ANKRD9

Summary

ANKRD9 (ankyrin repeat domain 9, HGNC:20096) is a protein-coding gene on chromosome 14q32.31, encoding Ankyrin repeat domain-containing protein 9 (Q96BM1). Substrate receptor subunit of a cullin-RING superfamily E3 ligase complex (CUL5-based E3 ubiquitin ligase complex) which mediates the ubiquitination and subsequent proteasomal degradation of target proteins.

Enables ubiquitin-like ligase-substrate adaptor activity. Involved in intracellular copper ion homeostasis; proteasome-mediated ubiquitin-dependent protein catabolic process; and protein ubiquitination. Located in cytoplasmic vesicle and cytosol. Part of Cul5-RING ubiquitin ligase complex.

Source: NCBI Gene 122416 — RefSeq curated summary.

At a glance

• GWAS associations: 4
• Clinical variants (ClinVar): 70 total
• MANE Select transcript: NM_152326

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:20096
Approved symbol	ANKRD9
Name	ankyrin repeat domain 9
Location	14q32.31
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000156381
Ensembl biotype	protein_coding
OMIM	618605
Entrez	122416

Gene structure

Transcript identifiers

Ensembl transcripts: 26 — 26 protein_coding

ENST00000286918, ENST00000557902, ENST00000559404, ENST00000559651, ENST00000560748, ENST00000879305, ENST00000879306, ENST00000879307, ENST00000879308, ENST00000879309, ENST00000879310, ENST00000879311, ENST00000879312, ENST00000940708, ENST00000940709, ENST00000955312, ENST00000955313, ENST00000955314, ENST00000955315, ENST00000955316, ENST00000955317, ENST00000955318, ENST00000955319, ENST00000955320, ENST00000955321, ENST00000955322

RefSeq mRNA: 3 — MANE Select: NM_152326 NM_001348651, NM_001348652, NM_152326

CCDS: CCDS9973

Canonical transcript exons

ENST00000286918 — 4 exons

Exon	Start	End
ENSE00001223972	102508641	102508846
ENSE00001513061	102508475	102508549
ENSE00001513062	102509529	102509776
ENSE00003720155	102501767	102507942

Expression profiles

Bgee: expression breadth ubiquitous, 256 present calls, max score 98.85.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 6.4336 / max 104.9816, expressed in 1637 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
145042	2.8499	1230
145043	2.3919	1344
145044	0.5864	334
145040	0.4518	230
145041	0.1535	65

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
pancreatic ductal cell	CL:0002079	98.85	gold quality
vastus lateralis	UBERON:0001379	98.54	gold quality
quadriceps femoris	UBERON:0001377	98.47	gold quality
left ventricle myocardium	UBERON:0006566	98.44	gold quality
apex of heart	UBERON:0002098	98.26	gold quality
jejunal mucosa	UBERON:0000399	98.14	gold quality
body of tongue	UBERON:0011876	98.13	gold quality
sperm	CL:0000019	97.96	gold quality
heart right ventricle	UBERON:0002080	97.96	gold quality
jejunum	UBERON:0002115	97.78	gold quality
biceps brachii	UBERON:0001507	97.55	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	97.48	gold quality
ileal mucosa	UBERON:0000331	97.40	gold quality
hindlimb stylopod muscle	UBERON:0004252	97.32	gold quality
myocardium	UBERON:0002349	97.23	gold quality
tibialis anterior	UBERON:0001385	97.13	gold quality
cardiac muscle of right atrium	UBERON:0003379	96.67	gold quality
lateral nuclear group of thalamus	UBERON:0002736	96.64	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	96.45	gold quality
cardiac ventricle	UBERON:0002082	95.79	gold quality
skeletal muscle tissue	UBERON:0001134	95.73	gold quality
gastrocnemius	UBERON:0001388	95.72	gold quality
heart left ventricle	UBERON:0002084	95.71	gold quality
trabecular bone tissue	UBERON:0002483	95.05	gold quality
skeletal muscle organ	UBERON:0014892	95.00	gold quality
cardiac atrium	UBERON:0002081	94.75	gold quality
deltoid	UBERON:0001476	94.74	gold quality
parotid gland	UBERON:0001831	94.64	gold quality
right atrium auricular region	UBERON:0006631	94.57	gold quality
muscle of leg	UBERON:0001383	94.42	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-HCAD-9	yes	5.32
E-ANND-3	yes	4.85

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 2)

• show that ANKRD9 is genetically and functionally associated with tumor suppression by acting as a substrate receptor subunit of a CUL5-based E3 ubiquitin ligase that ubiquitinates substrate proteins as IMPDH2 and presumably IMPDH1, marking them for proteasomal degradation and turnover. Furthermore, ANKRD9 accomplishes its anti-proliferative and tumor-suppressive function via IMPDH2 degradation. (PMID:30293565)
• ANKRD9 regulates IMPDH2 abundance and macro-assembly in response to metabolic changes. (PMID:31337707)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	ankrd9	ENSDARG00000028804
mus_musculus	Ankrd9	ENSMUSG00000037904
rattus_norvegicus	Ankrd9	ENSRNOG00000072270

Protein

Protein identifiers

Ankyrin repeat domain-containing protein 9 — Q96BM1 (reviewed: Q96BM1)

All UniProt accessions (3): Q96BM1, H0YM08, H0YNN1

UniProt curated annotations — full annotation on UniProt →

Function. Substrate receptor subunit of a cullin-RING superfamily E3 ligase complex (CUL5-based E3 ubiquitin ligase complex) which mediates the ubiquitination and subsequent proteasomal degradation of target proteins. Depending of the metabolic state of the cell, promotes the proteasomal degradation of IMPDH2, the rate-limiting enzyme in GTP biosynthesis or protects IMPDH2 by stabilizing IMPDH2 filaments assembly. Implicated in different cellular processes, like copper homeostasis and cell proliferation.

Subunit / interactions. Part of an E3 ubiquitin-protein ligase complex with Elongin BC (ELOB and ELOC), CUL5 and ANKRD9. Interacts with IMPDH2; leading to ubiquitination of IMPDH2 and its subsequent proteasomal degradation.

Subcellular location. Cytoplasmic vesicle. Cytoplasm. Cytosol.

Pathway. Protein modification; protein ubiquitination.

RefSeq proteins (3): NP_001335580, NP_001335581, NP_689539* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002110	Ankyrin_rpt	Repeat
IPR036770	Ankyrin_rpt-contain_sf	Homologous_superfamily
IPR052391	E3_Ligase-Neurotoxin	Family

UniProt features (9 total): repeat 3, mutagenesis site 3, chain 1, region of interest 1, short sequence motif 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96BM1-F1	82.45	0.43

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 (3):

Position	Phenotype
109	inhibits the vesicle-to-rods transition under nutrient-limiting conditions. inhibits the vesicle-to-rods transition unde
110	inhibits the vesicle-to-rods transition under nutrient-limiting conditions. inhibits the vesicle-to-rods transition unde
125	loss the vesicle-like pattern and becomes diffuse in the cytosol.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-8951664	Neddylation
R-HSA-392499	Metabolism of proteins
R-HSA-597592	Post-translational protein modification

MSigDB gene sets: 88 (showing top): GOBP_MACROMOLECULE_CATABOLIC_PROCESS, IVANOVA_HEMATOPOIESIS_MATURE_CELL, RICKMAN_TUMOR_DIFFERENTIATED_WELL_VS_POORLY_DN, GOBP_POST_TRANSLATIONAL_PROTEIN_MODIFICATION, NAKAMURA_TUMOR_ZONE_PERIPHERAL_VS_CENTRAL_DN, GOBP_MONOATOMIC_ION_HOMEOSTASIS, GOBP_COPPER_ION_HOMEOSTASIS, GOBP_PROTEASOMAL_PROTEIN_CATABOLIC_PROCESS, chr14q32, GOBP_PROTEIN_CATABOLIC_PROCESS, SENESE_HDAC3_TARGETS_DN, GOCC_TRANSFERASE_COMPLEX, GOBP_HOMEOSTATIC_PROCESS, GOBP_CHEMICAL_HOMEOSTASIS, GOBP_PROTEOLYSIS

GO Biological Process (3): intracellular copper ion homeostasis (GO:0006878), protein ubiquitination (GO:0016567), proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161)

GO Molecular Function (2): ubiquitin-like ligase-substrate adaptor activity (GO:1990756), protein binding (GO:0005515)

GO Cellular Component (4): cytosol (GO:0005829), cytoplasmic vesicle (GO:0031410), Cul5-RING ubiquitin ligase complex (GO:0031466), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Post-translational protein modification	1
Metabolism of proteins	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cytoplasm	2
cellular anatomical structure	2
intracellular monoatomic cation homeostasis	1
copper ion homeostasis	1
protein modification by small protein conjugation	1
ubiquitin-dependent protein catabolic process	1
proteasomal protein catabolic process	1
enzyme-substrate adaptor activity	1
binding	1
intracellular vesicle	1
cullin-RING ubiquitin ligase complex	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

1148 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ANKRD9	ASB11	Q8WXH4	650
ANKRD9	ASB14	A6NK59	641
ANKRD9	IMPDH2	P12268	589
ANKRD9	IQCF1	Q8N6M8	572
ANKRD9	KLHL21	Q9UJP4	560
ANKRD9	ZNF706	Q9Y5V0	549
ANKRD9	B7Z1P2	B7Z1P2	532
ANKRD9	ASB10	Q8WXI3	519
ANKRD9	DNAJC17	Q9NVM6	495
ANKRD9	CCDC181	Q5TID7	490
ANKRD9	KCTD9	Q7L273	482
ANKRD9	RUNDC3A	Q59EK9	480
ANKRD9	TRIM63	Q969Q1	473
ANKRD9	IBTK	Q9P2D0	450
ANKRD9	FBXO32	Q969P5	435

IntAct

12 interactions, top by confidence:

A	B	Type	Score
IMPDH1	BCAT2	psi-mi:“MI:0914”(association)	0.530
IMPDH2	IMPDH1	psi-mi:“MI:0914”(association)	0.530
IMPDH1	LCMT2	psi-mi:“MI:0914”(association)	0.350
IMPDH2	IMPDH1	psi-mi:“MI:0914”(association)	0.350
ANKRD9	TIMM8A	psi-mi:“MI:0914”(association)	0.350
CES2	SERPINF2	psi-mi:“MI:0914”(association)	0.350
IMPDH1	MGST3	psi-mi:“MI:0914”(association)	0.350
ANKRD9	UBB	psi-mi:“MI:0914”(association)	0.350
AMY2A	GYS1	psi-mi:“MI:0914”(association)	0.350

BioGRID (45): ANKRD9 (Affinity Capture-MS), ANKRD9 (Affinity Capture-MS), ANKRD9 (Affinity Capture-MS), TCEB2 (Affinity Capture-MS), TCEB1 (Affinity Capture-MS), IMPDH1 (Affinity Capture-MS), IMPDH2 (Affinity Capture-MS), TCEB2 (Affinity Capture-Western), TCEB1 (Affinity Capture-Western), IMPDH1 (Affinity Capture-Western), IMPDH2 (Affinity Capture-Western), CUL5 (Affinity Capture-Western), TCEB2 (Co-purification), TCEB1 (Co-purification), CUL5 (Co-purification)

ESM2 similar proteins: A0PJX8, A4IFG4, A5D7M7, A6NKF7, A7MBM2, E9PY61, J3QMI4, L5KLU7, O70491, Q03395, Q08E36, Q0V8E7, Q0VD38, Q1KZG0, Q2KJ98, Q3SWY4, Q3TYP4, Q49LS1, Q4QR83, Q53RY4, Q5GH56, Q5GH64, Q5GH72, Q5R7B4, Q5T1A1, Q5XK03, Q66K66, Q674R7, Q6EBV9, Q6GQT5, Q6P5W5, Q6PEY1, Q6PRD1, Q80WF4, Q80ZU9, Q86XJ0, Q8BG75, Q8K177, Q8N144, Q8N4L1

Diamond homologs: A0A072VIM5, A0A0K0PU92, A2CIR7, B9DHT4, C9JJ37, E7BQV0, G3LSH3, G8GTN7, Q05823, Q0JJ01, Q2HW56, Q2QXZ2, Q2RAQ5, Q5D0W8, Q5ICL9, Q5XIU1, Q75HA6, Q8L746, Q96BM1, Q96DX5, Q99LJ2, Q9FDY4, Q9M1I7, Q9SZI3, Q9ZVC2, S4VGD0, Q8BH83, Q9CQM6, A6QPA3

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	67
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

765 predictions. Top by Δscore:

Variant	Effect	Δscore
14:102507938:CACAC:C	acceptor_gain	1.0000
14:102507939:ACAC:A	acceptor_gain	1.0000
14:102507940:CAC:C	acceptor_gain	1.0000
14:102507940:CACC:C	acceptor_gain	1.0000
14:102507941:AC:A	acceptor_gain	1.0000
14:102507941:ACCTG:A	acceptor_loss	1.0000
14:102507942:CC:C	acceptor_gain	1.0000
14:102507943:C:CC	acceptor_gain	1.0000
14:102507943:CTGCG:C	acceptor_loss	1.0000
14:102507944:T:C	acceptor_loss	1.0000
14:102507946:C:CT	acceptor_gain	0.9900
14:102508470:CCTA:C	donor_loss	0.9900
14:102508471:CTA:C	donor_loss	0.9900
14:102508472:TA:T	donor_loss	0.9900
14:102508473:A:C	donor_loss	0.9900
14:102508474:C:CT	donor_loss	0.9900
14:102509524:CTCA:C	donor_loss	0.9900
14:102509525:TCA:T	donor_loss	0.9900
14:102509526:CA:C	donor_loss	0.9900
14:102509528:C:CT	donor_loss	0.9900
14:102507947:G:T	acceptor_gain	0.9800
14:102508550:C:CC	acceptor_gain	0.9800
14:102509522:GACT:G	donor_loss	0.9800
14:102509523:ACT:A	donor_loss	0.9800
14:102508473:A:AC	donor_gain	0.9700
14:102508474:C:CC	donor_gain	0.9700
14:102508547:TATC:T	acceptor_loss	0.9700
14:102508548:ATCTG:A	acceptor_loss	0.9700
14:102508549:TCT:T	acceptor_loss	0.9700
14:102508550:CTGT:C	acceptor_loss	0.9700

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000045356 (14:102508643 G>GT), RS1000084441 (14:102503433 G>A), RS1000199947 (14:102511028 T>G), RS1000266126 (14:102506138 C>T), RS1000428938 (14:102511676 C>T), RS1000649653 (14:102507226 C>A,G), RS1001144514 (14:102504346 G>A,C), RS1001296172 (14:102504885 A>G), RS1001311607 (14:102502829 G>A), RS1001417919 (14:102510516 C>G,T), RS1001433132 (14:102510237 C>A,G), RS1001492688 (14:102504612 G>A), RS1002314824 (14:102504116 G>A,C), RS1002471389 (14:102511639 T>A), RS1002929957 (14:102501914 T>A,C)

Disease associations

OMIM: gene MIM:618605 | disease phenotypes: MIM:615031

GenCC curated gene-disease

Mondo (1): hereditary spastic paraplegia 49 (MONDO:0014016)

Orphanet (1): Hereditary sensory and autonomic neuropathy due to TECPR2 mutation (Orphanet:320385)

HPO phenotypes

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

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST002500_73	QT interval	4.000000e-11
GCST005951_8	Body mass index	7.000000e-09
GCST008839_89	Height	2.000000e-11
GCST010002_161	Refractive error	1.000000e-20

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004682	QT interval
EFO:0004340	body mass index

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

29 total (human), top 29 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Valproic Acid	increases methylation, affects expression	2
aristolochic acid I	increases expression	1
dicrotophos	decreases expression	1
bisphenol A	increases expression	1
beta-lapachone	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
ICG 001	increases expression	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
Bortezomib	increases expression	1
Temozolomide	decreases expression	1
Sunitinib	increases expression	1
Leflunomide	increases expression	1
Benzo(a)pyrene	affects methylation	1
Cadmium	increases abundance, increases expression	1
Cisplatin	increases expression	1
Citrulline	decreases expression	1
Doxorubicin	decreases expression	1
Methyl Methanesulfonate	increases expression	1
Oxygen	decreases expression	1
Smoke	decreases expression	1
Thimerosal	decreases expression	1
Tobacco Smoke Pollution	increases expression	1
1-Methyl-4-phenylpyridinium	increases expression	1
Cyclosporine	decreases expression	1
Cadmium Chloride	increases abundance, increases expression	1
Palmitic Acid	decreases expression	1
Copper Sulfate	decreases expression	1

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_E1QG	HAP1 ANKRD9 (-) 1	Cancer cell line	Male
CVCL_E1QH	HAP1 ANKRD9 (-) 2	Cancer cell line	Male
CVCL_E1QI	HAP1 ANKRD9 (-) 3	Cancer cell line	Male

Clinical trials (associated diseases)

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