ANKLE1

Summary

ANKLE1 (ankyrin repeat and LEM domain containing 1, HGNC:26812) is a protein-coding gene on chromosome 19p13.11, encoding Structure-specific endonuclease ANKLE1 (Q8NAG6). Structure-selective DNA endonuclease that specifically cleaves branched DNA.

Enables DNA endonuclease activity and metal ion binding activity. Involved in DNA damage response and protein export from nucleus. Located in cytosol; midbody; and nucleoplasm.

Source: NCBI Gene 126549 — automated summary from GO annotations (Alliance of Genome Resources).

At a glance

• GWAS associations: 5
• Clinical variants (ClinVar): 132 total
• GTEx eGene: eQTL in 44 tissues, sQTL in 2 (q < 0.05)
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 1.37 (unconstrained)
• MANE Select transcript: NM_152363
• Notable: 132 clinical variants but no curated precision-oncology (CIViC) evidence yet

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:26812
Approved symbol	ANKLE1
Name	ankyrin repeat and LEM domain containing 1
Location	19p13.11
Locus type	gene with protein product
Status	Approved
Aliases	FLJ39369, LEMD6
Ensembl gene	ENSG00000160117
Ensembl biotype	protein_coding
OMIM	619348
Entrez	126549

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 8 protein_coding, 4 retained_intron, 1 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

MANE Select: ENST00000404085

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 1, TSL 2: 4, TSL 4: 1, TSL 5: 3

ENST00000404085, ENST00000394458, ENST00000404261, ENST00000594072, ENST00000596099, ENST00000596626, ENST00000596834, ENST00000598347, ENST00000601401, ENST00000651416, ENST00000652132, ENST00000935386, ENST00000935387, ENST00001140930

RefSeq mRNA: 4 — MANE Select: NM_152363 NM_001278443, NM_001278444, NM_001278445, NM_152363

CCDS: CCDS12354, CCDS92554

Canonical transcript exons

ENST00000404085 — 9 exons

Exon	Start	End
ENSE00003462974	17282057	17282209
ENSE00003567096	17284089	17284266
ENSE00003569839	17285681	17285819
ENSE00003589268	17282656	17282761
ENSE00003653674	17283225	17283962
ENSE00003680932	17285431	17285590
ENSE00003713755	17282864	17283002
ENSE00003716386	17286380	17287646
ENSE00003894930	17281901	17281982

Expression profiles

Bgee: expression breadth ubiquitous, 160 present calls, max score 75.94.

FANTOM5 (CAGE): breadth broad, TPM avg 1.4767 / max 198.7961, expressed in 346 samples.

Highest expression (Bgee): male germ line stem cell (sensu Vertebrata) in testis, bone marrow, bone marrow cell, cerebellar hemisphere, hemisphere of cerebellum.

Genetic regulation across tissues (GTEx eQTL / sQTL)

ANKLE1 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 44 tissues and its splicing (sQTL) in 2 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 46 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Nerve Tibial	eqtl	1.7e-40	+0.52	19:17278347:C:T
Esophagus Mucosa	eqtl	1.3e-30	+1.34	19:17281821:G:GC
Cells Cultured fibroblasts	eqtl	1.5e-29	+0.93	19:17281821:G:GC
Skin Sun Exposed Lower leg	eqtl	8.2e-29	+0.44	19:17282640:T:G
Adipose Subcutaneous	eqtl	3.3e-24	+0.44	19:17273842:C:T
Skin Not Sun Exposed Suprapubic	eqtl	3.8e-18	+0.42	19:17311227:A:G
Testis	eqtl	6.4e-18	+0.54	19:17278347:C:T
Breast Mammary Tissue	eqtl	1.2e-17	+0.48	19:17276367:A:G
Thyroid	eqtl	5.3e-17	+0.36	19:17292552:A:G
Cells EBV-transformed lymphocytes	eqtl	1.5e-13	-0.52	19:17281820:G:A
Artery Tibial	eqtl	3.0e-13	-0.32	19:17278129:G:A
Adipose Visceral Omentum	eqtl	5.7e-12	+0.42	19:17277256:T:C
Ovary	eqtl	1.4e-10	+0.62	19:17273194:C:A
Colon Transverse	eqtl	4.0e-10	+0.34	19:17278347:C:T
Esophagus Muscularis	eqtl	1.1e-08	+0.26	19:17286891:A:C
Esophagus Gastroesophageal Junction	eqtl	3.3e-08	+0.35	19:17278347:C:T
Brain Caudate basal ganglia	eqtl	1.1e-07	-0.45	19:17278129:G:A
Brain Cerebellum	eqtl	1.1e-07	+0.41	19:17295499:T:C
Whole Blood	eqtl	1.3e-07	-0.25	19:17288960:C:T
Heart Atrial Appendage	eqtl	1.5e-06	+0.35	19:17278114:C:T

FANTOM5 promoters

6 alternative TSS:

Promoter ID	TPM avg	Samples expressed
174481	0.9234	278
174478	0.2116	68
174482	0.1210	62
174480	0.0990	15
174477	0.0939	46
174479	0.0278	6

Top tissues by expression

showing 100 of 243 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	75.94	silver quality
bone marrow	UBERON:0002371	75.59	gold quality
bone marrow cell	CL:0002092	73.95	gold quality
cerebellar hemisphere	UBERON:0002245	73.55	gold quality
right hemisphere of cerebellum	UBERON:0014890	73.55	gold quality
cerebellar cortex	UBERON:0002129	73.47	gold quality
granulocyte	CL:0000094	73.34	gold quality
trabecular bone tissue	UBERON:0002483	73.24	gold quality
monocyte	CL:0000576	71.74	gold quality
cerebellum	UBERON:0002037	71.55	gold quality
leukocyte	CL:0000738	71.44	gold quality
stromal cell of endometrium	CL:0002255	68.27	gold quality
tendon of biceps brachii	UBERON:0008188	66.89	gold quality
spleen	UBERON:0002106	66.85	gold quality
lymph node	UBERON:0000029	66.71	gold quality
ventricular zone	UBERON:0003053	66.09	gold quality
vermiform appendix	UBERON:0001154	65.61	gold quality
ganglionic eminence	UBERON:0004023	65.35	gold quality
lower esophagus mucosa	UBERON:0035834	64.29	gold quality
cortical plate	UBERON:0005343	63.48	gold quality
mucosa of stomach	UBERON:0001199	62.49	gold quality
right ovary	UBERON:0002118	62.20	gold quality
blood	UBERON:0000178	62.02	gold quality
right frontal lobe	UBERON:0002810	61.53	gold quality
left ovary	UBERON:0002119	61.09	gold quality
medial globus pallidus	UBERON:0002477	60.19	silver quality
caecum	UBERON:0001153	60.10	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	59.83	gold quality
lower esophagus	UBERON:0013473	59.57	gold quality
lower esophagus muscularis layer	UBERON:0035833	59.55	gold quality
lower lobe of lung	UBERON:0008949	59.17	silver quality
C1 segment of cervical spinal cord	UBERON:0006469	59.15	gold quality
body of uterus	UBERON:0009853	59.12	gold quality
right coronary artery	UBERON:0001625	59.08	gold quality
Brodmann (1909) area 9	UBERON:0013540	59.03	gold quality
secondary oocyte	CL:0000655	58.97	gold quality
gastrocnemius	UBERON:0001388	58.86	gold quality
anterior cingulate cortex	UBERON:0009835	58.59	gold quality
muscle layer of sigmoid colon	UBERON:0035805	58.50	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	58.42	gold quality
muscle of leg	UBERON:0001383	58.18	gold quality
descending thoracic aorta	UBERON:0002345	58.09	gold quality
ovary	UBERON:0000992	57.69	gold quality
tibial nerve	UBERON:0001323	57.50	gold quality
right lung	UBERON:0002167	57.45	gold quality
spinal cord	UBERON:0002240	57.42	gold quality
hypothalamus	UBERON:0001898	57.37	gold quality
prefrontal cortex	UBERON:0000451	57.36	gold quality
smooth muscle tissue	UBERON:0001135	57.16	gold quality
tibial artery	UBERON:0007610	56.99	gold quality
popliteal artery	UBERON:0002250	56.96	gold quality
endocervix	UBERON:0000458	56.88	gold quality
right lobe of liver	UBERON:0001114	56.85	gold quality
globus pallidus	UBERON:0001875	56.80	silver quality
dorsolateral prefrontal cortex	UBERON:0009834	56.51	gold quality
aorta	UBERON:0000947	56.41	gold quality
neocortex	UBERON:0001950	56.34	gold quality
nucleus accumbens	UBERON:0001882	56.33	gold quality
left adrenal gland cortex	UBERON:0035825	56.15	gold quality
thoracic aorta	UBERON:0001515	55.90	gold quality
ascending aorta	UBERON:0001496	55.83	gold quality
frontal cortex	UBERON:0001870	55.75	gold quality
left adrenal gland	UBERON:0001234	55.74	gold quality
brain	UBERON:0000955	55.70	gold quality
small intestine Peyer’s patch	UBERON:0003454	55.63	gold quality
hindlimb stylopod muscle	UBERON:0004252	55.49	gold quality
upper lobe of lung	UBERON:0008948	55.37	gold quality
esophagus	UBERON:0001043	55.31	gold quality
ectocervix	UBERON:0012249	55.30	gold quality
right adrenal gland	UBERON:0001233	55.20	gold quality
putamen	UBERON:0001874	55.18	gold quality
skin of leg	UBERON:0001511	55.13	gold quality
upper lobe of left lung	UBERON:0008952	55.12	gold quality
caudate nucleus	UBERON:0001873	54.90	gold quality
adrenal cortex	UBERON:0001235	54.72	gold quality
left uterine tube	UBERON:0001303	54.67	gold quality
right adrenal gland cortex	UBERON:0035827	54.55	gold quality
adenohypophysis	UBERON:0002196	54.43	gold quality
uterine cervix	UBERON:0000002	54.37	gold quality
omental fat pad	UBERON:0010414	54.27	gold quality
peritoneum	UBERON:0002358	54.26	gold quality
amygdala	UBERON:0001876	54.25	gold quality
oviduct epithelium	UBERON:0004804	54.17	gold quality
subcutaneous adipose tissue	UBERON:0002190	54.10	gold quality
anatomical system	UBERON:0000467	54.08	gold quality
cerebral cortex	UBERON:0000956	54.06	gold quality
parotid gland	UBERON:0001831	54.04	gold quality
tonsil	UBERON:0002372	53.93	gold quality
small intestine	UBERON:0002108	53.89	gold quality
adrenal gland	UBERON:0002369	53.89	gold quality
transverse colon	UBERON:0001157	53.88	gold quality
forebrain	UBERON:0001890	53.83	gold quality
multicellular organism	UBERON:0000468	53.82	gold quality
material anatomical entity	UBERON:0000465	53.81	gold quality
left coronary artery	UBERON:0001626	53.80	gold quality
right atrium auricular region	UBERON:0006631	53.62	gold quality
heart left ventricle	UBERON:0002084	53.60	gold quality
vagina	UBERON:0000996	53.54	gold quality
adipose tissue of abdominal region	UBERON:0007808	53.52	gold quality
coronary artery	UBERON:0001621	53.46	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.27

HPA expression

RNA tissue specificity: Tissue enriched

showing 60 of 74 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Postcentral gyrus	tissue	23.8
Bone marrow	tissue	23.4	low
Hippocampus	tissue	17.8	not detected
Nucleus accumbens	tissue	16.9
Choroid plexus	tissue	16.4
Locus coeruleus	tissue	15.9
Cerebellum	tissue	6.0	not detected
Olfactory bulb	tissue	5.3
Cerebral cortex	tissue	3.9	not detected
Retrosplenial cortex	tissue	3.9
Corpus callosum	tissue	3.8
Insular cortex	tissue	3.8
Retrosplenial and cingulate cortex	tissue	3.6
Temporal cortex	tissue	3.6
Lymph node	tissue	3.5	not detected
Basal ganglia	tissue	3.5	not detected
Occipital cortex	tissue	3.5
Amygdala	tissue	3.4
Hippocampal formation	tissue	3.4
Entorhinal cortex	tissue	3.4
Ventral forebrain	tissue	3.3
Prefrontal cortex	tissue	3.2
Periaqueductal gray	tissue	3.1
Motor cortex	tissue	3.0
Septum	tissue	3.0
Somatosensory cortex	tissue	3.0
Tonsil	tissue	2.9	not detected
Putamen	tissue	2.8
Hypothalamus	tissue	2.6
Midbrain	tissue	2.5
Medulla oblongata	tissue	2.5
Substantia nigra	tissue	2.5
Spinal cord	tissue	2.3
Thalamus	tissue	2.2
Retina	tissue	2.1
Superior colliculi	tissue	2.0
Appendix	tissue	1.9	not detected
Pons	tissue	1.8
Skin 1	tissue	1.4	not detected
Spleen	tissue	1.4	not detected
Testis	tissue	1.2	not detected
Pancreas	tissue	1.2	not detected
Epididymis	tissue	1.2	not detected
Thymus	tissue	1.2
Placenta	tissue	1.0	not detected
Salivary gland	tissue	0.8	not detected
Endometrium 1	tissue	0.8	not detected
Ovary	tissue	0.7	not detected
Smooth muscle	tissue	0.7	not detected
Pituitary gland	tissue	0.6
Breast	tissue	0.6	not detected
Heart muscle	tissue	0.6	not detected
Seminal vesicle	tissue	0.6	not detected
Lung	tissue	0.6	not detected
Stomach 1	tissue	0.5	not detected
Vagina	tissue	0.5	not detected
Adipose tissue	tissue	0.5	not detected
Rectum	tissue	0.5	not detected
Urinary bladder	tissue	0.5	not detected
Liver	tissue	0.5	not detected

Brain sub-regions (HPA Brain Atlas): detected in 189; highest nTPM — Vermis (31.8), Flocculonodular lobe (31.5), Cerebellar cortex (26.2), Parietal operculum (25.1), Posterior insular cortex (24.1).

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

Targeting ANKLE1 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

30 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-3682-3P	99.58	67.63	865
HSA-MIR-486-3P	99.51	66.82	1901
HSA-MIR-578	99.46	68.36	1787
HSA-MIR-504-3P	99.30	67.18	1745
HSA-MIR-4651	99.06	67.57	2002
HSA-MIR-7151-3P	99.04	69.72	2370
HSA-MIR-3619-5P	99.00	68.87	2308
HSA-MIR-12135	98.99	70.26	1814
HSA-MIR-608	98.93	67.83	2013
HSA-MIR-4477A	98.83	69.75	2952
HSA-MIR-6846-5P	98.81	65.86	1121
HSA-MIR-6848-5P	98.81	65.49	1126
HSA-MIR-6769B-5P	98.73	64.91	1092
HSA-MIR-6852-3P	98.54	67.60	1468
HSA-MIR-660-3P	98.14	66.04	1434
HSA-MIR-6769A-5P	97.99	64.16	851
HSA-MIR-3159	97.94	66.79	1098
HSA-MIR-6502-3P	97.86	65.43	569
HSA-MIR-3909	97.55	66.78	887
HSA-MIR-5685	97.02	64.34	1004
HSA-MIR-4690-3P	97.02	64.72	981
HSA-MIR-656-5P	96.82	67.67	372
HSA-MIR-1182	96.41	64.89	336
HSA-MIR-4509	96.19	65.80	900
HSA-MIR-584-5P	95.82	68.05	848
HSA-MIR-5681B	94.82	69.30	514

Functional genomics

gnomAD constraint: pLI 2.31e-22, LOEUF 1.37, missense Z 0.0719 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000404085 — one region, missense o/e 0.94.

Literature-anchored findings (GeneRIF, showing 10)

• Ankle1 is conserved in metazoans and contains a unique C-terminal GIY-YIG motif that confers endonuclease activity in vitro and in vivo (PMID:22399800)
• the domains mediating nuclear import and export of Ankle1, were identified. (PMID:27245214)
• Expression of RCCD1 in whole blood was also suggestively associated with disease risk (p-value: 1.2x10-05), as were expression of ACAP1 (p-value: 1.9x10-05) and LRRC25 (p-value: 5.2x10-05). While genome-wide association studies (GWAS) have implicated RCCD1 and ANKLE1 in breast cancer risk, they have not identified the remaining three genes (PMID:28362817)
• We used The Cancer Genome Atlas breast cancer patient data to identify ANKLE1 and ZNF404 as the target genes of candidate TF binding site SNPs in the 19p13.11 and 19q13.31 GWAS-identified loci. These SNPs are associated with the expression of ZNF404 and ANKLE1 in breast tissue. (PMID:28957321)
• ANKLE1 N(6) -Methyladenosine-related variant is associated with colorectal cancer risk by maintaining the genomic stability. (PMID:31509622)
• Human ANKLE1 Is a Nuclease Specific for Branched DNA. (PMID:32866453)
• Investigation of triple-negative breast cancer risk alleles in an International African-enriched cohort. (PMID:33927264)
• Human Endonuclease ANKLE1 Localizes at the Midbody and Processes Chromatin Bridges to Prevent DNA Damage and cGAS-STING Activation. (PMID:36825683)
• Dephosphocholination by Legionella effector Lem3 functions through remodelling of the switch II region of Rab1b. (PMID:37076474)
• Biochemical and mechanistic analysis of the cleavage of branched DNA by human ANKLE1. (PMID:37216589)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	zgc:85936	ENSDARG00000087529
mus_musculus	Ankle1	ENSMUSG00000046295
rattus_norvegicus	Ankle1	ENSRNOG00000017156

Paralogs (2): LEMD2 (ENSG00000161904), LEMD3 (ENSG00000174106)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:1918775) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 3 distinct phenotype terms.

Mouse phenotype (MP)	Records
decreased locomotor activity	1
abnormal coat/hair pigmentation	1
prenatal lethality, incomplete penetrance	1

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Caenorhabditis elegans	G5EGA3	44.8%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
BABAM1	protein-coding	29086
ANO8	protein-coding	57719
MRPL34	protein-coding	64981
DDA1	protein-coding	79016
ABHD8	protein-coding	79575
GTPBP3	protein-coding	84705
NR2F6	protein-coding	2063
OCEL1	protein-coding	79629
USHBP1	protein-coding	83878
PLVAP	protein-coding	83483

Protein

Protein identifiers

Structure-specific endonuclease ANKLE1 — Q8NAG6 (reviewed: Q8NAG6)

Alternative names: Ankyrin repeat and LEM domain-containing protein 1, Ankyrin repeat domain-containing protein 41, LEM-domain containing protein 3

All UniProt accessions (6): A0A0A0MSC6, A0A494C092, A0A499FJM0, Q8NAG6, M0QX15, M0R002

UniProt curated annotations — full annotation on UniProt →

Function. Structure-selective DNA endonuclease that specifically cleaves branched DNA. Processes chromatin bridges during cytokinesis by cleaving DNA, both priming TREX1-mediated resolution and directly resolving bridges. Proper processing of chromatin bridges prevents their breakage during cytokinesis, thereby reducing DNA damage, micronuclei formation, and the activation of immune responses such as the cGAS-STING pathway. Acts as a DNA tension sensor that resolves stretched chromatin bridges during cell division by cleaving mechanically stressed and supercoiled DNA. Its activity increases in response to mechanical stress and negative supercoiling, specifically cleaving both strands of negatively supercoiled DNA at higher stretching forces.

Subunit / interactions. Monomer. Interacts (via LEM domain) with BANF1; the interaction may favor BANF1 dimerization. Interacts with RACGAP1 and KIF23.

Subcellular location. Cytoplasm. Nucleus. Midbody.

Tissue specificity. Expression is predominant in adult bone marrow.

Domain organisation. The LEM domain is required for GIY-YIG domain-mediated DNA cleavage and induction of DNA damage response. The GIY-YIG domain is required for nuclease cleavage close to DNA branchpoints. The ANK repeats are essential for its localization to the midbody.

Isoforms (2)

UniProt ID	Names	Canonical?
Q8NAG6-2	1	yes
Q8NAG6-1	2

RefSeq proteins (4): NP_001265372, NP_001265373, NP_001265374, NP_689576* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000305	GIY-YIG_endonuc	Domain
IPR002110	Ankyrin_rpt	Repeat
IPR003887	LEM_dom	Domain
IPR011015	LEM/LEM-like_dom_sf	Homologous_superfamily
IPR034998	ANKLE1	Family
IPR036770	Ankyrin_rpt-contain_sf	Homologous_superfamily
IPR054739	LEM-3_GIY-YIG	Domain
IPR060771	GIY-YIG_LEM-3_Metazoa	Domain

Pfam: PF12796, PF22945

UniProt features (33 total): mutagenesis site 11, sequence variant 8, repeat 3, splice variant 2, domain 2, region of interest 2, short sequence motif 2, chain 1, compositionally biased region 1, sequence conflict 1

Structure

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8NAG6-F1	70.14	0.40

Human Protein Atlas

Protein class: Predicted membrane proteins, Predicted intracellular proteins

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): cytosol; nucleoplasm

Antibody reliability (HPA): IH approved · IF supported

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 (11)

Position	Phenotype
110–117	slight increase in nuclear localization.
271–280	increased nuclear localization.
453	loss of endonucleolytic activity.
486–488	probable loss of endonucleolytic activity. fails to induce dna damage response upon leptomycin-mediated nuclear localization. no nuclear …
486	loss of endonucleolytic activity.
488	loss of endonucleolytic activity.
498	reduced endonucleolytic activity.
519	reduced endonucleolytic activity.
551	loss of endonucleolytic activity.
565	loss of endonucleolytic activity.

Function

Pathways and Gene Ontology

Reactome pathways

0 curated (TAS) of 0; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

MSigDB gene sets: 101 (showing top): GOBP_HEMATOPOIETIC_PROGENITOR_CELL_DIFFERENTIATION, GOBP_REGULATION_OF_DNA_RECOMBINATION, GOMF_ENDONUCLEASE_ACTIVITY, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, GOMF_NUCLEASE_ACTIVITY, GOBP_NEGATIVE_REGULATION_OF_DNA_RECOMBINATION, GOBP_NUCLEAR_TRANSPORT, GOBP_ORGANELLE_FISSION, TGCTGAY_UNKNOWN, GOBP_DNA_DAMAGE_RESPONSE, GOBP_REGULATION_OF_HEMATOPOIETIC_PROGENITOR_CELL_DIFFERENTIATION, GOBP_MITOTIC_RECOMBINATION, GOBP_MEIOTIC_CELL_CYCLE_PROCESS, GOBP_NUCLEAR_EXPORT, GOBP_RECOMBINATIONAL_REPAIR

GO Biological Process (10): resolution of meiotic recombination intermediates (GO:0000712), double-strand break repair via homologous recombination (GO:0000724), protein export from nucleus (GO:0006611), DNA damage response (GO:0006974), negative regulation of mitotic recombination (GO:0045950), cell division (GO:0051301), nucleic acid metabolic process (GO:0090304), regulation of myeloid progenitor cell differentiation (GO:1905453), regulation of lymphoid progenitor cell differentiation (GO:1905456), DNA repair (GO:0006281)

GO Molecular Function (8): magnesium ion binding (GO:0000287), endonuclease activity (GO:0004519), DNA endonuclease activity (GO:0004520), hydrolase activity (GO:0016787), manganese ion binding (GO:0030145), cobalt ion binding (GO:0050897), nuclease activity (GO:0004518), protein binding (GO:0005515)

GO Cellular Component (5): nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), midbody (GO:0030496), nucleus (GO:0005634)

GO top-level categories

31 GO namespaces:

Category	Terms
cellular anatomical structure	4
regulation of hematopoietic progenitor cell differentiation	2
transition metal ion binding	2
reciprocal meiotic recombination	1
meiosis I cell cycle process	1
recombinational repair	1
double-strand break repair	1
intracellular protein transport	1
nuclear export	1
cellular response to stress	1
regulation of mitotic recombination	1
mitotic recombination	1
negative regulation of DNA recombination	1
cellular process	1
nucleobase-containing compound metabolic process	1
macromolecule metabolic process	1
myeloid progenitor cell differentiation	1
lymphoid progenitor cell differentiation	1
DNA metabolic process	1
DNA damage response	1
metal ion binding	1
nuclease activity	1
endonuclease activity	1
DNA nuclease activity	1
catalytic activity	1
catalytic activity, acting on a nucleic acid	1
binding	1
nuclear lumen	1
intracellular anatomical structure	1
cytoplasm	1
intracellular membrane-bounded organelle	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 11 of 23 annotations. The rest are phylogenetic / computational / electronic (IEA).

11 experimentally-supported GO terms:

GO term	NS	Evidence
DNA damage response	BP	direct assay
protein export from nucleus	BP	direct assay
cytoplasm	CC	direct assay
cytosol	CC	direct assay
midbody	CC	direct assay
nucleoplasm	CC	direct assay
DNA endonuclease activity	MF	direct assay
cobalt ion binding	MF	direct assay
endonuclease activity	MF	direct assay
magnesium ion binding	MF	direct assay
manganese ion binding	MF	direct assay

Protein interactions and networks

STRING

showing 15 of 484 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ANKLE1	ATP8B1	O43520	787
ANKLE1	NEO1	Q92859	766
ANKLE1	ANKLE2	Q86XL3	726
ANKLE1	ABHD8	Q96I13	702
ANKLE1	BABAM1	Q9NWV8	596
ANKLE1	CIMAP2	Q3ZCV2	588
ANKLE1	LEMD2	Q8NC56	572
ANKLE1	LEMD3	Q9Y2U8	547
ANKLE1	EMD	P50402	496
ANKLE1	SLX1A	Q9BQ83	492
ANKLE1	ERI1	Q8IV48	469
ANKLE1	BANF2	Q9H503	454
ANKLE1	MIMS2	Q96KR6	433
ANKLE1	LEMD1	Q68G75	428
ANKLE1	RCCD1	A6NED2	425

IntAct

BioGRID (6 interactions; top human partners by supporting records): EGFR (Negative Genetic), NUDT21 (Affinity Capture-RNA), PARP1 (Proximity Label-MS), SPPL3 (Positive Genetic), SRGN (Affinity Capture-MS), TOP3B (Affinity Capture-RNA)

Disease & clinical

Genetic variants

Variant evidence for ANKLE1: 132 ClinVar records (0 pathogenic / likely pathogenic); 5 GWAS associations.

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	107
Likely benign	10
Benign	7

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 31 predictions of 673):

Position(s)	Effect	Δscore	Sites
19:17282211	donor_loss	1.0000	2
19:17283003–17283004	donor_loss	1.0000	5
19:17284281	donor_gain	1.0000
19:17285524	donor_gain	1.0000
19:17285591–17285592	donor_loss	1.0000	4
19:17282210	donor_loss	0.9900	2
19:17282862–17282863	acceptor_loss	0.9900	5
19:17285429–17285430	acceptor_loss	0.9900	4
19:17285592	donor_loss	0.9900
19:17285679–17285680	acceptor_loss	0.9900	6

AlphaMissense

782 missense substitutions predicted likely pathogenic (of 3,908 scored), across 222 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
F539	8	0.945	0.990
F451	8	0.931	0.994
F485	8	0.919	0.990
F598	8	0.911	0.978
F433	8	0.900	0.985
F480	8	0.900	0.978
D106	8	0.885	0.939
H81	8	0.876	0.942
H498	8	0.860	0.964
H45	8	0.811	0.937
D457	8	0.796	0.914
W527	7	0.963	0.991
E551	7	0.937	0.978
W442	7	0.925	0.974
W578	7	0.919	0.983
E546	7	0.884	0.949
N565	7	0.874	0.959
C538	7	0.844	0.968
C553	7	0.796	0.967
E426	7	0.772	0.863

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Disease associations

OMIM: gene MIM:619348 | disease phenotypes:

GWAS associations

5 associations:

Study	Trait	p-value
GCST005076_32	Breast cancer (estrogen-receptor negative)	3e-37
GCST005075_8	Breast Cancer in BRCA1 mutation carriers	3e-17
GCST007394_2	Mitochondrial DNA copy number	1e-14
GCST000801_1	Breast cancer	2e-9
GCST000800_2	Ovarian cancer	1e-7

EFO canonical traits (from GWAS)

1 canonical traits:

EFO ID	Trait name
EFO:0006312	mitochondrial DNA measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (CPIC guideline: no)

CTD chemical–gene interactions

16 total (human), top 16 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
entinostat	increases expression, affects cotreatment	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Valproic Acid	increases methylation, increases expression	2
trichostatin A	increases expression	1
tris(2-butoxyethyl) phosphate	affects expression	1
arsenite	increases methylation	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	increases expression, decreases expression, affects cotreatment	1
dorsomorphin	affects cotreatment, increases expression, decreases expression	1
bisphenol S	increases methylation	1
Resveratrol	affects cotreatment, decreases expression	1
Leflunomide	decreases expression	1
Air Pollutants	increases abundance, increases expression	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Copper	decreases expression, affects cotreatment	1
Diazinon	decreases methylation	1
Particulate Matter	increases abundance, increases expression	1

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.