ANKS3

Summary

ANKS3 (ankyrin repeat and sterile alpha motif domain containing 3, HGNC:29422) is a protein-coding gene on chromosome 16p13.3, encoding Ankyrin repeat and SAM domain-containing protein 3 (Q6ZW76). May be involved in vasopressin signaling in the kidney.

Predicted to be located in cytoplasm. Predicted to be active in cilium.

Source: NCBI Gene 124401 — RefSeq curated summary.

At a glance

• Gene–disease (curated): situs inversus (Supportive, GenCC) — +1 more curated relationship
• GWAS associations: 1
• Clinical variants (ClinVar): 202 total — 1 pathogenic
• MANE Select transcript: NM_133450

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:29422
Approved symbol	ANKS3
Name	ankyrin repeat and sterile alpha motif domain containing 3
Location	16p13.3
Locus type	gene with protein product
Status	Approved
Aliases	KIAA1977, FLJ32345, FLJ32767
Ensembl gene	ENSG00000168096
Ensembl biotype	protein_coding
OMIM	617310
Entrez	124401

Gene structure

Transcript identifiers

Ensembl transcripts: 35 — 18 protein_coding, 9 retained_intron, 7 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000304283, ENST00000450067, ENST00000585773, ENST00000586159, ENST00000586166, ENST00000586605, ENST00000586632, ENST00000587005, ENST00000588398, ENST00000588513, ENST00000589035, ENST00000589065, ENST00000590147, ENST00000590193, ENST00000590689, ENST00000590730, ENST00000590803, ENST00000591185, ENST00000591281, ENST00000591653, ENST00000592068, ENST00000592077, ENST00000592190, ENST00000592421, ENST00000592698, ENST00000592711, ENST00000592840, ENST00000593120, ENST00000614075, ENST00000875662, ENST00000875663, ENST00000875664, ENST00000925898, ENST00000942653, ENST00000942654

RefSeq mRNA: 5 — MANE Select: NM_133450 NM_001242929, NM_001308089, NM_001324129, NM_001324130, NM_133450

CCDS: CCDS10520, CCDS73820

Canonical transcript exons

ENST00000304283 — 18 exons

Exon	Start	End
ENSE00001525996	4731512	4731579
ENSE00001525997	4733938	4734271
ENSE00003483278	4698427	4698599
ENSE00003498941	4698800	4698941
ENSE00003519903	4701434	4701543
ENSE00003522219	4705095	4705253
ENSE00003535498	4702102	4702242
ENSE00003552912	4697017	4697104
ENSE00003554433	4729980	4730151
ENSE00003586210	4726979	4727177
ENSE00003661744	4714051	4714186
ENSE00003673492	4697333	4697416
ENSE00003675082	4699052	4699176
ENSE00003678588	4697977	4698062
ENSE00003680271	4724750	4724831
ENSE00003790002	4700970	4701134
ENSE00003790790	4726659	4726780
ENSE00003892505	4696511	4696896

Expression profiles

Bgee: expression breadth ubiquitous, 195 present calls, max score 92.45.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 2.4818 / max 36.6681, expressed in 1350 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
156114	2.4818	1350

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cerebellar hemisphere	UBERON:0002245	92.45	gold quality
right hemisphere of cerebellum	UBERON:0014890	92.36	gold quality
cerebellar cortex	UBERON:0002129	92.27	gold quality
adenohypophysis	UBERON:0002196	92.16	gold quality
right uterine tube	UBERON:0001302	91.40	gold quality
pituitary gland	UBERON:0000007	91.19	gold quality
cerebellum	UBERON:0002037	91.07	gold quality
right ovary	UBERON:0002118	90.22	gold quality
left ovary	UBERON:0002119	90.06	gold quality
right frontal lobe	UBERON:0002810	89.97	gold quality
sural nerve	UBERON:0015488	89.58	gold quality
metanephros cortex	UBERON:0010533	89.31	gold quality
hypothalamus	UBERON:0001898	89.25	gold quality
pancreatic ductal cell	CL:0002079	89.19	silver quality
apex of heart	UBERON:0002098	89.14	gold quality
body of uterus	UBERON:0009853	88.96	gold quality
endocervix	UBERON:0000458	88.95	gold quality
right lobe of thyroid gland	UBERON:0001119	88.94	gold quality
muscle layer of sigmoid colon	UBERON:0035805	88.94	gold quality
Brodmann (1909) area 9	UBERON:0013540	88.93	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	88.89	gold quality
lower esophagus mucosa	UBERON:0035834	88.82	gold quality
anterior cingulate cortex	UBERON:0009835	88.63	gold quality
ascending aorta	UBERON:0001496	88.46	gold quality
thoracic aorta	UBERON:0001515	88.33	gold quality
stromal cell of endometrium	CL:0002255	88.30	gold quality
left lobe of thyroid gland	UBERON:0001120	88.15	gold quality
tibial nerve	UBERON:0001323	87.95	gold quality
aorta	UBERON:0000947	87.84	gold quality
nucleus accumbens	UBERON:0001882	87.84	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	4.31

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

8 targeting ANKS3, 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-4492	99.87	68.25	3611
HSA-MIR-6752-3P	99.72	66.71	1587
HSA-MIR-2116-5P	99.32	69.34	1273
HSA-MIR-6829-5P	98.86	65.12	1480
HSA-MIR-4656	98.79	66.22	1306
HSA-MIR-6776-5P	98.54	67.43	1304
HSA-MIR-3173-5P	97.35	65.82	1282
HSA-MIR-6799-3P	97.35	65.60	1302

Literature-anchored findings (GeneRIF, showing 2)

• Study finds that ANKS3-SAM polymerizes and ANKS6-SAM can bind to one end of the polymer; study presents crystal structures of both the ANKS3-SAM polymer and the ANKS3-SAM/ANKS6-SAM complex, revealing the molecular details of their association. (PMID:24998259)
• Consistent with the proposed role of the ANKS3 variant in the pathogenesis of the reported family’s phenotype, we show that the mutant RNA failed to rescue the laterality defect in anks3 morphants compared to wild-type RNA. Furthermore, we describe a new mutant anks3 line that also displays laterality defect in the homozygous state (PMID:27417436)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	anks3	ENSDARG00000038557
mus_musculus	Anks3	ENSMUSG00000022515
rattus_norvegicus	Anks3	ENSRNOG00000003186
caenorhabditis_elegans		WBGENE00012704

Protein

Protein identifiers

Ankyrin repeat and SAM domain-containing protein 3 — Q6ZW76 (reviewed: Q6ZW76)

All UniProt accessions (15): Q6ZW76, F6WF08, K7EJS9, K7EJX3, K7EJY2, K7EKD2, K7ELP3, K7ELU8, K7EM53, K7EPL7, K7EPP4, K7EPY5, K7EQE0, K7ERF3, K7ERR7

UniProt curated annotations — full annotation on UniProt →

Function. May be involved in vasopressin signaling in the kidney.

Subunit / interactions. Homooligomer. Interacts (via SAM domain) with ANKS6 (via SAM domain). Interacts with BICC1. Interacts with NPHP1. Interacts with NEK8. Interacts with HIF1AN. Interacts with NEK7; this interaction alters the subcellular distribution of NEK7 by preventing its nuclear translocation.

Subcellular location. Cell projection. Cilium. Cytoplasm.

Post-translational modifications. Hydroxylated at Asn-96, most probably by HIF1AN. Phosphorylations at Ser-5, Ser-225, Thr-319, Ser-320, Ser-368 and Ser-371 occur in a NEK7-dependent manner. Polyubiquitinated.

Domain organisation. The SAM domain mediates homooligomerization.

Isoforms (2)

UniProt ID	Names	Canonical?
Q6ZW76-1	1	yes
Q6ZW76-2	2

RefSeq proteins (5): NP_001229858, NP_001295018, NP_001311058, NP_001311059, NP_597707* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001660	SAM	Domain
IPR002110	Ankyrin_rpt	Repeat
IPR013761	SAM/pointed_sf	Homologous_superfamily
IPR036770	Ankyrin_rpt-contain_sf	Homologous_superfamily
IPR047238	ANKS3_SAM	Domain

Pfam: PF00536, PF12796, PF13637

UniProt features (44 total): modified residue 14, repeat 6, mutagenesis site 6, helix 6, region of interest 4, sequence variant 2, sequence conflict 2, chain 1, coiled-coil region 1, splice variant 1, domain 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
4NL9	X-RAY DIFFRACTION	1.5
4NJ8	X-RAY DIFFRACTION	1.6

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6ZW76-F1	68.94	0.37

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 (14): 2, 5, 96, 201, 225, 243, 244, 245, 319, 320, 368, 371, 375, 541

Mutagenesis-validated functional residues (6):

Position	Phenotype
450	decreased homooligomerization. no effect on interaction with anks6.
455	decreased homooligomerization. no effect on interaction with anks6.
466	decreased homooligomerization. no effect on interaction with anks6.
471	decreased homooligomerization. decreased interaction with anks6.
472	decreased homooligomerization. decreased interaction with anks6.
477	decreased homooligomerization. decreased interaction with anks6.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 67 (showing top): GSE45365_HEALTHY_VS_MCMV_INFECTION_CD8_TCELL_IFNAR_KO_DN, GAUSSMANN_MLL_AF4_FUSION_TARGETS_A_DN, TCCCRNNRTGC_UNKNOWN, GOCC_CILIUM, SCGGAAGY_ELK1_02, HOFFMANN_LARGE_TO_SMALL_PRE_BII_LYMPHOCYTE_DN, CBX5_TARGET_GENES, GLI4_TARGET_GENES, HOXB4_TARGET_GENES, KAT2A_TARGET_GENES, PRKDC_TARGET_GENES, SUPT16H_TARGET_GENES, TEAD2_TARGET_GENES, ZIM3_TARGET_GENES, ZSCAN30_TARGET_GENES

GO Biological Process (0):

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

GO Cellular Component (3): cytoplasm (GO:0005737), cilium (GO:0005929), cell projection (GO:0042995)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
binding	1
intracellular anatomical structure	1
intraciliary transport particle	1
membrane-bounded organelle	1
plasma membrane bounded cell projection	1

Protein interactions and networks

STRING

1335 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ANKS3	NEK8	Q86SG6	793
ANKS3	ANKS6	Q68DC2	793
ANKS3	NEK7	Q8TDX7	768
ANKS3	NEK9	Q8TD19	759
ANKS3	NPHP1	O15259	730
ANKS3	BICC1	Q9H694	691
ANKS3	NPHP3	Q7Z494	685
ANKS3	NEK6	Q9HC98	538
ANKS3	STRADA	Q7RTN6	506
ANKS3	PKD1	P98161	499
ANKS3	XPNPEP3	Q9NQH7	477
ANKS3	NPHP4	O75161	451
ANKS3	EML4	Q9HC35	442
ANKS3	STRADB	Q9C0K7	439
ANKS3	RMND5A	Q9H871	421

IntAct

30 interactions, top by confidence:

A	B	Type	Score
NEK7	ANKS6	psi-mi:“MI:0914”(association)	0.730
NEK8	ANKS6	psi-mi:“MI:0914”(association)	0.710
NEK6	DYNLL1	psi-mi:“MI:0914”(association)	0.560
ZNF689	ZNF593	psi-mi:“MI:0914”(association)	0.530
ZNF556	LRP4	psi-mi:“MI:0914”(association)	0.530
ZNF669	LRP4	psi-mi:“MI:0914”(association)	0.530
ZNF214	LRP4	psi-mi:“MI:0914”(association)	0.530
NEK7	EML3	psi-mi:“MI:0914”(association)	0.530
ANKS6	DCAF7	psi-mi:“MI:0914”(association)	0.510
NEK7	P4HA2	psi-mi:“MI:0914”(association)	0.510
ANKS3	NPM1	psi-mi:“MI:0915”(physical association)	0.400
ANKS3	FXR1	psi-mi:“MI:0915”(physical association)	0.370
CFTR	ANKS3	psi-mi:“MI:0915”(physical association)	0.370
Xpo1	IFT56	psi-mi:“MI:0914”(association)	0.350
M		psi-mi:“MI:0914”(association)	0.350
NEK7	SUPT5H	psi-mi:“MI:0914”(association)	0.350
SULF2	CCDC85C	psi-mi:“MI:0914”(association)	0.350
C1orf115	PRMT5	psi-mi:“MI:0914”(association)	0.350
ELOA2	XRCC2	psi-mi:“MI:0914”(association)	0.350
ANKS3	TNKS	psi-mi:“MI:0914”(association)	0.350
ZNF136	STAT4	psi-mi:“MI:0914”(association)	0.350
ABT1		psi-mi:“MI:0914”(association)	0.350
FHIP2A	MED19	psi-mi:“MI:2364”(proximity)	0.270
ANKS3	ANKS6	psi-mi:“MI:0915”(physical association)	0.000
ANKS3	NEK8	psi-mi:“MI:0915”(physical association)	0.000
ANKS3	NEK7	psi-mi:“MI:0915”(physical association)	0.000
GFI1B	ANKS3	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (45): ANKS3 (Affinity Capture-RNA), ANKS3 (Affinity Capture-MS), ANKS3 (Affinity Capture-MS), ANKS3 (Affinity Capture-MS), ANKS3 (Affinity Capture-MS), ANKS6 (Affinity Capture-MS), NEK7 (Affinity Capture-MS), NEK8 (Affinity Capture-MS), ANKS3 (Affinity Capture-RNA), ANKS3 (Affinity Capture-MS), ANKS3 (Proximity Label-MS), ANKS3 (Affinity Capture-MS), ANKS3 (Affinity Capture-RNA), ANKS3 (Two-hybrid), CNKSR3 (Affinity Capture-MS)

ESM2 similar proteins: A0A140LI67, A0A1W2PR48, A0JP70, D3YYM4, F1LW30, O13034, O15040, O70173, Q15345, Q3SXM0, Q3UDP0, Q3UJB9, Q3ULW6, Q3V129, Q3ZAV8, Q58DC2, Q5F479, Q5JV73, Q5M9H0, Q5M9H1, Q5R6T6, Q5R9H2, Q68DX3, Q6IRN0, Q6NV72, Q6P2E9, Q6P4K6, Q6PCD5, Q6ZPG2, Q6ZW76, Q7TNH6, Q80TQ5, Q8BLD6, Q8C008, Q8C5V5, Q8CBW4, Q8CIK8, Q8IWE5, Q8JZL1, Q8K1C9

Diamond homologs: A4II29, E9Q238, F1MJR8, O83515, P0C0T2, Q01317, Q05823, Q05921, Q14678, Q1LZH7, Q21920, Q24009, Q5M9H0, Q5SUE8, Q5U4T7, Q5U5A6, Q5XJ13, Q68DC2, Q6AI12, Q6GQX6, Q6NY19, Q6ZW76, Q7T3X9, Q7T3Y0, Q7Z6K4, Q8BX02, Q8IWB6, Q91ZA8, Q99MQ1, Q9CZK6, Q9H694, Q9IA00, Q9Z1P7, A2AS55, B4E2M5, D3Z7P3, O75762, O94925, P13264, P28492

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	153
Likely benign	18
Benign	4

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
599564	NM_133450.4(ANKS3):c.1960dup (p.Arg654fs)	Pathogenic

SpliceAI

2991 predictions. Top by Δscore:

Variant	Effect	Δscore
16:4697332:CCCAT:C	donor_gain	1.0000
16:4697417:C:CC	acceptor_gain	1.0000
16:4697976:CCAG:C	donor_gain	1.0000
16:4698059:GGCT:G	acceptor_gain	1.0000
16:4698061:CT:C	acceptor_gain	1.0000
16:4698063:C:CC	acceptor_gain	1.0000
16:4698067:C:CT	acceptor_gain	1.0000
16:4698153:AGC:A	donor_gain	1.0000
16:4698422:CTCA:C	donor_loss	1.0000
16:4698424:CA:C	donor_loss	1.0000
16:4698425:A:AC	donor_gain	1.0000
16:4698425:ACCG:A	donor_gain	1.0000
16:4698426:C:CT	donor_gain	1.0000
16:4698426:CCG:C	donor_gain	1.0000
16:4698426:CCGC:C	donor_gain	1.0000
16:4698426:CCGCA:C	donor_gain	1.0000
16:4698595:CAGCG:C	acceptor_gain	1.0000
16:4698598:CG:C	acceptor_gain	1.0000
16:4698795:CTCA:C	donor_loss	1.0000
16:4698796:TCAC:T	donor_loss	1.0000
16:4698797:CA:C	donor_loss	1.0000
16:4698798:A:AC	donor_gain	1.0000
16:4698798:AC:A	donor_gain	1.0000
16:4698799:C:CA	donor_gain	1.0000
16:4698799:CC:C	donor_gain	1.0000
16:4698799:CCT:C	donor_gain	1.0000
16:4698799:CCTT:C	donor_gain	1.0000
16:4698799:CCTTG:C	donor_gain	1.0000
16:4698938:CAGC:C	acceptor_gain	1.0000
16:4698939:AGCCT:A	acceptor_loss	1.0000

AlphaMissense

4291 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:4698903:G:T	A483D	0.997
16:4698906:A:T	I482N	0.997
16:4724793:G:T	A177D	0.997
16:4724797:C:G	A176P	0.997
16:4726724:A:C	C142W	0.997
16:4726737:G:T	A138D	0.997
16:4727140:A:G	W70R	0.997
16:4727140:A:T	W70R	0.997
16:4698900:C:G	R484P	0.996
16:4698918:A:G	M478T	0.996
16:4714134:G:T	A209D	0.996
16:4724794:C:G	A177P	0.996
16:4727121:G:T	A76D	0.996
16:4699091:A:G	L457P	0.995
16:4726689:A:G	L154P	0.995
16:4726986:A:G	L121P	0.995
16:4730025:G:T	A42D	0.995
16:4698898:A:G	W485R	0.994
16:4698898:A:T	W485R	0.994
16:4698923:C:A	R476S	0.994
16:4698923:C:G	R476S	0.994
16:4698933:C:T	G473E	0.994
16:4699093:A:C	F456L	0.994
16:4699093:A:T	F456L	0.994
16:4699095:A:G	F456L	0.994
16:4727022:G:T	A109D	0.994
16:4727085:A:G	L88P	0.994
16:4698850:C:G	A501P	0.993
16:4698904:C:G	A483P	0.993
16:4698910:C:G	A481P	0.993

dbSNP variants (sampled 300 via entrez): RS1000014433 (16:4723678 T>C), RS1000022640 (16:4701709 G>A,C), RS1000036840 (16:4712817 G>A,T), RS1000086207 (16:4735769 G>T), RS1000112282 (16:4709122 T>C), RS1000180535 (16:4704209 G>A), RS1000190980 (16:4725166 A>G), RS1000196675 (16:4731919 A>AAGGT), RS1000238796 (16:4698682 G>A,T), RS1000257320 (16:4705643 C>A,G,T), RS1000289281 (16:4716730 T>C), RS1000317532 (16:4721541 G>A), RS1000348445 (16:4721374 C>G,T), RS1000410146 (16:4727798 C>G), RS1000511229 (16:4705191 A>C)

Disease associations

OMIM: gene MIM:617310 | disease phenotypes: MIM:236750

GenCC curated gene-disease

Disease	Classification	Inheritance
situs inversus	Supportive	Autosomal dominant
laterality defects, autosomal dominant	Limited	Autosomal recessive

Mondo (3): non-immune hydrops fetalis (MONDO:0009369), laterality defects, autosomal dominant (MONDO:0010991), situs inversus (MONDO:0010029)

Orphanet (1): Non-immune hydrops fetalis (Orphanet:363999)

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST012226_383	Waist circumference adjusted for body mass index	3.000000e-08

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0007789	BMI-adjusted waist circumference

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D012857	Situs Inversus	C16.131.810
C563391	Laterality Defects, Autosomal Dominant (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

13 total (human), top 13 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
beta-lapachone	increases expression	1
aflatoxin B2	decreases methylation	1
coumarin	increases phosphorylation	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
Leflunomide	decreases expression	1
Arsenic	affects methylation	1
Atrazine	decreases expression	1
Smoke	decreases expression	1
Thiram	increases expression	1
Tobacco Smoke Pollution	decreases expression	1
Valproic Acid	increases methylation	1
Aflatoxin B1	increases methylation	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00608556	Not specified	COMPLETED	Dyskinesia, Heterotaxy and Congenital Heart Disease
NCT04308603	Not specified	COMPLETED	Multicentric Prospective Study to Screen Inborn Errors of Metabolism in Non-immune Hydrops (NIH) Fetalis by Massively Parallel Sequencing
NCT05528796	Not specified	ENROLLING_BY_INVITATION	Uncovering the Etiologies of Non-immune Hydrops Fetalis