WAPL

Summary

WAPL (WAPL cohesin release factor, HGNC:23293) is a protein-coding gene on chromosome 10q23.2, encoding Wings apart-like protein homolog (Q7Z5K2). Regulator of sister chromatid cohesion in mitosis which negatively regulates cohesin association with chromatin. It is a selective cancer dependency (DepMap: 17.9% of cell lines).

Enables ATP-dependent protein-DNA unloader activity. Involved in several processes, including negative regulation of DNA replication; negative regulation of sister chromatid cohesion; and protein localization to chromatin. Located in several cellular components, including intercellular bridge; mitotic spindle; and nucleoplasm.

Source: NCBI Gene 23063 — RefSeq curated summary.

At a glance

• Gene–disease (curated): complex neurodevelopmental disorder (Limited, GenCC)
• GWAS associations: 3
• Clinical variants (ClinVar): 133 total
• Phenotypes (HPO): 2
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• Cancer dependency (DepMap): dependent in 17.9% of screened cell lines
• MANE Select transcript: NM_015045

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:23293
Approved symbol	WAPL
Name	WAPL cohesin release factor
Location	10q23.2
Locus type	gene with protein product
Status	Approved
Aliases	FOE
Ensembl gene	ENSG00000062650
Ensembl biotype	protein_coding
OMIM	610754
Entrez	23063

Gene structure

Transcript identifiers

Ensembl transcripts: 22 — 20 protein_coding, 1 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000298767, ENST00000372075, ENST00000484070, ENST00000489996, ENST00000910169, ENST00000910170, ENST00000910171, ENST00000910172, ENST00000910173, ENST00000910174, ENST00000910175, ENST00000910176, ENST00000910177, ENST00000910178, ENST00000910179, ENST00000920312, ENST00000920313, ENST00000920314, ENST00000920315, ENST00000960550, ENST00000960551, ENST00000960552

RefSeq mRNA: 2 — MANE Select: NM_015045 NM_001318328, NM_015045

CCDS: CCDS7375

Canonical transcript exons

ENST00000298767 — 19 exons

Exon	Start	End
ENSE00000711641	86453656	86453831
ENSE00000830507	86451967	86452131
ENSE00000830508	86446242	86446449
ENSE00000830509	86443275	86443363
ENSE00000998818	86460399	86460496
ENSE00000998821	86461176	86461287
ENSE00000998822	86458989	86459065
ENSE00001387746	86521365	86521792
ENSE00001617790	86473878	86473973
ENSE00001702706	86499718	86500743
ENSE00001723650	86497201	86497319
ENSE00001731171	86472612	86472764
ENSE00001764181	86472208	86472344
ENSE00003287902	86517571	86518091
ENSE00003467906	86453220	86453335
ENSE00003557665	86435256	86437608
ENSE00003588441	86467279	86467506
ENSE00003588752	86470992	86471103
ENSE00003652005	86437920	86438015

Expression profiles

Bgee: expression breadth ubiquitous, 298 present calls, max score 98.03.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 16.4340 / max 130.3708, expressed in 1795 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
110410	16.4340	1795

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	98.03	gold quality
oocyte	CL:0000023	96.39	gold quality
sperm	CL:0000019	94.07	gold quality
ventricular zone	UBERON:0003053	93.85	gold quality
amniotic fluid	UBERON:0000173	92.88	gold quality
male germ cell	CL:0000015	92.80	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	92.57	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	92.48	gold quality
upper leg skin	UBERON:0004262	92.47	gold quality
calcaneal tendon	UBERON:0003701	92.15	gold quality
skin of hip	UBERON:0001554	91.91	gold quality
caput epididymis	UBERON:0004358	91.79	gold quality
jejunal mucosa	UBERON:0000399	91.72	gold quality
esophagus squamous epithelium	UBERON:0006920	91.65	gold quality
choroid plexus epithelium	UBERON:0003911	91.55	gold quality
trabecular bone tissue	UBERON:0002483	91.26	gold quality
islet of Langerhans	UBERON:0000006	91.00	gold quality
ganglionic eminence	UBERON:0004023	90.94	gold quality
leukocyte	CL:0000738	90.93	gold quality
monocyte	CL:0000576	90.87	gold quality
mononuclear cell	CL:0000842	90.84	gold quality
testis	UBERON:0000473	90.78	gold quality
germinal epithelium of ovary	UBERON:0001304	90.71	gold quality
mucosa of sigmoid colon	UBERON:0004993	90.71	gold quality
tonsil	UBERON:0002372	90.68	gold quality
gingival epithelium	UBERON:0001949	90.58	gold quality
cauda epididymis	UBERON:0004360	90.54	gold quality
gastrocnemius	UBERON:0001388	90.52	gold quality
right testis	UBERON:0004534	90.31	gold quality
corpus epididymis	UBERON:0004359	90.30	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

miRNA regulators (miRDB)

260 targeting WAPL, 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-3163	100.00	77.23	8605
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-433-3P	99.98	69.37	1203
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-5696	99.98	72.36	4487

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 17.9% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 20)

• FOE encodes a protein of 1227 amino acids with a functional bipartite nuclear localization signal, an arginine-rich motif, a putative nuclear export signal as well as with three highly acidic regions and a predicted coiled-coil domain. (PMID:15383329)
• Wapl is a new regulator of sister chromatid resolution and promotes release of cohesin from chromosomes by directly interacting with its regulatory subunits (PMID:17112726)
• Wapl is required to unlock cohesin from a particular state in which it is stably bound to chromatin. (PMID:17113138)
• our study suggests that unscheduled overexpression of WAPL disturbs mitosis and cytokinesis, and contributes to tumor progression by induction of chromosomal instability. (PMID:17382297)
• isolated a large number of additional alternatively spliced WAPL variants from various cervical epithelia. Each variant consists of a variable 5’-terminal region and the conserved remainder. (PMID:18662753)
• Depletion of Wapl, a negative cohesin regulator, rescues sister chromatid homologous recombination defects of Mms21-deficient or Scc1 mutant-expressing cells (PMID:22751501)
• Wapl-C interacts with other cohesin subunits and possibly unknown effectors to trigger cohesin release from chromatin (PMID:23776203)
• WAPL-depleted cells undergo anaphase with segregation errors, resulting in micronuclei and DNA damage. Stable WAPL depletion arrests cells in a p53-dependent manner but causes p53-deficient cells to become highly aneuploid. (PMID:24055153)
• Rs7083506 and rs11202058 polymorphisms of hWAPL and their haplotype T-A were associated with cervical cancer. (PMID:26722608)
• Study shows that chromatin loop size can be increased and that the duration with which cohesin embraces DNA determines the degree to which loops are enlarged. Cohesin’s DNA release factor WAPL restricts this loop extension and also prevents looping between incorrectly oriented CTCF sites. (PMID:28475897)
• The results indicate a kinase-dependent role for Haspin in antagonizing Wapl and protecting centromeric cohesion in mitosis. (PMID:29138236)
• The results show that cohesin has an essential genome-wide function in mediating long-range chromatin interactions and support the hypothesis that cohesin creates these by loop extrusion, until it is delayed by CTCF in a manner dependent on PDS5 proteins, or until it is released from DNA by WAPL. (PMID:29217591)
• Rec8-Stag3 cohesin is shown to be susceptible to Wapl-dependent ring opening and sororin-mediated protection. (PMID:29724914)
• We provide evidence that the underlying mechanism involves the viral NS3/4 protease and the cohesin regulator, WAPL (PMID:30698808)
• Absolute copy numbers and dynamics of cohesin, CTCF, NIPBL, WAPL and sororin were measured by mass spectrometry, fluorescence-correlation spectroscopy and fluorescence recovery after photobleaching in HeLa cells. (PMID:31204999)
• In p53-compromised cells we find that lethal replication stress confers WAPL-dependent centromere cohesion defects that maintain spindle assembly checkpoint-dependent mitotic arrest in the same cell cycle. (PMID:31530811)
• ESCO1 and CTCF enable formation of long chromatin loops by protecting cohesin(STAG1) from WAPL. (PMID:32065581)
• WAPL-Dependent Repair of Damaged DNA Replication Forks Underlies Oncogene-Induced Loss of Sister Chromatid Cohesion. (PMID:32084359)
• WAPL induces cervical intraepithelial neoplasia modulated with estrogen signaling without HPV E6/E7. (PMID:33947962)
• A Mediator-cohesin axis controls heterochromatin domain formation. (PMID:35136067)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	waplb	ENSDARG00000029768
danio_rerio	wapla	ENSDARG00000044144
mus_musculus	Wapl	ENSMUSG00000041408
rattus_norvegicus	Wapl	ENSRNOG00000052513
drosophila_melanogaster	wapl	FBGN0004655
caenorhabditis_elegans		WBGENE00019953

Protein

Protein identifiers

Wings apart-like protein homolog — Q7Z5K2 (reviewed: Q7Z5K2)

Alternative names: Friend of EBNA2 protein, WAPL cohesin release factor

All UniProt accessions (3): Q7Z5K2, B2RTX8, F6QZY1

UniProt curated annotations — full annotation on UniProt →

Function. Regulator of sister chromatid cohesion in mitosis which negatively regulates cohesin association with chromatin. Involved in both sister chromatid cohesion during interphase and sister-chromatid resolution during early stages of mitosis. Couples DNA replication to sister chromatid cohesion. Cohesion ensures that chromosome partitioning is accurate in both meiotic and mitotic cells and plays an important role in DNA repair.

Subunit / interactions. Interacts with the cohesin complex throughout the cell cycle; interacts with both chromatin-bound and soluble pools of the complex. Interacts with RAD21; the interaction is direct. Interacts with PDS5A; the interaction is direct, cohesin-dependent and competitive with CDCA5/SORORIN. Interacts (via FGF motifs) with PDS5B; the interaction is direct. Interacts with a SMC1 protein (SMC1A or SMC1B) and SMC3. (Microbial infection) Isoform 2 interacts with Epstein-Barr virus EBNA2.

Subcellular location. Nucleus Nucleus. Chromosome. Cytoplasm.

Tissue specificity. Isoform 1 is highly expressed in uterine cervix tumor. Isoform 2 is widely expressed with a high level in skeletal muscle and heart.

Post-translational modifications. Deubiquitinated by USP37; leading to stabilization.

Similarity. Belongs to the WAPL family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q7Z5K2-1	1	yes
Q7Z5K2-2	2
Q7Z5K2-3	3

RefSeq proteins (2): NP_001305257, NP_055860* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR011989	ARM-like	Homologous_superfamily
IPR012502	WAPL_dom	Domain
IPR016024	ARM-type_fold	Homologous_superfamily
IPR022771	WAPL_C	Domain
IPR039874	WAPL	Family

Pfam: PF07814

UniProt features (74 total): helix 28, modified residue 11, mutagenesis site 11, compositionally biased region 4, region of interest 4, short sequence motif 3, splice variant 3, turn 3, sequence variant 2, coiled-coil region 2, chain 1, domain 1, strand 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
4K6J	X-RAY DIFFRACTION	2.62
5HDT	X-RAY DIFFRACTION	2.71
9EP3	X-RAY DIFFRACTION	3.08

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q7Z5K2-F1	59.26	0.25

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 (11): 77, 168, 221, 223, 226, 347, 380, 443, 459, 461, 904

Mutagenesis-validated functional residues (11):

Position	Phenotype
73–75	loss of interaction with pds5b; when associated with 429-e–e-431 and 453-e–e-455.
429–431	loss of interaction with pds5b; when associated with 73-e–e-75 and 453-e–e-455.
453–455	loss of interaction with pds5b; when associated with 73-e–e-75 and 429-e–e-431.
639–640	impaired sister chromatid cohesion and resolution.
656–657	impaired sister chromatid cohesion and resolution.
770	no effect.
777	no effect.
787	no effect.
790	no effect.
1116	impaired sister chromatid cohesion and resolution; when associated with a-1120.
1120	impaired sister chromatid cohesion and resolution; when associated with a-1116.

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-2467813	Separation of Sister Chromatids
R-HSA-2468052	Establishment of Sister Chromatid Cohesion
R-HSA-2470946	Cohesin Loading onto Chromatin
R-HSA-2500257	Resolution of Sister Chromatid Cohesion

MSigDB gene sets: 320 (showing top): GOBP_MEIOTIC_CHROMOSOME_SEGREGATION, GOBP_CHROMOSOME_ORGANIZATION, AGGAAGC_MIR5163P, GOBP_ATTACHMENT_OF_SPINDLE_MICROTUBULES_TO_KINETOCHORE, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, TAATAAT_MIR126, GGTGTGT_MIR329, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, GOBP_POSITIVE_REGULATION_OF_FIBROBLAST_PROLIFERATION, GOBP_CHROMOSOME_LOCALIZATION, AAGCCAT_MIR135A_MIR135B, IVANOVA_HEMATOPOIESIS_LATE_PROGENITOR, GOBP_CHROMOSOME_SEPARATION, ATGCAGT_MIR217

GO Biological Process (6): mitotic sister chromatid segregation (GO:0000070), negative regulation of DNA replication (GO:0008156), negative regulation of chromatin binding (GO:0035562), negative regulation of sister chromatid cohesion (GO:0045875), cell division (GO:0051301), protein localization to chromatin (GO:0071168)

GO Molecular Function (2): ATP-dependent protein-DNA unloader activity (GO:0140083), protein binding (GO:0005515)

GO Cellular Component (9): chromosome, centromeric region (GO:0000775), chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), chromosome (GO:0005694), cytoplasm (GO:0005737), cytosol (GO:0005829), intercellular bridge (GO:0045171), mitotic spindle (GO:0072686)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Mitotic Anaphase	1
S Phase	1
Mitotic Telophase/Cytokinesis	1
Mitotic Prometaphase	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
sister chromatid segregation	1
mitotic nuclear division	1
mitotic cell cycle process	1
DNA replication	1
regulation of DNA replication	1
negative regulation of DNA metabolic process	1
chromatin binding	1
negative regulation of binding	1
sister chromatid cohesion	1
regulation of sister chromatid cohesion	1
negative regulation of cell cycle process	1
negative regulation of chromosome organization	1
cellular process	1
protein localization to chromosome	1
ATP-dependent activity, acting on DNA	1
binding	1
chromosomal region	1
chromosome	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
intracellular membraneless organelle	1
intracellular anatomical structure	1
cytoplasm	1
spindle	1

Protein interactions and networks

STRING

1666 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
WAPL	PDS5A	Q29RF7	999
WAPL	NIPBL	Q6KC79	995
WAPL	PDS5B	Q9NTI5	995
WAPL	SMC3	Q9UQE7	991
WAPL	RAD21	O60216	990
WAPL	CDCA5	Q96FF9	986
WAPL	STAG1	Q8WVM7	983
WAPL	ESCO1	Q5FWF5	967
WAPL	MAU2	Q9Y6X3	962
WAPL	STAG2	Q8N3U4	958
WAPL	ESCO2	Q56NI9	956
WAPL	ESPL1	Q14674	923
WAPL	CHTF18	Q8WVB6	914
WAPL	SMC1A	Q14683	892
WAPL	CHTF8	P0CG13	849

IntAct

150 interactions, top by confidence:

A	B	Type	Score
STAG2	RAD21	psi-mi:“MI:0914”(association)	0.970
SMC3	RAD21	psi-mi:“MI:0914”(association)	0.960
SMC3	RAD21	psi-mi:“MI:0915”(physical association)	0.960
STAG1	RAD21	psi-mi:“MI:0914”(association)	0.930
SMC1A	RAD21	psi-mi:“MI:0914”(association)	0.930
SMC1A	RAD21	psi-mi:“MI:0915”(physical association)	0.930
STAG1	RAD21	psi-mi:“MI:0915”(physical association)	0.930
RAD21	SMC1A	psi-mi:“MI:0914”(association)	0.930
WAPL	STAG2	psi-mi:“MI:0914”(association)	0.920
STAG2	WAPL	psi-mi:“MI:0915”(physical association)	0.920
WAPL	RAD21	psi-mi:“MI:0914”(association)	0.910
WAPL	RAD21	psi-mi:“MI:0915”(physical association)	0.910
RAD21	WAPL	psi-mi:“MI:0403”(colocalization)	0.910
RAD21	WAPL	psi-mi:“MI:0915”(physical association)	0.910

BioGRID (295): WAPAL (Affinity Capture-MS), WAPAL (Affinity Capture-MS), WAPAL (Affinity Capture-MS), WAPAL (Affinity Capture-MS), WAPAL (Affinity Capture-MS), WAPAL (Affinity Capture-MS), WAPAL (Affinity Capture-MS), PDS5A (Affinity Capture-MS), PDS5B (Affinity Capture-MS), SMC3 (Affinity Capture-MS), STAG2 (Affinity Capture-MS), SMC1A (Affinity Capture-MS), RAD21 (Affinity Capture-MS), RAD21 (Affinity Capture-Western), STAG2 (Affinity Capture-Western)

ESM2 similar proteins: A0A0G2L7I0, A2VDP0, A2YX04, A5D979, B4FM28, B6SLJ0, D3ZVU1, F4I8S3, F4KFC7, F6UH96, G3X912, O01835, Q0J9J6, Q22557, Q24595, Q2HJG4, Q32LR5, Q38796, Q4KM91, Q53WJ1, Q5U3H2, Q65Z40, Q680Q4, Q6E3D5, Q6PI47, Q6Z8M8, Q700C2, Q7KW09, Q7XC57, Q7Y1C4, Q7Y1C5, Q7Z5K2, Q7ZXG4, Q801E2, Q8L840, Q8RY95, Q91W18, Q91ZX6, Q941B6, Q9BVC5

Diamond homologs: Q65Z40, Q7Z5K2, Q9W517

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
WAPL	“down-regulates activity”	“Cohesin complex”
CDCA5	“down-regulates activity”	WAPL	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 155 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
S Phase	6	10.4×	2e-03
SUMO E3 ligases SUMOylate target proteins	6	10.2×	2e-03
SUMOylation	6	9.3×	2e-03
Signaling by Nuclear Receptors	9	8.7×	8e-05
Resolution of Sister Chromatid Cohesion	10	8.2×	6e-05
ESR-mediated signaling	6	7.3×	5e-03
Mitotic Metaphase and Anaphase	7	6.5×	4e-03
Mitotic Anaphase	7	6.5×	4e-03

GO biological processes:

GO term	Partners	Fold	FDR
mitotic sister chromatid cohesion	5	41.9×	3e-05
sister chromatid cohesion	5	28.6×	2e-04
mitotic spindle assembly	5	12.8×	7e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	111
Likely benign	3
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

2552 predictions. Top by Δscore:

Variant	Effect	Δscore
10:86437911:GCTAC:G	donor_loss	1.0000
10:86437912:CTACT:C	donor_loss	1.0000
10:86437913:TACTT:T	donor_loss	1.0000
10:86437914:ACTTA:A	donor_loss	1.0000
10:86437915:CTTAC:C	donor_loss	1.0000
10:86437916:T:TC	donor_loss	1.0000
10:86437917:TACAG:T	donor_loss	1.0000
10:86437918:A:AC	donor_gain	1.0000
10:86437918:ACA:A	donor_loss	1.0000
10:86437919:C:CA	donor_gain	1.0000
10:86437919:C:T	donor_loss	1.0000
10:86437919:CA:C	donor_gain	1.0000
10:86437919:CAG:C	donor_gain	1.0000
10:86437919:CAGT:C	donor_gain	1.0000
10:86437919:CAGTG:C	donor_gain	1.0000
10:86438011:TTGAT:T	acceptor_gain	1.0000
10:86443273:A:AC	donor_gain	1.0000
10:86443274:C:CC	donor_gain	1.0000
10:86443274:CTGGA:C	donor_gain	1.0000
10:86443373:T:TC	acceptor_gain	1.0000
10:86446237:TATA:T	donor_loss	1.0000
10:86446239:TACC:T	donor_loss	1.0000
10:86446240:A:AT	donor_loss	1.0000
10:86446241:C:A	donor_loss	1.0000
10:86446446:ATAG:A	acceptor_gain	1.0000
10:86446447:TAG:T	acceptor_gain	1.0000
10:86446448:AG:A	acceptor_gain	1.0000
10:86446449:GC:G	acceptor_loss	1.0000
10:86446450:C:CC	acceptor_gain	1.0000
10:86446460:T:TC	acceptor_gain	1.0000

AlphaMissense

7929 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
10:86437556:A:G	L1187S	1.000
10:86437924:A:G	L1168P	1.000
10:86437932:A:C	F1165L	1.000
10:86437932:A:T	F1165L	1.000
10:86437933:A:C	F1165C	1.000
10:86437933:A:G	F1165S	1.000
10:86437934:A:G	F1165L	1.000
10:86437934:A:T	F1165I	1.000
10:86437941:A:C	F1162L	1.000
10:86437941:A:T	F1162L	1.000
10:86437942:A:G	F1162S	1.000
10:86437943:A:G	F1162L	1.000
10:86437951:A:G	L1159P	1.000
10:86437951:A:T	L1159H	1.000
10:86437971:A:C	F1152L	1.000
10:86437971:A:T	F1152L	1.000
10:86437972:A:G	F1152S	1.000
10:86437973:A:G	F1152L	1.000
10:86437987:A:G	L1147P	1.000
10:86437996:C:G	R1144P	1.000
10:86443287:G:C	C1133W	1.000
10:86443288:C:T	C1133Y	1.000
10:86443289:A:G	C1133R	1.000
10:86443291:A:G	L1132P	1.000
10:86443297:C:T	G1130E	1.000
10:86443298:C:A	G1130W	1.000
10:86443298:C:G	G1130R	1.000
10:86443298:C:T	G1130R	1.000
10:86443300:A:G	L1129P	1.000
10:86443303:A:G	L1128P	1.000

dbSNP variants (sampled 300 via entrez): RS1000003930 (10:86499175 A>C), RS1000015941 (10:86471225 T>C), RS1000114847 (10:86476269 G>A), RS1000137605 (10:86510961 G>C,T), RS1000197551 (10:86469159 A>G), RS1000241768 (10:86505576 C>G,T), RS1000250721 (10:86474357 T>TA), RS1000259895 (10:86443152 G>A,T), RS1000298906 (10:86482506 A>T), RS1000302092 (10:86515080 T>C), RS1000327644 (10:86511427 T>C), RS1000348904 (10:86437769 G>A), RS1000370853 (10:86469501 A>C), RS1000397780 (10:86476435 T>A), RS1000404054 (10:86521058 C>CT)

Disease associations

OMIM: gene MIM:610754 | disease phenotypes: MIM:614429, MIM:119800

GenCC curated gene-disease

Disease	Classification	Inheritance
complex neurodevelopmental disorder	Limited	Autosomal dominant

Mondo (5): ventricular septal defect (MONDO:0002070), polyhydramnios (MONDO:0004585), clubfoot (MONDO:0007342), neurodevelopmental disorder (MONDO:0700092), complex neurodevelopmental disorder (MONDO:0100038)

Orphanet (2): Familial clubfoot with or without associated lower limb anomalies (Orphanet:199315), NON RARE IN EUROPE: Ventricular septal defect (Orphanet:1480)

HPO phenotypes

2 total (2 of 2 shown, HPO-id order):

HPO	Term
HP:0001629	Ventricular septal defect
HP:0001561	Polyhydramnios

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST001588_8	Periodontal microbiota	4.000000e-06
GCST002337_90	Amyotrophic lateral sclerosis (sporadic)	3.000000e-06
GCST009447_13	Parental longevity (father’s age at death)	3.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0007796	parental longevity

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D003025	Clubfoot	C05.330.488.655.063; C05.330.495.681.063; C05.660.585.512.380.813.063; C16.131.621.585.512.500.681.063
D006345	Heart Septal Defects, Ventricular	C14.240.400.560.540; C14.280.400.560.540; C16.131.240.400.560.540
D065886	Neurodevelopmental Disorders	F03.625
D006831	Polyhydramnios	C12.050.703.610

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5725044 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 1,538 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1232461	MOLIBRESIB	2	1,538

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

ChEMBL bioactivities

1 potent at pChembl≥5 of 1 total, top 1 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.25	IC50	560	nM	MOLIBRESIB

PubChem BioAssay actives

1 with measured affinity, of 6 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
2-[(4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]-N-ethylacetamide	2178751: Inhibition of WAPAL (unknown origin) incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	ic50	0.5600	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects methylation, increases expression	2
Formaldehyde	decreases expression	2
Tobacco Smoke Pollution	increases expression	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression, increases expression	2
aristolochic acid I	decreases expression	1
FR900359	affects phosphorylation	1
2,4,6-tribromophenol	decreases expression	1
bisphenol A	decreases expression	1
decabromobiphenyl ether	decreases expression	1
alpha-naphthoflavone	increases expression, increases reaction	1
arsenite	affects binding, decreases reaction	1
cobaltous chloride	increases expression	1
tetrabromobisphenol A	decreases expression	1
coumarin	decreases phosphorylation	1
3-methylcholanthrylene	increases expression, increases reaction	1
perfluorooctane sulfonic acid	decreases expression	1
K 7174	increases expression	1
ICG 001	decreases expression	1
abrine	increases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
pentabrominated diphenyl ether 100	decreases expression	1
hexabrominated diphenyl ether 153	decreases expression	1
1-(4-(6-bromobenzo(1,3)dioxol-5-yl)-3a,4,5,9b-tetrahydro-3H-cyclopenta(c)quinolin-8-yl)ethanone	increases phosphorylation	1
eprenetapopt	affects expression, affects reaction	1
jinfukang	affects cotreatment, decreases expression	1
PCI 5002	affects cotreatment, increases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	decreases expression	1
Irinotecan	decreases expression	1
Arsenic Trioxide	increases expression	1
Acetaminophen	decreases expression	1

ChEMBL screening assays

6 unique, capped per target: 6 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5697481	Binding	Inhibition of WAPAL (unknown origin) assessed as fold change at 10 uM incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia. — Nature

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT02914652	PHASE4	COMPLETED	The Cardiopulmonary Effect of Inhaled Beta-2-agonists on Adult Patients Born With Ventricular Septum Defects.
NCT05688670	PHASE4	COMPLETED	Regional Anesthesia Following Pediatric Cardiac Surgery
NCT04564430	PHASE4	UNKNOWN	Clonidine for Tourniquet-related Pain in Children
NCT04766684	PHASE4	COMPLETED	Clubfoot Tenotomy Trial
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT00000470	PHASE3	COMPLETED	Infant Heart Surgery: Central Nervous System Sequelae of Circulatory Arrest
NCT00113698	PHASE3	TERMINATED	Angiotensin Converting Enzyme Inhibition in Children With Mitral Regurgitation
NCT05253209	PHASE3	TERMINATED	A Study Evaluating the Efficacy and Safety of IV L-Citrulline for the Prevention of Clinical Sequelae of Acute Lung Injury Induced by Cardiopulmonary Bypass in Pediatric Patients Undergoing Surgery for Congenital Heart Defects
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT00199771	PHASE2	COMPLETED	Hypertonic Saline Dextran in Pediatric Cardiac Surgery
NCT00556361	PHASE2	COMPLETED	Use of Ketamine Prior to Cardiopulmonary Bypass in Children
NCT00848393	PHASE2	COMPLETED	Measures to Lower the Stress Response in Pediatric Cardiac Surgery
NCT04017975	PHASE2	ACTIVE_NOT_RECRUITING	Optical Tissue Identification for Myocardial Architecture
NCT02909959	PHASE2	COMPLETED	Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
NCT06081348	PHASE2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06352372	PHASE2	COMPLETED	Safety and Efficacy of tPBM for Epileptiform Activity in Autism
NCT01825369	PHASE1	WITHDRAWN	Aberrations in Carnitine Homeostasis in Congenital Heart Disease With Increased Pulmonary Blood Flow
NCT01915277	PHASE1	COMPLETED	A Phase I Study of Dexmedetomidine Bolus and Infusion in Corrective Infant Cardiac Surgery: Safety and Pharmacokinetics
NCT00503191	PHASE1	COMPLETED	NeuroModulation Technique Treatment of Autism
NCT04475848	PHASE1	COMPLETED	A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants
NCT06300398	PHASE1	COMPLETED	IAMA-6 Oral Dose Study in Healthy Adults
NCT06310681	Not specified	COMPLETED	Pilot Testing of a Co-adapted Group Programme for Parents/Carers of Children With Complex Neurodisability
NCT07303049	Not specified	NOT_YET_RECRUITING	Cognitive Benefit of Intensive Rehabilitation Using Rhythmic Music Training in Children With Complex Neurodevelopmental Disorder
NCT01120964	PHASE1/PHASE2	COMPLETED	Intravenous L-Citrulline to Treat Children Undergoing Heart Bypass Surgery : Revised Protocol
NCT06298344	EARLY_PHASE1	COMPLETED	The Role of Thiamine After Transcatheter Closure in Children With Left-to-Right Shunt Congenital Heart Disease
NCT00005190	Not specified	COMPLETED	Reproduction and Survival After Cardiac Defect Repair
NCT00005322	Not specified	COMPLETED	Molecular Genetic Epidemiology of Endocardial Cushion Defects - SCOR in Pediatric Cardiovascular Disease
NCT00005546	Not specified	COMPLETED	Molecular Genetic Epidemiology of Three Cardiac Defects -SCOR in Pediatric Cardiovascular Disease
NCT00006272	Not specified	UNKNOWN	Study of Energy Expenditure in Infants With Ventricular Septal Defects
NCT00173186	Not specified	UNKNOWN	Aortic Regurgitation After Surgical Repair of Outlet-Type Ventricular Septal Defect
NCT00229827	Not specified	TERMINATED	Optimal Timing for Repair of Left to Right Shunt Lesions
NCT00390702	Not specified	COMPLETED	Safety and Effectiveness of the Nit-Occlud® Lê VSD Spiral Coil System
NCT00583505	Not specified	NO_LONGER_AVAILABLE	Emergency/Compassionate Use - Membranous VSD Occluder
NCT00583791	Not specified	COMPLETED	Closure of Muscular Ventricular Septal Defects With The AMPLATZER™ Muscular VSD Occluder
NCT00590382	Not specified	APPROVED_FOR_MARKETING	Emergency/Compassionate Use - Muscular VSD Occluder
NCT00647387	Not specified	COMPLETED	Closure of Muscular Ventricular Septal Defects (VSDs) With the AMPLATZER Muscular VSD (MuVSD) Occluder - Post Approval Study