WWC1

Summary

WWC1 (WW and C2 domain containing 1, HGNC:29435) is a protein-coding gene on chromosome 5q34, encoding Protein KIBRA (Q8IX03). Regulator of the Hippo signaling pathway, also known as the Salvador-Warts-Hippo (SWH) pathway.

The protein encoded by this gene is a cytoplasmic phosphoprotein that interacts with PRKC-zeta and dynein light chain-1. Alleles of this gene have been found that enhance memory in some individuals. Three transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 23286 — RefSeq curated summary.

At a glance

• GWAS associations: 14
• Clinical variants (ClinVar): 186 total
• MANE Select transcript: NM_015238

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:29435
Approved symbol	WWC1
Name	WW and C2 domain containing 1
Location	5q34
Locus type	gene with protein product
Status	Approved
Aliases	KIBRA, KIAA0869, PPP1R168
Ensembl gene	ENSG00000113645
Ensembl biotype	protein_coding
OMIM	610533
Entrez	23286

Gene structure

Transcript identifiers

Ensembl transcripts: 25 — 14 protein_coding, 7 protein_coding_CDS_not_defined, 3 retained_intron, 1 TEC

ENST00000265293, ENST00000393895, ENST00000517425, ENST00000517646, ENST00000518204, ENST00000518334, ENST00000519659, ENST00000519859, ENST00000521089, ENST00000521391, ENST00000522140, ENST00000523043, ENST00000524038, ENST00000524093, ENST00000524228, ENST00000624315, ENST00000864868, ENST00000917779, ENST00000917780, ENST00000917781, ENST00000917782, ENST00000917783, ENST00000942218, ENST00000942219, ENST00000942220

RefSeq mRNA: 3 — MANE Select: NM_015238 NM_001161661, NM_001161662, NM_015238

CCDS: CCDS4366, CCDS54945

Canonical transcript exons

ENST00000265293 — 23 exons

Exon	Start	End
ENSE00000769147	168441682	168441834
ENSE00000812765	168467840	168467964
ENSE00000915398	168423533	168424068
ENSE00000915399	168428033	168428141
ENSE00000915400	168428707	168428787
ENSE00001251399	168406198	168406327
ENSE00001869765	168291645	168292271
ENSE00001901139	168468951	168472303
ENSE00003481676	168455356	168455520
ENSE00003486326	168430137	168430223
ENSE00003487150	168453968	168454100
ENSE00003489115	168371424	168371533
ENSE00003500818	168444494	168444585
ENSE00003502808	168399488	168399567
ENSE00003515773	168414348	168414590
ENSE00003516191	168464729	168464962
ENSE00003550491	168422008	168422097
ENSE00003566773	168397724	168397800
ENSE00003644815	168385211	168385414
ENSE00003645229	168408507	168408653
ENSE00003646707	168431252	168431444
ENSE00003657130	168409922	168409995
ENSE00003693974	168460650	168460742

Expression profiles

Bgee: expression breadth ubiquitous, 268 present calls, max score 98.18.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 11.8584 / max 260.8102, expressed in 1389 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
60073	8.8295	1128
60077	1.1310	440
60076	1.0732	550
60075	0.4881	239
60072	0.3033	164
60074	0.0333	8

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
ventricular zone	UBERON:0003053	98.18	gold quality
parotid gland	UBERON:0001831	98.15	gold quality
buccal mucosa cell	CL:0002336	98.13	gold quality
metanephros cortex	UBERON:0010533	95.90	gold quality
renal medulla	UBERON:0000362	94.79	gold quality
caudate nucleus	UBERON:0001873	94.44	gold quality
putamen	UBERON:0001874	94.22	gold quality
lower esophagus mucosa	UBERON:0035834	93.90	gold quality
nephron tubule	UBERON:0001231	93.88	gold quality
adult mammalian kidney	UBERON:0000082	93.85	gold quality
nucleus accumbens	UBERON:0001882	93.49	gold quality
cortical plate	UBERON:0005343	93.25	gold quality
saliva-secreting gland	UBERON:0001044	93.20	gold quality
islet of Langerhans	UBERON:0000006	92.79	gold quality
amygdala	UBERON:0001876	92.24	gold quality
medial globus pallidus	UBERON:0002477	92.24	gold quality
ganglionic eminence	UBERON:0004023	92.12	gold quality
cingulate cortex	UBERON:0003027	92.08	gold quality
kidney	UBERON:0002113	92.04	gold quality
anterior cingulate cortex	UBERON:0009835	92.04	gold quality
minor salivary gland	UBERON:0001830	91.84	gold quality
cervix squamous epithelium	UBERON:0006922	91.76	gold quality
cortex of kidney	UBERON:0001225	91.35	gold quality
right frontal lobe	UBERON:0002810	91.30	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	91.28	gold quality
endothelial cell	CL:0000115	90.92	gold quality
prefrontal cortex	UBERON:0000451	90.75	gold quality
mouth mucosa	UBERON:0003729	90.74	gold quality
globus pallidus	UBERON:0001875	90.56	gold quality
oviduct epithelium	UBERON:0004804	90.31	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	17.15
E-MTAB-7249	yes	11.21
E-GEOD-98556	no	89.94
E-GEOD-124858	no	13.89

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): MYCN, TCF7L2, YAP1

miRNA regulators (miRDB)

115 targeting WWC1, 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-4795-3P	100.00	74.62	4024
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-520G-5P	99.99	66.76	658
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-2110	99.96	66.68	1930
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-8082	99.95	67.27	1170
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-1-3P	99.93	72.35	1914
HSA-MIR-206	99.93	72.50	1893
HSA-MIR-3682-5P	99.93	67.97	1163
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-613	99.91	71.50	1710
HSA-MIR-15A-5P	99.90	72.80	2787
HSA-MIR-15B-5P	99.90	72.78	2798
HSA-MIR-16-5P	99.90	72.80	2780
HSA-MIR-195-5P	99.90	72.81	2805
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-6838-5P	99.89	71.94	2690

Literature-anchored findings (GeneRIF, showing 40)

• Data describe the isolation of a cDNA coding for a novel protein, KIBRA, possessing two amino-terminal WW domains, an internal C2-like domain and a carboxy-terminal glutamic acid-rich stretch (PMID:12559952)
• identification as novel substrate for protein kinase C zeta and regulation of cellular function by same enzyme (PMID:15081397)
• the DLC1-KIBRA interaction is essential for ER transactivation in breast cancer cells (PMID:16684779)
• gene expression studies showed that KIBRA was expressed in memory-related brain structures; KIBRA allele-dependent differences in hippocampal activations during memory retrieval were detected (PMID:17053149)
• The impact of KIBRA on memory is most likely of high relevance in elderly subjects as it is in young. (PMID:17353070)
• The current study reveals that KIBRA (rs17070145) T allele (CT and TT genotypes) is associated with an increased risk (OR 2.89; p=0.03) for very-late-onset (after the age of 86 years) AD. (PMID:17707552)
• KIBRA may play a role in how the reproductive state influences the mammary epithelial cell to respond to changing cell-context information, such as experienced during the tissue remodeling events of mammary gland development. (PMID:18190796)
• KIBRA T–>C polymorphism contributes to modulate episodic memory amongst community-dwelling older adults free of dementia (PMID:18194457)
• No association is found between Kibra and memory performance in multiple memory tasks. (PMID:18205171)
• the KIBRA genotype could affect memory performance in a different way in those that complain of memory deficits compared to those that do not. (PMID:18378080)
• This study findings suggest that KIBRA is associated with both individual variation in normal episodic memory and predisposition to late-onset Alzheimer’s disease. (PMID:18789830)
• Results suggest a role for the T–>C substitution in intron 9 of KIBRA in a component of episodic memory involved in long-term storage in an aged population. (PMID:19397951)
• study concludes that variation in KIBRA influences cognitive flexibility in a population-specific way, and that current smoking status moderates this effect (PMID:19606085)
• This study showed that the KIBRA and CLSTN2 genes interactively modulate episodic memory performance. (PMID:19804789)
• Even if T/C polymorphism of the KIBRA gene induces memory disturbances, they may be unspecific and unselective for recurrent depressive disorder. (PMID:20150879)
• This study replicates the association between the KIBRA gene and episodic memory and suggests a possibly differential effect of the polymorphism in psychotic and non-psychotic individuals. (PMID:20185150)
• KIBRA is highly expressed in the brain and kidneys, and is reported to be involved in synaptic plasticity. Therefore, we first tried to replicate the association between the SNP and memory performance in a Japanese subjects. (PMID:20509760)
• Results show a strong association between the KIBRA gene and episodic memory impairment in Alzheimer’s disease (AD), but show no influence on AD in our Japanese cohort. KIBRA might have an effect similar to cognitive reserve. (PMID:20881395)
• KIBRA methylation occurs frequently in B-cell acute lymphocytic leukemia but not in epithelial cancers and is linked to specific genetic event in B-ALL. (PMID:21173572)
• The results of this study suggested a modest role for KIBRA as a cognition and AD risk gene, and also highlight the multifactorial complexity of its genetic associations. (PMID:21185624)
• a pooled GWAS study undertaken to find novel genes associated with episodic memory performance; a genomic locus for KIBRA was found to be associated with memory performance in three cognitively normal cohorts from Switzerland and the USA (PMID:21204039)
• KIBRA associates with and activates Lats (large tumor suppressor) 1 and 2 kinases by stimulating their phosphorylation on the hydrophobic motif (PMID:21233212)
• Potential associations of the common KIBRA rs17070450 genotype are comprehensively tested with cognitive functions in a medically well-characterized cohort of community-dwelling elderly individuals. (PMID:21346737)
• The results strongly support the notion that KIBRA regulates epithelial cell polarity by suppressing apical exocytosis through direct inhibition of aPKC kinase activity in the PAR3-aPKC-PAR6 complex. (PMID:21497093)
• No increased risk of any type of late development, and cognitive impairment was associated with KIBRA (rs17070145) (PMID:21643791)
• KIBRA protein phosphorylation is regulated by mitotic kinase aurora and protein phosphatase 1. (PMID:21878642)
• These results indicate that KIBRA regulates higher brain function by regulating AMPAR trafficking and synaptic plasticity. (PMID:21943600)
• Enhanced memory performance in KIBRA T allele carriers is linked to elevated hippocampal functioning, rather than to neural compensation in noncarriers. (PMID:21976506)
• KIBRA genotype, as well as the number of intake drug abuse problems and a younger age, were associated with an increased risk of relapse (PMID:22129841)
• analysis of clinical-pathological parameters showed that KIBRA methylation was associated with unfavorable biological prognostic parameters, including unmutated IGHV genes (p = 0.007) and high CD38 expression (p < 0.05). (PMID:22430796)
• Decreased expression of KIBRA is associated with breast cancer. (PMID:22614006)
• identified KIBRA Ser(542) and Ser(931) as main phosphorylation sites for CDK1 both in vitro and in vivo (PMID:22784093)
• The results suggest that the KIBRA rs17070145 T-allele effects are specific to episodic memory and support the hypothesis that associations between rs17070145 variation and memory are disparate between healthy and impaired populations. (PMID:22794909)
• the KIBRA-Aurora-Lats2 protein complexes form a novel axis that regulates precise mitosis. (PMID:22904328)
• findings indicate that SNP rs17070145 located within KIBRA explains 0.5 percent of the variance for episodic memory tasks and 0.1 percent of the variance for working memory tasks in samples of primarily Caucasian background (PMID:23065961)
• High expression of KIBRA is correlated with lymphatic (P = 0.046) and venous invasion (P = 0.039). (PMID:23163744)
• findings suggest that the polymorphism in the KIBRA gene affects matter volume and the function of the default-mode network and executive control network (PMID:23266749)
• study reveals an association between two WWC1 SNPs and the likelihood of PTSD development. (PMID:23582269)
• KIBRA/WWC1 rs17070145 polymorphism has effect on spatial memory in humans and age differences in the reliance on landmark and boundary-related spatial information. (PMID:23733450)
• exonic missense variants in the C2 domain modify lipid binding and cognitive performance (PMID:23778582)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	wwc1	ENSDARG00000076041
mus_musculus	Wwc1	ENSMUSG00000018849
rattus_norvegicus	Wwc1	ENSRNOG00000008065
drosophila_melanogaster	kibra	FBGN0262127

Paralogs (2): WWC3 (ENSG00000047644), WWC2 (ENSG00000151718)

Protein

Protein identifiers

Protein KIBRA — Q8IX03 (reviewed: Q8IX03)

Alternative names: HBeAg-binding protein 3, Kidney and brain protein, WW domain-containing protein 1

All UniProt accessions (4): Q8IX03, H0YAU4, H0YBE8, H3BLZ3

UniProt curated annotations — full annotation on UniProt →

Function. Regulator of the Hippo signaling pathway, also known as the Salvador-Warts-Hippo (SWH) pathway. Enhances phosphorylation of LATS1 and YAP1 and negatively regulates cell proliferation and organ growth due to a suppression of the transcriptional activity of YAP1, the major effector of the Hippo pathway. Along with NF2 can synergistically induce the phosphorylation of LATS1 and LATS2 and function in the regulation of Hippo signaling pathway. Acts as a transcriptional coactivator of ESR1 which plays an essential role in DYNLL1-mediated ESR1 transactivation. Regulates collagen-stimulated activation of the ERK/MAPK cascade. Modulates directional migration of podocytes. Plays a role in cognition and memory performance. Plays an important role in regulating AMPA-selective glutamate receptors (AMPARs) trafficking underlying synaptic plasticity and learning.

Subunit / interactions. Homodimer. Forms heterodimers with WWC2 and WWC3. Interacts with DDN. Interacts with DYNLL1 and histone H3. The interaction with DYNLL1 is mandatory for the recruitment and transactivation functions of ESR1 or DYNLL1 to the target chromatin and the interaction with histone H3 ensures proper regulatory interaction of WWC1-DYNLL1-ESR1 complexes with target chromatin. Interacts (via WW domains) with DDR1 (via PPxY motif) in a collagen-regulated manner. Interacts with PRKCZ (via the protein kinase domain). Forms a tripartite complex with DDR1 and PRKCZ, but predominantly in the absence of collagen. Interacts (via the ADDV motif) with PATJ (via PDZ domain 8). Interacts (via WW domains) with SYNPO (via PPxY motifs). Interacts with NF2 and SNX4. Interacts with DLC1 and PRKCZ. Interacts (via WW domains) with LATS1 and LATS2.

Subcellular location. Cytoplasm. Perinuclear region. Nucleus. Cell projection. Ruffle membrane. Cytosol.

Tissue specificity. Expressed in mammary epithelial cells and breast cancer cell lines. Found in the luminal epithelium surrounding the ducts in the normal breast. In the brain, expressed in somatodendritic compartment of neurons in the cortex and hippocampus and in the cerebellum it is found in the Purkinje cells and some granule cells (at protein level). Detected in brain, heart, colon and kidney. In the kidney, expressed in glomerular podocytes, in some tubules and in the collecting duct.

Post-translational modifications. Phosphorylation at Ser-542 and Ser-931 by CDK1 in response to spindle damage stress regulates mitotic exit, these two sites are dephosphorylated by CDC14B.

Domain organisation. The C2-domain mediates homodimerization. It is a calcium-sensitive lipid-binding domain with preference for PI(3)P.

Induction. Strongly up-regulated by progestin treatment.

Polymorphism. Genetic variations in WWC1 define the memory quantitative trait locus (MEMRYQTL) [MIM:615602].

Similarity. Belongs to the WWC family. KIBRA subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
Q8IX03-1	1	yes
Q8IX03-2	2

RefSeq proteins (3): NP_001155133, NP_001155134, NP_056053* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000008	C2_dom	Domain
IPR001202	WW_dom	Domain
IPR035892	C2_domain_sf	Homologous_superfamily
IPR036020	WW_dom_sf	Homologous_superfamily
IPR037771	C2_WWC	Domain
IPR051105	WWC/KIBRA_Hippo_Reg	Family
IPR057747	WWC1_hairpin	Domain

Pfam: PF00168, PF00397, PF25802

UniProt features (55 total): modified residue 11, strand 10, sequence conflict 7, region of interest 6, compositionally biased region 4, domain 3, coiled-coil region 3, sequence variant 3, helix 3, turn 2, chain 1, short sequence motif 1, splice variant 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
2Z0U	X-RAY DIFFRACTION	2.2
6FB4	X-RAY DIFFRACTION	2.42
6FJC	X-RAY DIFFRACTION	2.6
6FD0	X-RAY DIFFRACTION	2.64
6FJD	X-RAY DIFFRACTION	2.9

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8IX03-F1	61.72	0.11

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): 141, 535, 542, 899, 912, 927, 929, 931, 947, 975, 978

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-2028269	Signaling by Hippo
R-HSA-9013508	NOTCH3 Intracellular Domain Regulates Transcription
R-HSA-157118	Signaling by NOTCH
R-HSA-162582	Signal Transduction
R-HSA-9012852	Signaling by NOTCH3

MSigDB gene sets: 235 (showing top): REACTOME_SIGNALING_BY_NOTCH, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, GOBP_ESTABLISHMENT_OR_MAINTENANCE_OF_CELL_POLARITY, GOBP_REGULATION_OF_DEVELOPMENTAL_GROWTH, GCANCTGNY_MYOD_Q6, GOBP_GROWTH, GOBP_POSITIVE_REGULATION_OF_MAPK_CASCADE, TGACCTY_ERR1_Q2, TAL1ALPHAE47_01, GOBP_HIPPO_SIGNALING, GOCC_RUFFLE, GOBP_NEGATIVE_REGULATION_OF_DEVELOPMENTAL_GROWTH, GOBP_NEGATIVE_REGULATION_OF_INTRACELLULAR_SIGNAL_TRANSDUCTION, GOBP_NEGATIVE_REGULATION_OF_ORGAN_GROWTH, GOBP_ESTABLISHMENT_OF_CELL_POLARITY

GO Biological Process (12): negative regulation of transcription by RNA polymerase II (GO:0000122), regulation of DNA-templated transcription (GO:0006355), negative regulation of cell population proliferation (GO:0008285), cell migration (GO:0016477), establishment of cell polarity (GO:0030010), hippo signaling (GO:0035329), regulation of hippo signaling (GO:0035330), negative regulation of hippo signaling (GO:0035331), positive regulation of MAPK cascade (GO:0043410), negative regulation of organ growth (GO:0046621), positive regulation of hippo signaling (GO:0035332), positive regulation of DNA-templated transcription (GO:0045893)

GO Molecular Function (5): transcription coactivator activity (GO:0003713), kinase binding (GO:0019900), signaling adaptor activity (GO:0035591), molecular adaptor activity (GO:0060090), protein binding (GO:0005515)

GO Cellular Component (8): nucleus (GO:0005634), cytoplasm (GO:0005737), cytosol (GO:0005829), ruffle membrane (GO:0032587), perinuclear region of cytoplasm (GO:0048471), plasma membrane (GO:0005886), membrane (GO:0016020), cell projection (GO:0042995)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Signal Transduction	2
Signaling by NOTCH3	1
Signaling by NOTCH	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
hippo signaling	3
DNA-templated transcription	2
regulation of hippo signaling	2
positive regulation of intracellular signal transduction	2
binding	2
cytoplasm	2
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
negative regulation of DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
cell population proliferation	1
regulation of cell population proliferation	1
negative regulation of cellular process	1
cell motility	1
establishment or maintenance of cell polarity	1
intracellular signal transduction	1
regulation of intracellular signal transduction	1
negative regulation of intracellular signal transduction	1
MAPK cascade	1
regulation of MAPK cascade	1
organ growth	1
regulation of organ growth	1
negative regulation of developmental growth	1
negative regulation of multicellular organismal process	1
regulation of DNA-templated transcription	1
positive regulation of RNA biosynthetic process	1
transcription coregulator activity	1
positive regulation of DNA-templated transcription	1
enzyme binding	1
protein-macromolecule adaptor activity	1
molecular_function	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
ruffle	1
cell projection membrane	1
leading edge membrane	1
membrane	1
cell periphery	1

Protein interactions and networks

STRING

988 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
WWC1	DDN	O94850	998
WWC1	NF2	P35240	979
WWC1	KIAA0513	O60268	925
WWC1	PRKCZ	Q05513	846
WWC1	SAV1	Q9H4B6	838
WWC1	SNX4	O95219	831
WWC1	FRMD6	Q96NE9	825
WWC1	LATS2	Q9NRM7	814
WWC1	DYNLL1	P63167	801
WWC1	LATS1	O95835	794
WWC1	INTS4	Q96HW7	785
WWC1	CCDC192	P0DO97	767
WWC1	CTXN3	Q4LDR2	764
WWC1	GFER	P55789	747
WWC1	AMOT	Q4VCS5	736

IntAct

49 interactions, top by confidence:

A	B	Type	Score
PRKCZ	PRKCI	psi-mi:“MI:0914”(association)	0.890
DYNLL1	BLTP3B	psi-mi:“MI:0914”(association)	0.730
PRKCZ	NIPSNAP2	psi-mi:“MI:0914”(association)	0.730
RHPN1	PODXL	psi-mi:“MI:0914”(association)	0.690
DYNLL2	BLTP3B	psi-mi:“MI:0914”(association)	0.640
ARRDC1	NEDD4	psi-mi:“MI:0914”(association)	0.640
YWHAH	PLEKHG3	psi-mi:“MI:0914”(association)	0.610
PRKCZ	IPO5	psi-mi:“MI:0914”(association)	0.530
PARD6B	ZZEF1	psi-mi:“MI:0914”(association)	0.530
WWC1	EPB41L2	psi-mi:“MI:0914”(association)	0.530
YWHAB	PLEKHG3	psi-mi:“MI:0914”(association)	0.480
YWHAQ	PLEKHG3	psi-mi:“MI:0914”(association)	0.480
WWC1	USP19	psi-mi:“MI:0407”(direct interaction)	0.440
WWC1	YWHAZ	psi-mi:“MI:0915”(physical association)	0.400
WWC1		psi-mi:“MI:0915”(physical association)	0.370
WWC1	MAPK6	psi-mi:“MI:0915”(physical association)	0.370
	WWC1	psi-mi:“MI:0915”(physical association)	0.370
C	WWC1	psi-mi:“MI:0915”(physical association)	0.370
Xpo1	IFT56	psi-mi:“MI:0914”(association)	0.350
YWHAG	C1orf226	psi-mi:“MI:0914”(association)	0.350
PRKCZ	POLRMT	psi-mi:“MI:0914”(association)	0.350
M		psi-mi:“MI:0914”(association)	0.350
YWHAE	DEPDC5	psi-mi:“MI:0914”(association)	0.350

BioGRID (160): WWC1 (Affinity Capture-RNA), WWC1 (Affinity Capture-RNA), WWC1 (Affinity Capture-MS), WWC1 (Affinity Capture-MS), WWC1 (Affinity Capture-Western), PTPN14 (Affinity Capture-Western), WWC1 (Affinity Capture-Western), LATS1 (Affinity Capture-Western), YWHAB (Affinity Capture-MS), YWHAE (Affinity Capture-MS), YWHAH (Affinity Capture-MS), YWHAG (Affinity Capture-MS), YWHAQ (Affinity Capture-MS), AMOT (Affinity Capture-MS), ATAD3A (Affinity Capture-MS)

ESM2 similar proteins: A0A0G2JUG7, A1L390, E9Q0S6, O08774, O14924, O15085, O43182, O54834, O54960, O60307, O75052, P57095, Q13009, Q3U1V8, Q3U214, Q3UHC7, Q4VAC9, Q5DU25, Q5JU85, Q5RBI7, Q5SXA9, Q5VWQ8, Q60610, Q64512, Q6AX33, Q6DN90, Q6NXJ0, Q6P0Q8, Q6P1I6, Q6ZMN7, Q76G19, Q76LL6, Q76M68, Q7T2V3, Q810W7, Q8CGE9, Q8IX03, Q8R0S2, Q8R4H2, Q8WYP3

Diamond homologs: A0A8C0NGY6, A0A8I3PQN6, A1A5G4, A1CQG2, A1D3C5, A2QQ28, A4IIJ3, B0XQ72, B3LWS4, B3P3M8, B4HEJ6, B4K6I9, B4M5X4, B4NAD3, B4PSQ2, B8N7E5, D6C652, G0S9J5, H2LBU8, O14326, O88382, P39940, P46934, P46935, P46936, P46937, P46938, Q0CCL1, Q19404, Q1L8J7, Q2EJA0, Q2UBP1, Q32NJ6, Q45VV3, Q4L1J4, Q4WTF3, Q54T86, Q5BDP1, Q5F488, Q5RBF2

SIGNOR signaling

19 interactions.

A	Effect	B	Mechanism
AURKA	unknown	WWC1	phosphorylation
AURKB	unknown	WWC1	phosphorylation
MAPK1	unknown	WWC1	phosphorylation
MAPK3	unknown	WWC1	phosphorylation
RPS6KA1	up-regulates	WWC1	phosphorylation
RPS6KA3	up-regulates	WWC1	phosphorylation
RPS6K	up-regulates	WWC1	phosphorylation
WWC1	“up-regulates activity”	STK3
WWC1	“up-regulates activity”	STK4
WWC1	“up-regulates activity”	LATS1/2	binding
YAP1	“up-regulates quantity by expression”	WWC1	“transcriptional regulation”
WWC1	“up-regulates activity”	STK3/4
Gbeta	unknown	WWC1	phosphorylation
ERK1/2	unknown	WWC1	phosphorylation
PRKCZ	unknown	WWC1	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 50 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
Activation of BAD and translocation to mitochondria	6	126.9×	4e-10
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	6	112.0×	4e-10
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	6	112.0×	4e-10
Activation of BH3-only proteins	6	82.8×	3e-09
RHO GTPases activate PKNs	6	52.9×	4e-08
Intrinsic Pathway for Apoptosis	6	48.8×	6e-08
SARS-CoV-1-host interactions	6	29.3×	1e-06
Apoptosis	6	28.0×	1e-06

GO biological processes:

GO term	Partners	Fold	FDR
protein targeting	5	43.6×	2e-05
intracellular protein localization	7	17.4×	2e-05
protein phosphorylation	6	9.7×	3e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	145
Likely benign	7
Benign	8

Top pathogenic / likely-pathogenic (0)

SpliceAI

4781 predictions. Top by Δscore:

Variant	Effect	Δscore
5:168292269:CAGG:C	donor_loss	1.0000
5:168292270:AGGTA:A	donor_loss	1.0000
5:168292271:GGTA:G	donor_loss	1.0000
5:168292272:G:A	donor_loss	1.0000
5:168292273:T:G	donor_loss	1.0000
5:168371529:CACCA:C	donor_gain	1.0000
5:168371530:ACCA:A	donor_gain	1.0000
5:168371531:CCA:C	donor_gain	1.0000
5:168371532:CA:C	donor_gain	1.0000
5:168371532:CAGT:C	donor_loss	1.0000
5:168371534:G:A	donor_loss	1.0000
5:168371534:G:GG	donor_gain	1.0000
5:168371536:AA:A	donor_loss	1.0000
5:168385387:GAGCA:G	donor_gain	1.0000
5:168385412:GCT:G	donor_gain	1.0000
5:168385415:G:GG	donor_gain	1.0000
5:168397719:TACA:T	acceptor_loss	1.0000
5:168397720:ACAGT:A	acceptor_gain	1.0000
5:168397722:A:AC	acceptor_loss	1.0000
5:168397722:A:AG	acceptor_gain	1.0000
5:168397722:AGT:A	acceptor_gain	1.0000
5:168397723:G:GC	acceptor_gain	1.0000
5:168397723:GT:G	acceptor_gain	1.0000
5:168397723:GTG:G	acceptor_gain	1.0000
5:168397723:GTGGT:G	acceptor_gain	1.0000
5:168399475:T:TA	acceptor_gain	1.0000
5:168399478:T:A	acceptor_gain	1.0000
5:168399486:A:AG	acceptor_gain	1.0000
5:168399487:G:GG	acceptor_gain	1.0000
5:168399563:AAGAA:A	donor_gain	1.0000

AlphaMissense

7247 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:168292186:T:A	W12R	1.000
5:168292186:T:C	W12R	1.000
5:168292219:T:G	Y23D	1.000
5:168292252:T:A	W34R	1.000
5:168292252:T:C	W34R	1.000
5:168292254:G:C	W34C	1.000
5:168292254:G:T	W34C	1.000
5:168371479:T:A	W59R	1.000
5:168371479:T:C	W59R	1.000
5:168371481:G:C	W59C	1.000
5:168371481:G:T	W59C	1.000
5:168455485:T:C	F930L	1.000
5:168455487:C:A	F930L	1.000
5:168455487:C:G	F930L	1.000
5:168292188:G:C	W12C	0.999
5:168292188:G:T	W12C	0.999
5:168292261:C:T	P37S	0.999
5:168292262:C:A	P37Q	0.999
5:168292265:G:C	R38P	0.999
5:168371443:T:C	F47L	0.999
5:168371444:T:C	F47S	0.999
5:168371445:T:A	F47L	0.999
5:168371445:T:G	F47L	0.999
5:168371454:C:G	C50W	0.999
5:168371468:T:C	L55S	0.999
5:168371471:C:A	P56Q	0.999
5:168371476:G:A	G58R	0.999
5:168371476:G:C	G58R	0.999
5:168371477:G:A	G58E	0.999
5:168371480:G:C	W59S	0.999

dbSNP variants (sampled 300 via entrez): RS1000013520 (5:168440394 A>T), RS1000014535 (5:168458096 T>C), RS1000034667 (5:168402271 G>A), RS1000059887 (5:168369883 A>G,T), RS1000070396 (5:168448888 G>A), RS1000113441 (5:168317301 C>T), RS1000131357 (5:168454628 G>A), RS1000164326 (5:168339133 G>A), RS1000164558 (5:168347182 C>G), RS1000167780 (5:168305627 G>T), RS1000173240 (5:168413018 T>C), RS1000213460 (5:168376063 T>A,G), RS1000231193 (5:168417406 A>C,G), RS1000238523 (5:168434471 T>G), RS1000241036 (5:168417735 T>C)

Disease associations

OMIM: gene MIM:610533 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

14 associations (top):

Study	Trait	p-value
GCST001588_7	Periodontal microbiota	1.000000e-06
GCST003542_122	Night sleep phenotypes	5.000000e-06
GCST006922_13	Regular attendance at a religious group	5.000000e-10
GCST007022_2	Type 2 diabetes nephropathy including microalbuminuria	1.000000e-06
GCST007326_61	Number of sexual partners	5.000000e-09
GCST008476_2	Emphysema annual change measurement in smokers (percent low attenuation area)	4.000000e-07
GCST008476_26	Emphysema annual change measurement in smokers (percent low attenuation area)	5.000000e-06
GCST008549_4	Mental health study participation (provided email address)	3.000000e-08
GCST009008_3	Epithelial ovarian cancer	9.000000e-07
GCST009203_3	Cerebellum cortex volume	7.000000e-06
GCST009391_1672	Metabolite levels	8.000000e-06
GCST009391_452	Metabolite levels	4.000000e-06
GCST009391_891	Metabolite levels	3.000000e-06
GCST010988_347	Adult body size	2.000000e-08

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0009592	social interaction measurement
EFO:0007626	emphysema imaging measurement
EFO:0010130	health study participation
EFO:0010470	carnosine measurement
EFO:0010521	phosphocreatine measurement
EFO:0010440	triacylglycerol 58:6 measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, affects cotreatment, increases expression	6
trichostatin A	affects cotreatment, increases expression	3
Benzo(a)pyrene	affects methylation, decreases expression	3
Estradiol	affects binding, increases reaction, increases expression	3
Panobinostat	affects cotreatment, increases expression	2
Cisplatin	affects cotreatment, decreases expression, affects response to substance	2
Formaldehyde	decreases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Tobacco Smoke Pollution	decreases expression	2
Cyclosporine	decreases expression	2
Raloxifene Hydrochloride	affects expression, decreases expression	2
bisphenol F	increases methylation	1
napabucasin	decreases expression	1
pirinixic acid	affects binding, increases activity, increases expression	1
bisphenol A	decreases expression	1
2,5,2’,5’-tetrachlorobiphenyl	decreases expression	1
beta-lapachone	increases expression	1
afimoxifene	decreases reaction, increases expression	1
sodium arsenite	decreases expression	1
rutecarpine	decreases expression	1
nickel sulfate	decreases expression	1
coumarin	decreases phosphorylation	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
ICG 001	increases expression	1
abrine	increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
jinfukang	affects cotreatment, decreases expression	1
Temozolomide	increases expression	1

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_3377	HCC3153	Cancer cell line	Female
CVCL_WW15	NCC-375	Cancer cell line	Female

Clinical trials (associated diseases)

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