ANKRA2

Summary

ANKRA2 (ankyrin repeat family A member 2, HGNC:13208) is a protein-coding gene on chromosome 5q13.2, encoding Ankyrin repeat family A protein 2 (Q9H9E1). May regulate the interaction between the 3M complex and the histone deacetylases HDAC4 and HDAC5.

Enables enzyme binding activity and low-density lipoprotein particle receptor binding activity. Involved in regulation of protein-containing complex assembly. Located in 3M complex; cytosol; and membrane. Part of protein-containing complex.

Source: NCBI Gene 57763 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 43 total
• MANE Select transcript: NM_023039

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:13208
Approved symbol	ANKRA2
Name	ankyrin repeat family A member 2
Location	5q13.2
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000164331
Ensembl biotype	protein_coding
OMIM	605787
Entrez	57763

Gene structure

Transcript identifiers

Ensembl transcripts: 12 — 6 protein_coding, 6 retained_intron

ENST00000296785, ENST00000504641, ENST00000505301, ENST00000506130, ENST00000509433, ENST00000514916, ENST00000515249, ENST00000515804, ENST00000860773, ENST00000860774, ENST00000956658, ENST00000956659

RefSeq mRNA: 1 — MANE Select: NM_023039 NM_023039

CCDS: CCDS4020

Canonical transcript exons

ENST00000296785 — 9 exons

Exon	Start	End
ENSE00001083614	73552190	73552852
ENSE00001083615	73554861	73554986
ENSE00001083616	73555488	73555585
ENSE00001083618	73557575	73557640
ENSE00001383651	73565132	73565639
ENSE00003489264	73561130	73561288
ENSE00003562253	73562593	73562985
ENSE00003578376	73554322	73554388
ENSE00003638207	73553406	73553486

Expression profiles

Bgee: expression breadth ubiquitous, 284 present calls, max score 96.47.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 17.8783 / max 200.9506, expressed in 1796 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
62061	8.4783	1679
62059	6.0797	1743
62062	2.9783	1367
62060	0.3420	133

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
left ovary	UBERON:0002119	96.47	gold quality
right lung	UBERON:0002167	96.19	gold quality
right uterine tube	UBERON:0001302	95.92	gold quality
right ovary	UBERON:0002118	95.79	gold quality
endocervix	UBERON:0000458	95.57	gold quality
body of uterus	UBERON:0009853	95.13	gold quality
adrenal tissue	UBERON:0018303	95.12	gold quality
left lobe of thyroid gland	UBERON:0001120	94.97	gold quality
right lobe of thyroid gland	UBERON:0001119	94.48	gold quality
thyroid gland	UBERON:0002046	94.33	gold quality
rectum	UBERON:0001052	94.22	gold quality
ectocervix	UBERON:0012249	94.21	gold quality
tibial nerve	UBERON:0001323	94.04	gold quality
minor salivary gland	UBERON:0001830	94.01	gold quality
mucosa of stomach	UBERON:0001199	93.96	gold quality
body of pancreas	UBERON:0001150	93.70	gold quality
calcaneal tendon	UBERON:0003701	93.49	gold quality
secondary oocyte	CL:0000655	93.12	gold quality
descending thoracic aorta	UBERON:0002345	93.10	gold quality
ovary	UBERON:0000992	92.98	gold quality
epithelium of nasopharynx	UBERON:0001951	92.91	gold quality
nasopharynx	UBERON:0001728	92.89	gold quality
gall bladder	UBERON:0002110	92.88	gold quality
mucosa of paranasal sinus	UBERON:0005030	92.79	gold quality
skin of abdomen	UBERON:0001416	92.70	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	92.68	gold quality
muscle layer of sigmoid colon	UBERON:0035805	92.66	gold quality
small intestine Peyer’s patch	UBERON:0003454	92.60	gold quality
right adrenal gland cortex	UBERON:0035827	92.57	gold quality
mouth mucosa	UBERON:0003729	92.55	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): RFXANK

miRNA regulators (miRDB)

85 targeting ANKRA2, 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-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-12121	99.99	66.64	255
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-LET-7G-5P	99.98	72.37	1784
HSA-LET-7I-5P	99.98	72.37	1788
HSA-MIR-98-5P	99.98	72.33	1787
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-12136	99.98	72.81	5713
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

Literature-anchored findings (GeneRIF, showing 2)

• ANKRA, RFXANK, and CIITA are novel targets of class IIa HDACs which may deacetylases play a role in regulating MHCII expression (PMID:15964851)
• Structural basis for the recognition of RFX7 by ANKRA2 and RFXANK. (PMID:31864703)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	ankra2	ENSDARG00000035399
mus_musculus	Ankra2	ENSMUSG00000021661
rattus_norvegicus	Ankra2l1	ENSRNOG00000016622
rattus_norvegicus	Ankra2	ENSRNOG00000048118

Paralogs (3): RFXANK (ENSG00000064490), NFKBIZ (ENSG00000144802), NFKBID (ENSG00000167604)

Protein

Protein identifiers

Ankyrin repeat family A protein 2 — Q9H9E1 (reviewed: Q9H9E1)

Alternative names: RFXANK-like protein 2

All UniProt accessions (2): D6RBK8, Q9H9E1

UniProt curated annotations — full annotation on UniProt →

Function. May regulate the interaction between the 3M complex and the histone deacetylases HDAC4 and HDAC5. May also regulate LRP2/megalin.

Subunit / interactions. Interacts (via ANK repeats) with CCDC8 (via PxLPxI/L motif); mediates the interaction with the 3M complex which is composed of CCDC8, CUL7 and OBSL1. Interacts (via ANK repeats) with HDAC4 (via PxLPxI/L motif). Interacts (via ANK repeats) with HDAC5 (via PxLPxI/L motif). Interacts (via ANK repeats) with LRP2/megalin (via PxLPxI/L motif). Interacts (via ANK repeats) with RFX7 (via PxLPxI/L motif). Interacts with AHRR. Interacts with NEK6.

Subcellular location. Cytoplasm. Cytoskeleton. Membrane.

Domain organisation. The ankyrin repeats, mainly ANK 2, ANK 3 and ANK 4, mediate interaction with a wide array of PxLPxI/L motif-containing proteins including HDAC4 and LRP2. The PxLPxI/L motif of interactors can contain a Ser or a Thr residue in position 2, which phosphorylation prevents the interaction with ANKRA2.

RefSeq proteins (1): NP_075526* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002110	Ankyrin_rpt	Repeat
IPR036770	Ankyrin_rpt-contain_sf	Homologous_superfamily

Pfam: PF00023, PF12796

UniProt features (21 total): helix 12, repeat 5, mutagenesis site 3, chain 1

Structure

Experimental structures (PDB)

9 structures.

PDB	Method	Resolution (Å)
3V31	X-RAY DIFFRACTION	1.57
4LG6	X-RAY DIFFRACTION	1.8
3V2X	X-RAY DIFFRACTION	1.85
3V2O	X-RAY DIFFRACTION	1.89
3SO8	X-RAY DIFFRACTION	1.9
4QQI	X-RAY DIFFRACTION	2.03
8CXG	ELECTRON MICROSCOPY	3.2
8CXH	ELECTRON MICROSCOPY	3.2
8CXI	ELECTRON MICROSCOPY	3.4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9H9E1-F1	67.37	0.47

Antibody-complex structures (SAbDab): 3 — 8CXG, 8CXH, 8CXI

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
31	no effect on interaction with ccdc8.
188	loss of interaction with ccdc8. decreased affinity for hdac4.
254	decreased affinity for hdac4.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 150 (showing top): GSE45365_NK_CELL_VS_CD8_TCELL_UP, GCM_GSPT1, FISCHER_G1_S_CELL_CYCLE, GOBP_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, MODULE_239, GOBP_REGULATION_OF_PROTEIN_CONTAINING_COMPLEX_ASSEMBLY, GCM_NUMA1, TGTTTAC_MIR30A5P_MIR30C_MIR30D_MIR30B_MIR30E5P, FISCHER_DREAM_TARGETS, GCM_NF2, LIU_CMYB_TARGETS_UP, GOMF_SIGNALING_RECEPTOR_BINDING, LIU_VMYB_TARGETS_UP, EVI1_04, NUYTTEN_EZH2_TARGETS_DN

GO Biological Process (2): regulation of gene expression (GO:0010468), regulation of protein-containing complex assembly (GO:0043254)

GO Molecular Function (5): protein kinase binding (GO:0019901), ubiquitin protein ligase binding (GO:0031625), histone deacetylase binding (GO:0042826), low-density lipoprotein particle receptor binding (GO:0050750), protein binding (GO:0005515)

GO Cellular Component (7): nucleus (GO:0005634), cytosol (GO:0005829), cytoskeleton (GO:0005856), membrane (GO:0016020), protein-containing complex (GO:0032991), cytoplasm (GO:0005737), 3M complex (GO:1990393)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
gene expression	1
regulation of macromolecule biosynthetic process	1
regulation of cellular component biogenesis	1
regulation of cellular component organization	1
protein-containing complex assembly	1
kinase binding	1
ubiquitin-like protein ligase binding	1
enzyme binding	1
lipoprotein particle receptor binding	1
binding	1
intracellular membrane-bounded organelle	1
cytoplasm	1
intracellular membraneless organelle	1
cellular_component	1
intracellular anatomical structure	1
protein-containing complex	1

Protein interactions and networks

STRING

1588 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ANKRA2	LRP2	P98164	936
ANKRA2	HDAC4	P56524	893
ANKRA2	PRR19	A6NJB7	826
ANKRA2	AHRR	A9YTQ3	632
ANKRA2	CCDC8	Q9H0W5	627
ANKRA2	HDAC5	Q9UQL6	622
ANKRA2	D6RE68	D6RE68	611
ANKRA2	RFX5	P48382	585
ANKRA2	LRP2BP	Q9P2M1	532
ANKRA2	RFXAP	O00287	426
ANKRA2	ZNF697	Q5TEC3	420
ANKRA2	CD180	Q99467	414
ANKRA2	PPP1R26	Q5T8A7	396
ANKRA2	ZNF337	Q9Y3M9	391
ANKRA2	UTP15	Q8TED0	375

IntAct

26 interactions, top by confidence:

A	B	Type	Score
RFX5	RFXAP	psi-mi:“MI:0914”(association)	0.880
ANKRA2	CCDC8	psi-mi:“MI:0915”(physical association)	0.640
CCDC8	ANKRA2	psi-mi:“MI:0407”(direct interaction)	0.640
ANKRA2	RFX7	psi-mi:“MI:0407”(direct interaction)	0.590
ANKRA2	HDAC5	psi-mi:“MI:0407”(direct interaction)	0.590
ANKRA2	HDAC4	psi-mi:“MI:0915”(physical association)	0.560
TSHZ3	ANKRA2	psi-mi:“MI:0915”(physical association)	0.560
ANKRA2	SAMD4A	psi-mi:“MI:0915”(physical association)	0.560
ZNF362	ANKRA2	psi-mi:“MI:0407”(direct interaction)	0.440
ANKRA2	C16orf46	psi-mi:“MI:0407”(direct interaction)	0.440
ANKRA2	RINL	psi-mi:“MI:0407”(direct interaction)	0.440
ANKRA2	RTL9	psi-mi:“MI:0407”(direct interaction)	0.440
ANKRA2	HDAC9	psi-mi:“MI:0407”(direct interaction)	0.440
CDKN2A	ANKRA2	psi-mi:“MI:0915”(physical association)	0.370
KSR1	FAM168B	psi-mi:“MI:0914”(association)	0.350
ANKRA2	RFXAP	psi-mi:“MI:0914”(association)	0.350
SLC16A11	ESYT2	psi-mi:“MI:0914”(association)	0.350
TSHZ3	ANKRA2	psi-mi:“MI:0915”(physical association)	0.000
SAMD4A	ANKRA2	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (55): ANKRA2 (Two-hybrid), ANKRA2 (Affinity Capture-Western), CCDC8 (Affinity Capture-MS), RFX7 (Affinity Capture-MS), HUWE1 (Affinity Capture-MS), RFX5 (Affinity Capture-MS), ZNF462 (Affinity Capture-MS), CUL7 (Affinity Capture-MS), LMNB2 (Affinity Capture-MS), TRIM28 (Affinity Capture-MS), SOGA1 (Affinity Capture-MS), CCAR2 (Affinity Capture-MS), OBSL1 (Affinity Capture-MS), LMNA (Affinity Capture-MS), CDK4 (Affinity Capture-MS)

ESM2 similar proteins: A1A4L6, A1YG61, A2T737, O70273, O75747, P01105, P10157, P11308, P13474, P14921, P15036, P15037, P15062, P18755, P19102, P27577, P41156, P41157, P41212, P57782, P81270, P97360, Q08AW4, Q15052, Q32LN0, Q3SZL0, Q3US16, Q58DT0, Q60641, Q6GPJ8, Q6P3D7, Q7ZYI3, Q8BZ05, Q8C7R7, Q8HWS3, Q8N8B7, Q8NDB2, Q8VDK3, Q90837, Q90VY2

Diamond homologs: B4E2M5, O14593, Q09701, Q18297, Q2KI79, Q495M9, Q4R7L8, Q5RD76, Q6RI86, Q80T11, Q99PE2, Q9BQG2, Q9DCN1, Q9H9E1, Q9Z205, Q9Z2X2, Q9Z2X3, A0A509AIU5, A2VDR2, A7J1T2, F4JTP5, O08648, O22558, O55222, P18161, P35916, P54644, P57044, Q12852, Q13418, Q3SWY2, Q54TA1, Q55E58, Q55GU0, Q5R5V4, Q60700, Q63796, Q66JD7, Q8RWL6, Q93Z30

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	38
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1490 predictions. Top by Δscore:

Variant	Effect	Δscore
5:73554384:CCATT:C	acceptor_gain	1.0000
5:73554385:CATT:C	acceptor_gain	1.0000
5:73554385:CATTC:C	acceptor_gain	1.0000
5:73554386:ATTCT:A	acceptor_loss	1.0000
5:73554387:TT:T	acceptor_gain	1.0000
5:73554388:TCT:T	acceptor_loss	1.0000
5:73554389:C:CC	acceptor_gain	1.0000
5:73554390:T:A	acceptor_loss	1.0000
5:73554855:ACTT:A	donor_loss	1.0000
5:73554856:CTTA:C	donor_loss	1.0000
5:73554857:TTACC:T	donor_loss	1.0000
5:73554858:T:TG	donor_loss	1.0000
5:73554859:A:AC	donor_gain	1.0000
5:73554859:A:C	donor_loss	1.0000
5:73554859:AC:A	donor_gain	1.0000
5:73554860:C:CA	donor_loss	1.0000
5:73554860:C:CC	donor_gain	1.0000
5:73554860:CC:C	donor_gain	1.0000
5:73554985:CC:C	acceptor_gain	1.0000
5:73554986:CC:C	acceptor_gain	1.0000
5:73554992:A:C	acceptor_gain	1.0000
5:73555487:CATT:C	donor_gain	1.0000
5:73557636:CAAAG:C	acceptor_gain	1.0000
5:73557641:C:CC	acceptor_gain	1.0000
5:73561128:A:AC	donor_gain	1.0000
5:73561129:C:CC	donor_gain	1.0000
5:73561129:CA:C	donor_gain	1.0000
5:73561129:CAA:C	donor_gain	1.0000
5:73561129:CAAT:C	donor_gain	1.0000
5:73561285:TCAG:T	acceptor_gain	1.0000

AlphaMissense

2047 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:73554327:A:G	L267P	1.000
5:73554898:A:G	L234P	1.000
5:73555495:A:G	L202P	1.000
5:73555498:A:G	L201P	1.000
5:73557619:G:T	A157D	1.000
5:73553432:A:G	L287P	0.999
5:73554327:A:C	L267R	0.999
5:73554327:A:T	L267H	0.999
5:73554363:G:T	A255D	0.999
5:73554364:C:G	A255P	0.999
5:73554372:A:G	L252P	0.999
5:73554865:T:A	D245V	0.999
5:73554895:A:G	L235P	0.999
5:73554907:A:T	V231D	0.999
5:73554922:C:A	G226V	0.999
5:73554930:A:C	C223W	0.999
5:73554931:C:T	C223Y	0.999
5:73554932:A:G	C223R	0.999
5:73554934:G:T	A222D	0.999
5:73555498:A:C	L201R	0.999
5:73555498:A:T	L201Q	0.999
5:73555522:C:A	G193V	0.999
5:73555523:C:A	G193W	0.999
5:73555531:G:T	A190E	0.999
5:73555532:C:G	A190P	0.999
5:73555534:G:T	A189D	0.999
5:73555535:C:G	A189P	0.999
5:73555538:A:G	W188R	0.999
5:73555538:A:T	W188R	0.999
5:73555543:A:G	L186P	0.999

dbSNP variants (sampled 300 via entrez): RS1000120750 (5:73564025 T>G), RS1000309739 (5:73555995 G>A), RS1000316267 (5:73565931 C>G,T), RS1000329196 (5:73566316 C>T), RS1000456824 (5:73563693 C>T), RS1000657839 (5:73564881 G>A,T), RS1000721020 (5:73565395 G>A), RS1000821748 (5:73558238 C>A), RS1000880225 (5:73559749 G>T), RS1000988992 (5:73562529 G>T), RS1001294995 (5:73559935 AT>A,ATT), RS1001413388 (5:73565696 C>G), RS1001466679 (5:73565798 T>C,G), RS1001644688 (5:73559646 CTATT>C), RS1001786756 (5:73565495 C>G)

Disease associations

OMIM: gene MIM:605787 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST003477_7	Monobrow thickness	4.000000e-07

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases expression, affects expression, affects cotreatment	5
Aflatoxin B1	increases expression, affects expression, decreases methylation	5
Benzo(a)pyrene	increases expression	4
Air Pollutants	decreases expression, increases abundance, increases expression	3
Cisplatin	affects cotreatment, increases expression, decreases expression	2
Hydrogen Peroxide	affects expression, increases expression	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	increases expression	2
Cadmium Chloride	decreases expression	2
Particulate Matter	increases abundance, increases expression, decreases expression	2
dicrotophos	decreases expression	1
chloroacetaldehyde	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
sodium arsenite	increases expression	1
potassium chromate(VI)	decreases expression	1
beta-methylcholine	affects expression	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	increases expression	1
CGP 52608	increases reaction, affects binding	1
K 7174	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
nutlin 3	affects cotreatment, increases expression	1
ICG 001	increases expression	1
abrine	increases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine	increases expression, increases response to substance	1
jinfukang	affects cotreatment, increases expression	1
Zoledronic Acid	increases expression	1
Cidofovir	decreases expression	1
Camptothecin	increases expression	1
Dactinomycin	affects cotreatment, increases expression	1

Clinical trials (associated diseases)

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