ANKRD2

Summary

ANKRD2 (ankyrin repeat domain 2, HGNC:495) is a protein-coding gene on chromosome 10q24.2, encoding Ankyrin repeat domain-containing protein 2 (Q9GZV1). Functions as a negative regulator of myocyte differentiation.

This gene encodes a protein that belongs to the muscle ankyrin repeat protein (MARP) family. A similar gene in rodents is a component of a muscle stress response pathway and plays a role in the stretch-response associated with slow muscle function. Alternative splicing results in multiple transcript variants encoding different isoforms.

Source: NCBI Gene 26287 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 65 total
• MANE Select transcript: NM_001346793

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:495
Approved symbol	ANKRD2
Name	ankyrin repeat domain 2
Location	10q24.2
Locus type	gene with protein product
Status	Approved
Aliases	ARPP
Ensembl gene	ENSG00000165887
Ensembl biotype	protein_coding
OMIM	610734
Entrez	26287

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 10 protein_coding

ENST00000298808, ENST00000307518, ENST00000370655, ENST00000455090, ENST00000909340, ENST00000909341, ENST00000960741, ENST00000960742, ENST00000960743, ENST00000960744

RefSeq mRNA: 5 — MANE Select: NM_001346793 NM_001129981, NM_001291218, NM_001291219, NM_001346793, NM_020349

CCDS: CCDS44468, CCDS7466, CCDS86133, CCDS86134

Canonical transcript exons

ENST00000370655 — 9 exons

Exon	Start	End
ENSE00001097704	97581316	97581414
ENSE00001097706	97583576	97583884
ENSE00001097707	97578498	97578605
ENSE00001097708	97578240	97578398
ENSE00001097709	97577800	97577901
ENSE00001097711	97582315	97582413
ENSE00001241719	97582604	97582702
ENSE00001241794	97580855	97580953
ENSE00001612561	97572779	97572875

Expression profiles

Bgee: expression breadth ubiquitous, 180 present calls, max score 99.46.

FANTOM5 (CAGE): breadth broad, TPM avg 5.3694 / max 5313.6281, expressed in 199 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
106442	4.9966	72
106439	0.2165	113
106440	0.1037	34
106441	0.0526	17

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
hindlimb stylopod muscle	UBERON:0004252	99.46	gold quality
diaphragm	UBERON:0001103	99.17	gold quality
apex of heart	UBERON:0002098	99.16	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	98.60	gold quality
gastrocnemius	UBERON:0001388	97.93	gold quality
heart left ventricle	UBERON:0002084	97.89	gold quality
cardiac ventricle	UBERON:0002082	97.72	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	97.53	gold quality
triceps brachii	UBERON:0001509	97.52	gold quality
skeletal muscle tissue	UBERON:0001134	97.46	gold quality
gluteal muscle	UBERON:0002000	97.44	gold quality
deltoid	UBERON:0001476	97.41	gold quality
biceps brachii	UBERON:0001507	97.19	gold quality
vastus lateralis	UBERON:0001379	97.07	gold quality
quadriceps femoris	UBERON:0001377	97.03	gold quality
tibialis anterior	UBERON:0001385	96.64	gold quality
muscle organ	UBERON:0001630	96.24	gold quality
skeletal muscle organ	UBERON:0014892	96.24	gold quality
muscle of leg	UBERON:0001383	95.86	gold quality
body of tongue	UBERON:0011876	94.52	gold quality
heart right ventricle	UBERON:0002080	91.81	gold quality
muscle tissue	UBERON:0002385	90.86	gold quality
tongue	UBERON:0001723	89.57	gold quality
heart	UBERON:0000948	88.85	gold quality
right atrium auricular region	UBERON:0006631	87.24	gold quality
cardiac atrium	UBERON:0002081	85.69	gold quality
superior surface of tongue	UBERON:0007371	85.04	gold quality
left ventricle myocardium	UBERON:0006566	84.57	gold quality
renal medulla	UBERON:0000362	84.13	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	82.62	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): AP1, KMT2A, MYOD1, NFKB, NKX2-5, SSRP1, TCF3, TP53

miRNA regulators (miRDB)

5 targeting ANKRD2, 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-548P	99.98	72.25	3784
HSA-MIR-4505	99.27	67.81	2678
HSA-MIR-5787	99.22	67.86	2628
HSA-MIR-5701	98.97	69.54	1502
HSA-MIR-4536-5P	98.47	64.39	657

Literature-anchored findings (GeneRIF, showing 12)

• These findings suggest that type-specific expression patterns of ARPP and CARP are altered in skeletal muscles of amyotrophic lateral sclerosis. (PMID:12679596)
• Ankrd2 may be involved in sensing stress signals and linking these to muscle gene regulation (PMID:15136035)
• The orthologs of ANKRD2 in mouse and rat, which are also titin binding proteins, are stretch-response genes associated with slow muscle function and these proteins are part of a separate mechanotransduction system to the one that regulates muscle mass. (PMID:15677738)
• Arpp is a novel skeletal muscle-specific marker, which is useful for differential diagnosis of rhabdomyosarcoma (PMID:16021567)
• ARPP was localized in mitochondria and nuclei in both the normal distal renal tubule and oncocytoma but not in chromophobe renal cell carcinomas. (PMID:17206105)
• Ankrd2 is a novel Akt2 specific substrate and regulates myogenic differentiation (PMID:21737686)
• Ankrd2 is a potent regulator in muscle cells affecting a multitude of pathways and processes (PMID:22016770)
• Although analyzed in a limited number of patients, there is a considerable body of evidence that MARP proteins could be suitable candidates for prognostic and diagnostic biomarkers. (PMID:22185618)
• Ankrd2 as a potent repressor of inflammatory responses through direct interaction with the NF-kappaB repressor subunit p50. (PMID:24434510)
• Report structure activity relationships for ANKRD2. (PMID:25125175)
• The Ankrd2 was found to be expressed in both the cytoplasm and nucleus, independently from maturation status of cardiomyocytes. (PMID:25585647)
• The results set the stage for investigation of the specific functions and interactions of the Ankrd2 isoforms in healthy and diseased human striated muscles. (PMID:27393496)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	ankrd2	ENSDARG00000002722
mus_musculus	Ankrd2	ENSMUSG00000025172
rattus_norvegicus	Ankrd2	ENSRNOG00000013840

Paralogs (1): ANKRD1 (ENSG00000148677)

Protein

Protein identifiers

Ankyrin repeat domain-containing protein 2 — Q9GZV1 (reviewed: Q9GZV1)

Alternative names: Skeletal muscle ankyrin repeat protein

All UniProt accessions (3): A0A0A0MRN9, Q9GZV1, Q5T457

UniProt curated annotations — full annotation on UniProt →

Function. Functions as a negative regulator of myocyte differentiation. May interact with both sarcoplasmic structural proteins and nuclear proteins to regulate gene expression during muscle development and in response to muscle stress.

Subunit / interactions. Interacts with ID3; both proteins cooperate in myoblast differentiation. Interacts with TTN/titin. Interacts (via ANK repeats) with TCAP; the interaction is direct. Interacts with TJP1 (via PDZ domains). Interacts with PML; the interaction is direct. Interacts with p53/TP53. Interacts with YBX1. Interacts with AKT2.

Subcellular location. Cytoplasm. Myofibril. Sarcomere. I band. Cytosol. Nucleus. PML body.

Tissue specificity. Mostly expressed in skeletal and cardiac muscles. Found in slow fibers. Also expressed in kidney, but to a lower extent (at protein level).

Post-translational modifications. Phosphorylation at Ser-99 by PKB/AKT2 in response to oxidative stress induces translocation to the nucleus and negatively regulates myoblast differentiation.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9GZV1-1	1	yes
Q9GZV1-2	2

RefSeq proteins (5): NP_001123453, NP_001278147, NP_001278148, NP_001333722, NP_065082 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002110	Ankyrin_rpt	Repeat
IPR036770	Ankyrin_rpt-contain_sf	Homologous_superfamily

Pfam: PF00023, PF12796

UniProt features (16 total): repeat 5, region of interest 3, compositionally biased region 2, chain 1, modified residue 1, splice variant 1, sequence variant 1, mutagenesis site 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9GZV1-F1	77.30	0.53

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 (1): 99

Mutagenesis-validated functional residues (1):

Position	Phenotype
99	loss of interaction and phosphorylation by pkb/akt2, loss of translocation to the nucleus and loss of function in myocyt

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 98 (showing top): MYOGENIN_Q6, MODULE_511, CHEN_LVAD_SUPPORT_OF_FAILING_HEART_UP, CCANNAGRKGGC_UNKNOWN, GOBP_REGULATION_OF_MYOBLAST_DIFFERENTIATION, GOBP_MUSCLE_STRUCTURE_DEVELOPMENT, MYOD_01, GOBP_MUSCLE_CONTRACTION, GOBP_NEGATIVE_REGULATION_OF_MYOBLAST_DIFFERENTIATION, GOBP_MYOBLAST_DIFFERENTIATION, MYOD_Q6, GOBP_NEGATIVE_REGULATION_OF_DEVELOPMENTAL_PROCESS, GOBP_MUSCLE_SYSTEM_PROCESS, GOMF_STRUCTURAL_CONSTITUENT_OF_MUSCLE, E12_Q6

GO Biological Process (6): negative regulation of transcription by RNA polymerase II (GO:0000122), regulation of transcription by RNA polymerase II (GO:0006357), muscle contraction (GO:0006936), muscle organ development (GO:0007517), negative regulation of myoblast differentiation (GO:0045662), regulation of gene expression (GO:0010468)

GO Molecular Function (4): structural constituent of muscle (GO:0008307), protein kinase B binding (GO:0043422), RNA polymerase II-specific DNA-binding transcription factor binding (GO:0061629), protein binding (GO:0005515)

GO Cellular Component (6): euchromatin (GO:0000791), nucleus (GO:0005634), cytosol (GO:0005829), PML body (GO:0016605), I band (GO:0031674), cytoplasm (GO:0005737)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
transcription by RNA polymerase II	2
regulation of transcription by RNA polymerase II	1
negative regulation of DNA-templated transcription	1
regulation of DNA-templated transcription	1
muscle system process	1
animal organ development	1
muscle structure development	1
myoblast differentiation	1
negative regulation of cell differentiation	1
regulation of myoblast differentiation	1
gene expression	1
regulation of macromolecule biosynthetic process	1
structural molecule activity	1
protein kinase binding	1
DNA-binding transcription factor binding	1
binding	1
chromatin	1
intracellular membrane-bounded organelle	1
cytoplasm	1
nuclear body	1
sarcomere	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

1630 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ANKRD2	TTN	Q8WZ42	952
ANKRD2	TCAP	O15273	908
ANKRD2	MYPN	Q86TC9	692
ANKRD2	YBX1	P16990	655
ANKRD2	CSRP3	P50461	636
ANKRD2	MYOZ2	Q9NPC6	617
ANKRD2	MYH3	P11055	605
ANKRD2	MYOD1	P15172	562
ANKRD2	MYH7	P12883	557
ANKRD2	LDB3	O75112	552
ANKRD2	TP53	P04637	522
ANKRD2	PRKD3	O94806	513
ANKRD2	PRKD2	Q9BZL6	500
ANKRD2	ACTA2	P03996	492
ANKRD2	CAPN3	P20807	491

IntAct

15 interactions, top by confidence:

A	B	Type	Score
MAPK6	ANKRD2	psi-mi:“MI:0915”(physical association)	0.560
	ANKRD2	psi-mi:“MI:0915”(physical association)	0.560
FCMR	ANKRD2	psi-mi:“MI:0915”(physical association)	0.370
ANKRD2	HBP1	psi-mi:“MI:0915”(physical association)	0.370
ANKRD2	ZBTB3	psi-mi:“MI:0915”(physical association)	0.370
MICB	TNFRSF10B	psi-mi:“MI:0914”(association)	0.350
ANKRD2	MAPK6	psi-mi:“MI:0915”(physical association)	0.000
ANKRD2		psi-mi:“MI:0915”(physical association)	0.000

BioGRID (19): ANKRD2 (Affinity Capture-Western), TCAP (Reconstituted Complex), ANKRD2 (Affinity Capture-Western), YBX1 (Reconstituted Complex), ANKRD2 (Affinity Capture-Western), ANKRD2 (Reconstituted Complex), ANKRD2 (Affinity Capture-Western), ANKRD2 (Reconstituted Complex), ANKRD2 (Affinity Capture-Western), LDB3 (Affinity Capture-Western), LDB3 (Far Western), ANKRD2 (Reconstituted Complex), ANKRD2 (Two-hybrid), HOMEZ (Two-hybrid), ANKRD2 (Affinity Capture-MS)

ESM2 similar proteins: A3KMV1, A8JAM0, B7PXE3, B9EHT4, B9FS74, F4HX15, F4IAE9, F5HB62, O46072, O70161, P0C5J9, P34442, P35228, P53904, Q257B3, Q3MHJ7, Q3V0G7, Q4FE47, Q5I6B8, Q5R686, Q5U243, Q5VVW2, Q63430, Q65XV2, Q66HD5, Q6NRL1, Q6P5D3, Q6P7W2, Q6TNT2, Q6YUL8, Q76K24, Q7JVP4, Q7XI08, Q8BFX3, Q8BTZ5, Q8BXK8, Q8CI96, Q8IY37, Q8N3C7, Q8TBC3

Diamond homologs: Q15327, Q3ZBX7, Q4KL97, Q5BKI6, Q7ZT11, Q812A3, Q865U8, Q86SG2, Q8R560, Q9CR42, Q9GZV1, Q9TU71, Q9WV06

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
AKT2	up-regulates	ANKRD2	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	54
Likely benign	2
Benign	3

Top pathogenic / likely-pathogenic (0)

SpliceAI

1501 predictions. Top by Δscore:

Variant	Effect	Δscore
10:97572861:G:GT	donor_gain	1.0000
10:97572864:G:GT	donor_gain	1.0000
10:97572867:GAGAA:G	donor_gain	1.0000
10:97577900:AG:A	donor_loss	1.0000
10:97577901:GGT:G	donor_loss	1.0000
10:97577902:G:C	donor_loss	1.0000
10:97577903:T:G	donor_loss	1.0000
10:97578393:G:GT	donor_gain	1.0000
10:97578395:GATC:G	donor_gain	1.0000
10:97578399:G:GG	donor_gain	1.0000
10:97580853:A:AG	acceptor_gain	1.0000
10:97580854:G:GA	acceptor_gain	1.0000
10:97580854:GTTCC:G	acceptor_gain	1.0000
10:97580951:CGGG:C	donor_loss	1.0000
10:97580952:GG:G	donor_gain	1.0000
10:97580953:GG:G	donor_gain	1.0000
10:97580954:G:A	donor_loss	1.0000
10:97580954:G:GG	donor_gain	1.0000
10:97580955:T:G	donor_loss	1.0000
10:97580956:G:GT	donor_loss	1.0000
10:97581408:GGA:G	donor_gain	1.0000
10:97582410:CAGGG:C	donor_loss	1.0000
10:97582411:AGGGT:A	donor_loss	1.0000
10:97582412:GG:G	donor_gain	1.0000
10:97582413:GG:G	donor_gain	1.0000
10:97582414:GTG:G	donor_loss	1.0000
10:97582415:TGAG:T	donor_loss	1.0000
10:97582416:GA:G	donor_loss	1.0000
10:97572874:AGG:A	donor_loss	0.9900
10:97572876:G:A	donor_loss	0.9900

AlphaMissense

2169 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
10:97580948:G:C	D211H	0.999
10:97580949:A:T	D211V	0.999
10:97578313:T:C	L115P	0.998
10:97578601:A:T	D178V	0.998
10:97580949:A:C	D211A	0.998
10:97581409:G:C	D244H	0.998
10:97581410:A:T	D244V	0.998
10:97578286:T:C	I106T	0.997
10:97578600:G:C	D178H	0.997
10:97578601:A:C	D178A	0.997
10:97580916:T:C	L200P	0.997
10:97580948:G:T	D211Y	0.997
10:97581343:T:C	C222R	0.997
10:97581345:C:G	C222W	0.997
10:97581410:A:C	D244A	0.997
10:97582409:A:T	D277V	0.997
10:97578274:T:C	L102P	0.996
10:97578286:T:G	I106S	0.996
10:97581344:G:A	C222Y	0.996
10:97581377:T:C	L233P	0.996
10:97581409:G:T	D244Y	0.996
10:97582340:C:A	A254E	0.996
10:97582628:G:C	A287P	0.996
10:97582665:T:C	L299P	0.996
10:97578600:G:T	D178Y	0.995
10:97580855:T:C	F180L	0.995
10:97580857:C:A	F180L	0.995
10:97580857:C:G	F180L	0.995
10:97580862:G:C	R182P	0.995
10:97580877:G:C	R187P	0.995

dbSNP variants (sampled 300 via entrez): RS1000304628 (10:97570965 C>T), RS1000362212 (10:97571155 C>T), RS1000422942 (10:97581263 C>A,G,T), RS1000838610 (10:97583872 C>T), RS1001387327 (10:97581250 G>A), RS1001839650 (10:97575356 C>A), RS1001930341 (10:97581694 G>A), RS1001932016 (10:97576168 G>A), RS1002281238 (10:97575754 A>G), RS1002426643 (10:97581363 G>A,T), RS1002767467 (10:97577038 C>G,T), RS1002862676 (10:97576807 G>C), RS1002977573 (10:97582780 AGCC>A), RS1003079447 (10:97570763 C>A), RS1003104547 (10:97579648 T>C)

Disease associations

OMIM: gene MIM:610734 | 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

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases expression	2
perfluorooctane sulfonic acid	decreases expression, increases expression	2
Estradiol	affects cotreatment, decreases expression, increases expression	2
Smoke	decreases expression	2
Aflatoxin B1	decreases expression, increases methylation	2
aristolochic acid I	increases expression	1
Esketamine	decreases expression	1
sotorasib	affects cotreatment, increases expression	1
testosterone enanthate	affects expression	1
methyleugenol	decreases expression	1
propionaldehyde	increases expression	1
bisphenol A	decreases methylation	1
lead acetate	decreases expression	1
sulforaphane	decreases expression	1
butyraldehyde	increases expression	1
aflatoxin B2	increases methylation	1
pentanal	increases expression	1
jinfukang	decreases expression	1
trametinib	affects cotreatment, increases expression	1
NVP-BKM120	affects cotreatment, increases expression	1
Arsenic Trioxide	decreases response to substance	1
Air Pollutants	decreases expression, increases abundance	1
Aldehydes	increases expression	1
Benzo(a)pyrene	decreases methylation	1
Cisplatin	decreases expression	1
Doxorubicin	decreases expression	1
Formaldehyde	decreases expression	1
Ivermectin	decreases expression	1
N-Nitrosopyrrolidine	decreases expression	1
Testosterone	increases expression	1

Clinical trials (associated diseases)

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