	7965
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-548AW	99.99	72.57	3559
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-3065-5P	99.97	71.56	3281
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-5688	99.96	73.23	4504
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-144-3P	99.94	73.98	2698
HSA-MIR-8063	99.91	69.76	3146
HSA-MIR-95-5P	99.89	72.17	3973
HSA-MIR-1343-3P	99.89	66.78	1815

Literature-anchored findings (GeneRIF, showing 6)

• Diversin, containing several nuclear localization signals, translocates to the nucleus, where it interacts with the transcription factor AF9. (PMID:19591803)
• ANKRD6 genetic variants were associated with the muscle size and strength response to resistance training and habitual physical activity levels. (PMID:22580979)
• diversin is overexpressed in human glioma and regulates glioma cell proliferation and invasion, possibly through MMP9 (PMID:24833088)
• study demonstrated that diversin was overexpressed in human breast cancers. Diversin could contribute to breast cancer cell proliferation and invasion. (PMID:24858714)
• missense mutations in ANKRD6 are associated with neural tube defects. (PMID:25200652)
• Diversin upregulates the proliferative ability of colorectal cancer by inducing cell cycle proteins. (PMID:36623636)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	ankrd6b	ENSDARG00000029370
mus_musculus	Ankrd6	ENSMUSG00000040183
rattus_norvegicus	Ankrd6	ENSRNOG00000007110
drosophila_melanogaster	dgo	FBGN0086898

Paralogs (2): ANKRD10 (ENSG00000088448), NRARP (ENSG00000198435)

Protein

Protein identifiers

Ankyrin repeat domain-containing protein 6 — Q9Y2G4 (reviewed: Q9Y2G4)

Alternative names: Diversin

All UniProt accessions (12): A0AA34QVS0, E5RH98, E5RIJ4, E5RIN9, Q9Y2G4, E5RIS1, E5RJ05, E5RJ45, E5RJR9, H0YBG4, H0YBH4, H0YBW6

UniProt curated annotations — full annotation on UniProt →

Function. Recruits CKI-epsilon to the beta-catenin degradation complex that consists of AXN1 or AXN2 and GSK3-beta and allows efficient phosphorylation of beta-catenin, thereby inhibiting beta-catenin/Tcf signals.

Subunit / interactions. Interacts with AXN1, AXN2 and CSNK1E/CKI-epsilon.

Isoforms (4)

UniProt ID	Names	Canonical?
Q9Y2G4-2	1	yes
Q9Y2G4-1	2
Q9Y2G4-3	3
Q9Y2G4-4	4

RefSeq proteins (5): NP_001229738, NP_001229740, NP_001229742, NP_001229743, NP_055757 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002110	Ankyrin_rpt	Repeat
IPR036770	Ankyrin_rpt-contain_sf	Homologous_superfamily

Pfam: PF00023, PF12796, PF13637

UniProt features (31 total): repeat 8, compositionally biased region 7, sequence variant 5, splice variant 4, region of interest 3, coiled-coil region 2, chain 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y2G4-F1	70.82	0.47

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 146 (showing top): chr6q15, GOBP_ESTABLISHMENT_OR_MAINTENANCE_OF_CELL_POLARITY, GOBP_NON_CANONICAL_WNT_SIGNALING_PATHWAY, GOBP_REGULATION_OF_NON_CANONICAL_WNT_SIGNALING_PATHWAY, GOBP_REGULATION_OF_WNT_SIGNALING_PATHWAY, GOBP_CANONICAL_WNT_SIGNALING_PATHWAY, KINSEY_TARGETS_OF_EWSR1_FLII_FUSION_DN, GOBP_POSITIVE_REGULATION_OF_NON_CANONICAL_WNT_SIGNALING_PATHWAY, SCHAEFFER_PROSTATE_DEVELOPMENT_48HR_DN, HELLER_HDAC_TARGETS_SILENCED_BY_METHYLATION_UP, RICKMAN_HEAD_AND_NECK_CANCER_A, JAATINEN_HEMATOPOIETIC_STEM_CELL_UP, HAN_SATB1_TARGETS_DN, GOBP_POSITIVE_REGULATION_OF_WNT_SIGNALING_PATHWAY, GOBP_NEGATIVE_REGULATION_OF_WNT_SIGNALING_PATHWAY

GO Biological Process (4): establishment or maintenance of cell polarity (GO:0007163), regulation of Wnt signaling pathway (GO:0030111), negative regulation of canonical Wnt signaling pathway (GO:0090090), positive regulation of Wnt signaling pathway, planar cell polarity pathway (GO:2000096)

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

GO Cellular Component (2): nucleus (GO:0005634), cytoplasm (GO:0005737)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular process	1
regulation of signal transduction	1
Wnt signaling pathway	1
negative regulation of Wnt signaling pathway	1
canonical Wnt signaling pathway	1
regulation of canonical Wnt signaling pathway	1
Wnt signaling pathway, planar cell polarity pathway	1
positive regulation of non-canonical Wnt signaling pathway	1
regulation of Wnt signaling pathway, planar cell polarity pathway	1
binding	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1252 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ANKRD6	AXIN1	O15169	991
ANKRD6	DVL1	O14640	973
ANKRD6	CSNK1E	P49674	850
ANKRD6	PRICKLE4	Q2TBC4	844
ANKRD6	PRICKLE2	Q7Z3G6	842
ANKRD6	PRICKLE3	O43900	841
ANKRD6	PRICKLE1	Q96MT3	831
ANKRD6	GSK3B	P49841	830
ANKRD6	VANGL2	Q9ULK5	754
ANKRD6	VANGL1	Q8TAA9	752
ANKRD6	AXIN2	Q9Y2T1	639
ANKRD6	CELSR1	Q9NYQ6	613
ANKRD6	ALB	P02768	565
ANKRD6	CTNNB1	P35222	530
ANKRD6	DVL2	O14641	497

IntAct

5 interactions, top by confidence:

A	B	Type	Score
csrp1a	ANKRD6	psi-mi:“MI:0915”(physical association)	0.400
ANKRD6	Smurf2	psi-mi:“MI:0915”(physical association)	0.400
WWOX	ANKRD6	psi-mi:“MI:0915”(physical association)	0.370
RAB5IF	ANKRD6	psi-mi:“MI:0915”(physical association)	0.000
RIPK4	ANKRD6	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (10): ANKRD6 (Affinity Capture-MS), AXIN2 (Affinity Capture-Western), GSK3B (Affinity Capture-Western), CSNK1E (Affinity Capture-Western), ANKRD6 (Affinity Capture-Western), ANKRD6 (Two-hybrid), ANKRD6 (Two-hybrid), SMC2 (Cross-Linking-MS (XL-MS)), ANKRD6 (Affinity Capture-MS), ANKRD6 (Affinity Capture-Luminescence)

ESM2 similar proteins: A0A0A6YYL3, A0JP26, A2A2Z9, A2RUR9, A6NC57, A6NI47, A6QR20, A8MYB1, A9JSR5, A9ZSY0, B2RU33, B7ZQJ9, F1M5M3, H3BUK9, O15050, P51954, P98182, Q19UN5, Q4UJ75, Q501X2, Q5CZ79, Q5DW34, Q5SQ80, Q5TYW2, Q5VUR7, Q66HB6, Q6NSI1, Q6S545, Q6S5H5, Q6S8J7, Q71S21, Q7TPV2, Q7TSC3, Q7ZT11, Q80X59, Q811D2, Q86Y13, Q86YR6, Q8IVF6, Q8IYA2

Diamond homologs: P81069, Q00420, Q06547, Q0V8G2, Q1RMI3, Q69ZU8, Q8TAK5, Q9Y2G4

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
ANKRD6	up-regulates	DVL2	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	126
Likely benign	10
Benign	12

Top pathogenic / likely-pathogenic (0)

SpliceAI

4399 predictions. Top by Δscore:

Variant	Effect	Δscore
6:89596015:G:GG	donor_gain	1.0000
6:89603016:T:TA	acceptor_gain	1.0000
6:89603020:A:AG	acceptor_gain	1.0000
6:89603021:C:G	acceptor_gain	1.0000
6:89603024:T:TA	acceptor_gain	1.0000
6:89603024:TGCA:T	acceptor_loss	1.0000
6:89603026:CA:C	acceptor_loss	1.0000
6:89603027:A:AG	acceptor_gain	1.0000
6:89603027:AG:A	acceptor_gain	1.0000
6:89603027:AGG:A	acceptor_gain	1.0000
6:89603027:AGGG:A	acceptor_gain	1.0000
6:89603027:AGGGG:A	acceptor_gain	1.0000
6:89603028:G:GT	acceptor_gain	1.0000
6:89603028:GG:G	acceptor_gain	1.0000
6:89603028:GGG:G	acceptor_gain	1.0000
6:89603028:GGGG:G	acceptor_gain	1.0000
6:89603028:GGGGG:G	acceptor_gain	1.0000
6:89603126:AGGTG:A	donor_loss	1.0000
6:89603127:GGTG:G	donor_loss	1.0000
6:89603128:G:GC	donor_loss	1.0000
6:89603128:G:GG	donor_gain	1.0000
6:89603129:T:A	donor_loss	1.0000
6:89623523:G:GT	donor_gain	1.0000
6:89623961:G:GT	donor_gain	1.0000
6:89623962:A:T	donor_gain	1.0000
6:89624533:TCTTA:T	acceptor_loss	1.0000
6:89624534:CTTA:C	acceptor_loss	1.0000
6:89624536:TAGGC:T	acceptor_loss	1.0000
6:89624537:A:AG	acceptor_gain	1.0000
6:89624537:AGGC:A	acceptor_loss	1.0000

AlphaMissense

4751 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:89567062:T:C	L29P	0.999
6:89606102:C:A	N138K	0.999
6:89606102:C:G	N138K	0.999
6:89567017:T:C	L14P	0.998
6:89595938:T:C	L48P	0.998
6:89595944:C:A	A50D	0.998
6:89595977:T:C	L61S	0.998
6:89603051:G:C	R81P	0.998
6:89603053:G:C	A82P	0.998
6:89612294:T:C	L147P	0.998
6:89617979:C:A	A247D	0.998
6:89595941:C:A	A49D	0.997
6:89595943:G:C	A50P	0.997
6:89596009:G:C	D72H	0.997
6:89603090:T:C	L94P	0.997
6:89606015:T:A	N109K	0.997
6:89606015:T:G	N109K	0.997
6:89606037:T:A	W117R	0.997
6:89606037:T:C	W117R	0.997
6:89606068:T:C	L127P	0.997
6:89606101:A:T	N138I	0.997
6:89612299:T:C	C149R	0.997
6:89612320:A:C	S156R	0.997
6:89612322:C:A	S156R	0.997
6:89612322:C:G	S156R	0.997
6:89613823:G:C	R183P	0.997
6:89617978:G:C	A247P	0.997
6:89618015:T:C	L259P	0.997
6:89624010:T:G	Y391D	0.997
6:89624019:T:G	Y394D	0.997

dbSNP variants (sampled 300 via entrez): RS1000005008 (6:89606412 G>C), RS1000013792 (6:89564067 G>A,T), RS1000025754 (6:89498620 G>A), RS1000042547 (6:89503732 A>G), RS1000045113 (6:89597282 C>T), RS1000064944 (6:89475775 C>T), RS1000072132 (6:89433454 G>C,T), RS1000085855 (6:89557637 G>A,C), RS1000087772 (6:89504211 G>A), RS1000090145 (6:89514024 T>C), RS1000099335 (6:89606948 T>C), RS1000102990 (6:89448737 T>C), RS1000126123 (6:89540509 A>G), RS1000129577 (6:89486324 A>G), RS1000137178 (6:89620816 A>G)

Disease associations

OMIM: gene MIM:610583 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST001188_4	vWF and FVIII levels	5.000000e-06
GCST002118_18	Metabolite levels (Pyroglutamine)	4.000000e-06
GCST002809_3	Bipolar disorder	5.000000e-06
GCST004881_3	Knee osteoarthritis	4.000000e-07
GCST005194_75	Coronary artery disease	4.000000e-06
GCST008155_24	Waist-hip ratio	9.000000e-06
GCST010866_116	Coronary artery disease	2.000000e-08

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0005408	pyroglutamine measurement
EFO:0004343	waist-hip ratio

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

26 total (human), top 26 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression, affects expression, increases expression	8
trichostatin A	decreases expression, increases expression, affects cotreatment	3
Benzo(a)pyrene	affects methylation, decreases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
aristolochic acid I	decreases expression	1
bisphenol F	affects cotreatment, decreases methylation	1
methylmercuric chloride	decreases expression	1
pyrimidin-2-one beta-ribofuranoside	decreases expression	1
sodium arsenite	affects cotreatment, increases abundance, increases expression	1
manganese chloride	affects cotreatment, increases abundance, increases expression	1
nickel sulfate	increases expression	1
entinostat	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
Sunitinib	decreases expression	1
Arsenic Trioxide	increases expression	1
Fulvestrant	affects cotreatment, decreases methylation	1
Arsenic	affects cotreatment, increases abundance, increases expression	1
Lead	decreases expression	1
Manganese	affects cotreatment, increases abundance, increases expression	1
Tobacco Smoke Pollution	decreases expression	1
Vanadates	decreases expression	1
Aflatoxin B1	increases methylation	1
tert-Butylhydroperoxide	increases expression	1
Permethrin	decreases expression	1

Clinical trials (associated diseases)

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