WLS

Summary

WLS (Wnt ligand secretion mediator, HGNC:30238) is a protein-coding gene on chromosome 1p31.3, encoding Protein wntless homolog (Q5T9L3). Regulates Wnt proteins sorting and secretion in a feedback regulatory mechanism.

Enables Wnt-protein binding activity and identical protein binding activity. Involved in positive regulation of cell communication and protein transport. Located in several cellular components, including Golgi apparatus; early endosome; and endoplasmic reticulum membrane. Implicated in Zaki syndrome.

Source: NCBI Gene 79971 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Zaki syndrome (Strong, GenCC)
• GWAS associations: 28
• Clinical variants (ClinVar): 7 total
• Phenotypes (HPO): 52
• MANE Select transcript: NM_024911

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:30238
Approved symbol	WLS
Name	Wnt ligand secretion mediator
Location	1p31.3
Locus type	gene with protein product
Status	Approved
Aliases	FLJ23091, MRP, EVI, mig-14
Ensembl gene	ENSG00000116729
Ensembl biotype	protein_coding
OMIM	611514
Entrez	79971

Gene structure

Transcript identifiers

Ensembl transcripts: 17 — 12 protein_coding, 4 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000262348, ENST00000354777, ENST00000370971, ENST00000370973, ENST00000370976, ENST00000471243, ENST00000491076, ENST00000491811, ENST00000497187, ENST00000498615, ENST00000527864, ENST00000530486, ENST00000533537, ENST00000534713, ENST00000911092, ENST00000911093, ENST00000963588

RefSeq mRNA: 3 — MANE Select: NM_024911 NM_001002292, NM_001193334, NM_024911

CCDS: CCDS30750, CCDS53331, CCDS642

Canonical transcript exons

ENST00000262348 — 12 exons

Exon	Start	End
ENSE00001007048	68137780	68137933
ENSE00001066661	68125360	68126335
ENSE00001454029	68232194	68232523
ENSE00003491318	68155099	68155260
ENSE00003507366	68150188	68150356
ENSE00003539589	68193955	68194227
ENSE00003593243	68145869	68146012
ENSE00003599222	68148136	68148199
ENSE00003611288	68144569	68144652
ENSE00003611996	68159123	68159247
ENSE00003684625	68148563	68148660
ENSE00003786865	68153517	68153653

Expression profiles

Bgee: expression breadth ubiquitous, 284 present calls, max score 98.79.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 62.0527 / max 1912.9067, expressed in 1636 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
12782	50.2976	1614
12783	11.7552	1537

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
stromal cell of endometrium	CL:0002255	98.79	gold quality
choroid plexus epithelium	UBERON:0003911	98.41	gold quality
pigmented layer of retina	UBERON:0001782	98.32	gold quality
corpus epididymis	UBERON:0004359	97.85	gold quality
lower esophagus muscularis layer	UBERON:0035833	97.83	gold quality
lower esophagus	UBERON:0013473	97.80	gold quality
mucosa of stomach	UBERON:0001199	97.79	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	97.72	gold quality
islet of Langerhans	UBERON:0000006	97.66	gold quality
gall bladder	UBERON:0002110	97.37	gold quality
cranial nerve II	UBERON:0000941	97.26	gold quality
endothelial cell	CL:0000115	97.25	gold quality
bronchial epithelial cell	CL:0002328	97.18	gold quality
caput epididymis	UBERON:0004358	97.05	gold quality
seminal vesicle	UBERON:0000998	96.92	gold quality
secondary oocyte	CL:0000655	96.90	gold quality
germinal epithelium of ovary	UBERON:0001304	96.82	gold quality
muscle layer of sigmoid colon	UBERON:0035805	96.79	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	96.76	gold quality
rectum	UBERON:0001052	96.29	gold quality
smooth muscle tissue	UBERON:0001135	96.18	gold quality
mucosa of paranasal sinus	UBERON:0005030	96.09	gold quality
urinary bladder	UBERON:0001255	96.07	gold quality
renal medulla	UBERON:0000362	95.95	gold quality
cauda epididymis	UBERON:0004360	95.92	gold quality
pancreas	UBERON:0001264	95.91	gold quality
esophagus squamous epithelium	UBERON:0006920	95.82	gold quality
left ovary	UBERON:0002119	95.79	gold quality
epithelium of bronchus	UBERON:0002031	95.75	gold quality
bronchus	UBERON:0002185	95.64	gold quality

Single-cell (SCXA)

Detected in 10 experiment(s), a significant marker in 10.

Experiment	Marker?	Max mean expression
E-MTAB-7008	yes	996.69
E-MTAB-9154	yes	705.99
E-HCAD-56	yes	562.72
E-MTAB-10485	yes	430.17
E-HCAD-5	yes	396.12
E-GEOD-75140	yes	370.22
E-MTAB-6108	yes	349.34
E-MTAB-10018	yes	250.07
E-GEOD-84465	yes	11.29
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

49 targeting WLS, 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-3148	99.97	75.06	6478
HSA-MIR-10527-5P	99.91	72.28	3754
HSA-MIR-10523-5P	99.91	69.22	2038
HSA-MIR-605-3P	99.88	69.22	1833
HSA-MIR-579-3P	99.86	71.66	3628
HSA-MIR-4503	99.85	71.45	1869
HSA-MIR-659-3P	99.85	70.69	1620
HSA-MIR-664B-3P	99.84	71.65	3590
HSA-MIR-374C-5P	99.80	72.06	2910
HSA-MIR-655-3P	99.80	72.19	2909
HSA-MIR-448	99.79	72.37	2103
HSA-MIR-200A-5P	99.76	69.10	949
HSA-MIR-200B-5P	99.76	69.05	948
HSA-MIR-29B-2-5P	99.67	68.98	1726
HSA-MIR-4470	99.66	69.35	1767
HSA-MIR-586	99.65	70.40	2051
HSA-MIR-4666B	99.64	68.69	1282
HSA-MIR-3975	99.62	65.97	697
HSA-MIR-451B	99.55	68.28	1380
HSA-MIR-549A-3P	99.54	68.17	825
HSA-MIR-888-3P	99.53	69.77	1057
HSA-MIR-154-3P	99.50	70.05	831
HSA-MIR-487A-3P	99.50	69.95	840
HSA-MIR-4672	99.50	71.58	2893
HSA-MIR-3612	99.45	66.02	1333
HSA-MIR-650	99.45	65.77	1309
HSA-MIR-6165	99.44	67.12	1389
HSA-MIR-5683	99.36	68.59	2083
HSA-MIR-548V	99.29	69.47	1157
HSA-MIR-548AS-3P	99.12	69.12	2294

Literature-anchored findings (GeneRIF, showing 34)

• These findings suggest a previously unrecognized role for GPR177 in regulating cellular response to opioid agonist drugs, and could create new avenues of investigation regarding the pharmacotherapy of drug dependence. (PMID:20214800)
• The relatively ubiquitous expression of GPR177 suggests that this protein may serve to regulate Wnt secretion in a variety of embryonic and adult tissue types. (PMID:20652957)
• Findings demonstrate that endocytosis motifs can occur in the intracellular loops of multipass membrane proteins and, moreover, provide direct evidence that the trafficking of Wls is required for efficient secretion of Wnt signaling proteins. (PMID:22027831)
• The Evi/Wls overexpression is sufficient to promote downstream Wnt signalling. (PMID:22147553)
• WLS functions as a negative regulator of melanoma proliferation and spontaneous metastasis by activating WNT/beta-catenin signalling. (PMID:23129487)
• findings lead to a proposed mechanism by which Gpr177 controls skeletal development through modulation of autocrine and paracrine Wnt signals in a lineage-specific fashion (PMID:23188710)
• The data suggest that the common variants of WLS analyzed in this study are not associated with opioid or cocaine addiction. (PMID:23566366)
• Evi expression in psoriatic skin biopsies is down-regulated, suggesting that Evi-deficient mice developed skin lesions that resemble human psoriasis. (PMID:23918954)
• Colorectal tumors express elevated levels of Wnt3 and GPR177. (PMID:24162018)
• endogenous WLS binds Wnts in the endoplasmic reticulum, cycles to the plasma membrane, and then returns to the endoplasmic reticulum through the Golgi. (PMID:24768165)
• GPR177 played an essential role in disease relapse and poor survival in patients with B-cell precursor acute lymphoblastic leukemia. (PMID:25115440)
• This study has revealed a strong association between the expression of WLS and HER2 that has important biological and clinical implications. (PMID:25258105)
• This study identified CMTM8 as a new candidate tumor suppressor gene and GPR177 as a new candidate oncogene in osteosarcoma. (PMID:25551557)
• Dysfunction of Wntless triggers the retrograde Golgi-to-ER transport of Wingless and induces ER stress. (PMID:26887613)
• Genetic variation at the WLS and CCDC170/ESR1 loci were found to be significantly associated with bone mineral density (PMID:26911590)
• These results indicate that WLS may play a role in invasion and metastasis of colorectal carcinoma. (PMID:27102079)
• we identified novel associations in WLS , ARHGAP1 , and 5’ of MEF2C ( P- values < 8x10 - 5 ; false discovery rate (FDR) q-values < 0.01) that were much more strongly associated with BMD compared to the GWAS SNPs. (PMID:27616567)
• Our data suggest that Wls protein is related to tumor metastasis and advanced TNM stage, and may be used as a new marker for prognosis of gastric carcinoma. (PMID:28110490)
• Wls-SEC12 binding is stable, with the interacting interface biochemically mapped to cytosolic segments of individual proteins. Mutant Wls that fails to communicate with the COPII machinery cannot effectively support Wnt secretion. These data suggest that formation of early Wnt secretory vesicles is carefully regulated to ensure proper export of functional ligands (PMID:28515233)
• WLS is an important locus for osteoporosis and its related quantitative phenotypes in a large sample derived from the Chinese Han population. In addition to the significant single SNPs that we identified, a possible regulatory role for the 20 kb genomic region around the most significant SNP, rs2566752, was defined by combining our results with ENCODE histone mark data. (PMID:29057911)
• These data showed that Wls was differentially expressed in HCC. Statistical analysis results suggest that Wls expression might increase as HCC progresses. (PMID:29127606)
• Wls is differentially expressed in Intrahepatic Cholangiocarcinoma tissues and positively related to tumor stage and lymphatic invasion. (PMID:29526886)
• GPR177 as a novel candidate for prognostic marker as well as a promising target for treatment of gastric cancer patients. (PMID:29555015)
• This study provides a brand new evidence that GOLPH3 promotes glioma cell proliferation by facilitating Wls recycling and Wnt/beta-catenin signaling. (PMID:29990993)
• MicroRNA-31 Regulates Expression of Wntless in Both Drosophila melanogaster and Human Oral Cancer Cells. (PMID:33007980)
• SNHG17 upregulates WLS expression to accelerate lung adenocarcinoma progression by sponging miR-485-5p. (PMID:33109341)
• Structural Basis of WLS/Evi-Mediated Wnt Transport and Secretion. (PMID:33357447)
• Responses of Porcupine and Wntless proteins to oxidative, hypoxic and endoplasmic reticulum stresses. (PMID:34015469)
• Cryo-EM structure of human Wntless in complex with Wnt3a. (PMID:34315898)
• GPR177 in A-fiber sensory neurons drives diabetic neuropathic pain via WNT-mediated TRPV1 activation. (PMID:35385340)
• Mutations in the WLS are associated with dental anomalies, torus palatinus, and torus mandibularis. (PMID:36374649)
• The role of Evi/Wntless in exporting Wnt proteins. (PMID:36763105)
• Compound heterozygous variants in WLS gene causes Zaki syndrome. (PMID:37005218)
• Expanding the phenotypic spectrum and clinical severity associated with WLS gene. (PMID:37106064)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	wls	ENSDARG00000009534
mus_musculus	Wls	ENSMUSG00000028173
rattus_norvegicus	Wls	ENSRNOG00000036816
drosophila_melanogaster	wls	FBGN0036141
caenorhabditis_elegans		WBGENE00003246

Protein

Protein identifiers

Protein wntless homolog — Q5T9L3 (reviewed: Q5T9L3)

Alternative names: Integral membrane protein GPR177, Protein evenness interrupted homolog, Putative NF-kappa-B-activating protein 373

All UniProt accessions (8): Q5T9L3, E9PJW4, E9PKJ0, E9PM23, E9PM62, E9PQK1, H0YCG9, Q7Z430

UniProt curated annotations — full annotation on UniProt →

Function. Regulates Wnt proteins sorting and secretion in a feedback regulatory mechanism. This reciprocal interaction plays a key role in the regulation of expression, subcellular location, binding and organelle-specific association of Wnt proteins. Plays also an important role in establishment of the anterior-posterior body axis formation during development.

Subunit / interactions. Interacts with WNT3A. Interacts with WNT1, WNT3 and WNT5A.

Subcellular location. Golgi apparatus membrane. Cytoplasmic vesicle membrane. Cell membrane. Endoplasmic reticulum membrane. Early endosome membrane.

Post-translational modifications. N-glycosylated.

Disease relevance. Zaki syndrome (ZKS) [MIM:619648] An autosomal recessive disorder characterized by developmental delay, progressive microcephaly, and short stature, as well as dysmorphic features including sparse scalp hair, cupped ears, wide nose and mouth, short philtrum, and high-arched palate. Other variable features have been observed, including ocular, skeletal, cardiac, and renal anomalies. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the wntless family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q5T9L3-1	1	yes
Q5T9L3-2	2
Q5T9L3-3	3

RefSeq proteins (3): NP_001002292, NP_001180263, NP_079187* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR009551	Wntless	Family
IPR047843	WLS-like_TM	Domain
IPR053936	WLS_GOLD	Domain

Pfam: PF06664, PF21883

UniProt features (62 total): helix 16, strand 16, topological domain 9, transmembrane region 8, sequence variant 5, splice variant 3, turn 2, chain 1, region of interest 1, sequence conflict 1

Structure

Experimental structures (PDB)

6 structures.

PDB	Method	Resolution (Å)
7DRT	ELECTRON MICROSCOPY	2.2
8TZO	ELECTRON MICROSCOPY	3.1
7KC4	ELECTRON MICROSCOPY	3.19
8TZP	ELECTRON MICROSCOPY	3.23
8TZR	ELECTRON MICROSCOPY	3.5
8TZS	ELECTRON MICROSCOPY	3.84

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q5T9L3-F1	82.84	0.48

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-3238698	WNT ligand biogenesis and trafficking

MSigDB gene sets: 432 (showing top): GOBP_HINDBRAIN_DEVELOPMENT, GOBP_AXIS_SPECIFICATION, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, GOBP_FORMATION_OF_PRIMARY_GERM_LAYER, PAL_PRMT5_TARGETS_UP, GOZGIT_ESR1_TARGETS_DN, GOBP_CANONICAL_NF_KAPPAB_SIGNAL_TRANSDUCTION, GOBP_POSITIVE_REGULATION_OF_PROTEIN_LOCALIZATION, GAUSSMANN_MLL_AF4_FUSION_TARGETS_A_UP, GOBP_REGULATION_OF_WNT_SIGNALING_PATHWAY, GOBP_TOOTH_MINERALIZATION, GOBP_CELL_CELL_SIGNALING, GOBP_PANCREAS_DEVELOPMENT, GOBP_DIGESTIVE_SYSTEM_DEVELOPMENT, PICCALUGA_ANGIOIMMUNOBLASTIC_LYMPHOMA_UP

GO Biological Process (13): mesoderm formation (GO:0001707), intracellular protein transport (GO:0006886), anterior/posterior axis specification (GO:0009948), Wnt signaling pathway (GO:0016055), positive regulation of Wnt signaling pathway (GO:0030177), midbrain development (GO:0030901), hindbrain development (GO:0030902), exocrine pancreas development (GO:0031017), positive regulation of canonical NF-kappaB signal transduction (GO:0043123), Wnt protein secretion (GO:0061355), positive regulation of Wnt protein secretion (GO:0061357), cementum mineralization (GO:0071529), positive regulation of canonical Wnt signaling pathway (GO:0090263)

GO Molecular Function (3): Wnt-protein binding (GO:0017147), identical protein binding (GO:0042802), protein binding (GO:0005515)

GO Cellular Component (17): Golgi membrane (GO:0000139), early endosome (GO:0005769), endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), Golgi apparatus (GO:0005794), trans-Golgi network (GO:0005802), cytosol (GO:0005829), plasma membrane (GO:0005886), endomembrane system (GO:0012505), endocytic vesicle membrane (GO:0030666), organelle membrane (GO:0031090), cytoplasmic vesicle (GO:0031410), early endosome membrane (GO:0031901), extracellular exosome (GO:0070062), endosome (GO:0005768), membrane (GO:0016020), cytoplasmic vesicle membrane (GO:0030659)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Signaling by WNT	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cytoplasm	4
endomembrane system	3
cellular anatomical structure	3
brain development	2
anatomical structure development	2
protein binding	2
bounding membrane of organelle	2
intracellular membrane-bounded organelle	2
membrane	2
cytoplasmic vesicle	2
formation of primary germ layer	1
mesoderm morphogenesis	1
intracellular protein localization	1
protein transport	1
intracellular transport	1
axis specification	1
anterior/posterior pattern specification	1
cell surface receptor signaling pathway	1
positive regulation of signal transduction	1
Wnt signaling pathway	1
regulation of Wnt signaling pathway	1
pancreas development	1
exocrine system development	1
gland development	1
digestive system development	1
canonical NF-kappaB signal transduction	1
regulation of canonical NF-kappaB signal transduction	1
positive regulation of intracellular signal transduction	1
protein secretion	1
signal release	1
positive regulation of cell communication	1
positive regulation of signaling	1
positive regulation of protein secretion	1
Wnt protein secretion	1
regulation of Wnt protein secretion	1
tooth mineralization	1
positive regulation of Wnt signaling pathway	1
canonical Wnt signaling pathway	1
regulation of canonical Wnt signaling pathway	1
binding	1

Protein interactions and networks

STRING

938 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
WLS	TGFBR3	Q03167	791
WLS	WNT1	P04628	789
WLS	PORCN	Q9H237	710
WLS	VPS35	Q96QK1	698
WLS	LRP5	O75197	693
WLS	VPS29	Q9UBQ0	682
WLS	AXIN2	Q9Y2T1	657
WLS	WNT5A	P41221	617
WLS	WNT3A	P56704	585
WLS	WNT4	P56705	584
WLS	CTNNB1	P35222	584
WLS	WNT3	P56703	559
WLS	WNT11	O96014	554
WLS	SNX3	O60493	551
WLS	AXIN1	O15169	526

IntAct

108 interactions, top by confidence:

A	B	Type	Score
WLS	OPRM1	psi-mi:“MI:0915”(physical association)	0.820
OPRM1	WLS	psi-mi:“MI:0915”(physical association)	0.820
OPRM1	WLS	psi-mi:“MI:0403”(colocalization)	0.820
WNT3A	WLS	psi-mi:“MI:0915”(physical association)	0.780
WNT5A	WLS	psi-mi:“MI:0915”(physical association)	0.560
WNT7A	WLS	psi-mi:“MI:0915”(physical association)	0.560
CHRND	TPST2	psi-mi:“MI:0914”(association)	0.530
WNT7A	LDLR	psi-mi:“MI:0914”(association)	0.530
CD63	LGALS8	psi-mi:“MI:0914”(association)	0.530
WLS	CHRNB1	psi-mi:“MI:0914”(association)	0.530
CD53	FAM171A2	psi-mi:“MI:0914”(association)	0.530
CHRNA4	FZD6	psi-mi:“MI:0914”(association)	0.530
WNT4	TOMM40	psi-mi:“MI:0914”(association)	0.530
WLS	SLC6A3	psi-mi:“MI:0915”(physical association)	0.520
NRAS	ESYT2	psi-mi:“MI:2364”(proximity)	0.480
WLS	FAM241B	psi-mi:“MI:0915”(physical association)	0.400
WLS	EBP	psi-mi:“MI:0915”(physical association)	0.400
WLS	ADORA2A	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (159): WLS (Affinity Capture-RNA), WLS (Affinity Capture-RNA), WLS (Two-hybrid), WLS (Reconstituted Complex), WLS (Affinity Capture-Western), WLS (Affinity Capture-Western), WLS (Affinity Capture-Western), WLS (Affinity Capture-MS), WLS (Affinity Capture-MS), WLS (Proximity Label-MS), WLS (Proximity Label-MS), WLS (Affinity Capture-MS), WLS (Affinity Capture-MS), WLS (Affinity Capture-MS), WLS (Affinity Capture-MS)

ESM2 similar proteins: A0A2R8RY99, A0PK11, A9UL59, B2RVW2, B4L184, B4LC58, B4N5D3, D3ZFW5, O95473, P23290, P35801, P35802, P35803, P36964, P36965, P51674, P56749, P58418, P79826, Q0IIL2, Q0P4G7, Q0VD07, Q11085, Q13491, Q2YDD6, Q53R12, Q5R603, Q5R9K1, Q5R9Q3, Q5R9R3, Q5T9L3, Q5ZLR1, Q6AYR5, Q6CRM6, Q6DID7, Q6P689, Q6UX40, Q754N9, Q7YWX7, Q812E9

Diamond homologs: B3M3X7, B3NGS7, B4GZN1, B4HEB1, B4J2W3, B4L184, B4LC58, B4N5D3, B4PF15, B4QPR1, Q2LZ37, Q5FWK6, Q5R9R3, Q5T9L3, Q5ZLR1, Q66IZ4, Q6DID7, Q6P689, Q7YWX7, Q95ST2

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
WLS	“up-regulates activity”	WNT3A	relocalization

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 115 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
WNT ligand biogenesis and trafficking	13	70.5×	2e-19
Negative regulation of TCF-dependent signaling by WNT ligand antagonists	5	45.8×	8e-06
Class B/2 (Secretin family receptors)	14	34.2×	4e-16
Disassembly of the destruction complex and recruitment of AXIN to the membrane	5	22.9×	2e-04
PCP/CE pathway	5	19.3×	4e-04
TCF dependent signaling in response to WNT	8	12.1×	3e-05
Neurotransmitter receptors and postsynaptic signal transmission	6	7.7×	5e-03
Transmission across Chemical Synapses	7	6.8×	3e-03

GO biological processes:

GO term	Partners	Fold	FDR
cell fate commitment	13	39.6×	7e-15
non-canonical Wnt signaling pathway	5	29.9×	8e-05
cellular response to retinoic acid	10	24.1×	4e-09
canonical Wnt signaling pathway	15	23.7×	3e-14
Wnt signaling pathway, planar cell polarity pathway	5	23.5×	2e-04
sensory perception of pain	5	19.3×	5e-04
neuron differentiation	13	13.4×	4e-09
monoatomic ion transmembrane transport	6	12.9×	6e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	5
Likely benign	2
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

3017 predictions. Top by Δscore:

Variant	Effect	Δscore
1:68134137:T:TA	donor_gain	1.0000
1:68137772:AAACT:A	donor_loss	1.0000
1:68137773:AACT:A	donor_loss	1.0000
1:68137774:ACT:A	donor_loss	1.0000
1:68137775:CT:C	donor_loss	1.0000
1:68137776:TCAC:T	donor_loss	1.0000
1:68137777:CACC:C	donor_loss	1.0000
1:68137778:A:AC	donor_gain	1.0000
1:68137779:C:CC	donor_gain	1.0000
1:68144650:CCC:C	acceptor_gain	1.0000
1:68144651:CCC:C	acceptor_gain	1.0000
1:68144652:CCTAT:C	acceptor_gain	1.0000
1:68150355:CT:C	acceptor_gain	1.0000
1:68153515:A:AC	donor_gain	1.0000
1:68153516:C:CC	donor_gain	1.0000
1:68155093:ACTT:A	donor_loss	1.0000
1:68155095:TTA:T	donor_loss	1.0000
1:68155096:TA:T	donor_loss	1.0000
1:68155097:A:AC	donor_gain	1.0000
1:68155097:A:AG	donor_loss	1.0000
1:68155098:C:CC	donor_gain	1.0000
1:68155098:CCA:C	donor_gain	1.0000
1:68155261:C:CC	acceptor_gain	1.0000
1:68159119:ATAC:A	donor_loss	1.0000
1:68159121:AC:A	donor_loss	1.0000
1:68159243:TTCTC:T	acceptor_gain	1.0000
1:68159245:CTC:C	acceptor_gain	1.0000
1:68159246:TC:T	acceptor_gain	1.0000
1:68159247:CC:C	acceptor_gain	1.0000
1:68159247:CCTGC:C	acceptor_loss	1.0000

AlphaMissense

3641 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:68137855:A:G	W481R	1.000
1:68137855:A:T	W481R	1.000
1:68144639:C:A	R431M	1.000
1:68150217:A:G	W315R	1.000
1:68150217:A:T	W315R	1.000
1:68153630:G:C	F230L	1.000
1:68153630:G:T	F230L	1.000
1:68153632:A:G	F230L	1.000
1:68159185:A:G	W148R	1.000
1:68159185:A:T	W148R	1.000
1:68137850:A:C	N482K	0.999
1:68137850:A:T	N482K	0.999
1:68137870:C:G	G476R	0.999
1:68144635:G:C	F432L	0.999
1:68144635:G:T	F432L	0.999
1:68144636:A:G	F432S	0.999
1:68144637:A:G	F432L	0.999
1:68144639:C:G	R431T	0.999
1:68145960:A:G	L396P	0.999
1:68145979:A:G	C390R	0.999
1:68145985:A:G	C388R	0.999
1:68150206:G:C	F318L	0.999
1:68150206:G:T	F318L	0.999
1:68150208:A:G	F318L	0.999
1:68150218:G:C	F314L	0.999
1:68150218:G:T	F314L	0.999
1:68150220:A:G	F314L	0.999
1:68150228:A:G	L311P	0.999
1:68150247:C:G	G305R	0.999
1:68150304:A:G	W286R	0.999

dbSNP variants (sampled 300 via entrez): RS1000011433 (1:68169034 A>T), RS1000014452 (1:68130410 C>T), RS1000017847 (1:68218265 A>G), RS1000025161 (1:68187235 C>T), RS1000028309 (1:68212303 C>A), RS1000043479 (1:68124647 G>T), RS1000111021 (1:68231312 G>C,T), RS1000136811 (1:68193479 T>A), RS1000166737 (1:68100036 A>G), RS1000192349 (1:68108819 G>A), RS1000243478 (1:68119119 C>G), RS1000250339 (1:68103671 G>A), RS1000266779 (1:68216953 C>T), RS1000275493 (1:68209926 A>C), RS1000275638 (1:68229807 C>T)

Disease associations

OMIM: gene MIM:611514 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
Zaki syndrome	Strong	Autosomal recessive

Mondo (1): Zaki syndrome (MONDO:0859209)

Orphanet (0):

HPO phenotypes

52 total (30 of 52 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000104	Renal agenesis
HP:0000126	Hydronephrosis
HP:0000154	Wide mouth
HP:0000218	High palate
HP:0000252	Microcephaly
HP:0000322	Short philtrum
HP:0000340	Sloping forehead
HP:0000347	Micrognathia
HP:0000348	High forehead
HP:0000378	Cupped ear
HP:0000384	Preauricular skin tag
HP:0000431	Wide nasal bridge
HP:0000445	Wide nose
HP:0000463	Anteverted nares
HP:0000750	Delayed speech and language development
HP:0000776	Congenital diaphragmatic hernia
HP:0000960	Sacral dimple
HP:0000974	Hyperextensible skin
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001276	Hypertonia
HP:0001320	Cerebellar vermis hypoplasia
HP:0001347	Hyperreflexia
HP:0001643	Patent ductus arteriosus
HP:0001655	Patent foramen ovale
HP:0001770	Toe syndactyly
HP:0001800	Hypoplastic toenails
HP:0002064	Spastic gait

GWAS associations

28 associations (top):

Study	Trait	p-value
GCST000494_6	Bone mineral density (spine)	3.000000e-13
GCST000495_13	Bone mineral density (hip)	2.000000e-12
GCST001482_19	Lumbar spine bone mineral density	3.000000e-45
GCST001621_15	Airflow obstruction	3.000000e-06
GCST002276_14	Bone mineral density	1.000000e-11
GCST003380_1	Bone mineral density (spine)	3.000000e-09
GCST005795_13	Femoral neck bone mineral density	5.000000e-20
GCST005796_2	Lumbar spine bone mineral density	4.000000e-23
GCST006288_255	Heel bone mineral density	6.000000e-10
GCST006288_604	Heel bone mineral density	5.000000e-21
GCST006288_709	Heel bone mineral density	6.000000e-11
GCST006979_986	Heel bone mineral density	2.000000e-59
GCST007981_3	Postoperative complication after cardiac surgery	6.000000e-06
GCST008767_1	Perceived intensity of sucrose	9.000000e-06
GCST009723_63	Vertical cup-disc ratio (adjusted for vertical disc diameter)	5.000000e-10
GCST009724_83	Vertical cup-disc ratio (multi-trait analysis)	1.000000e-10
GCST009724_84	Vertical cup-disc ratio (multi-trait analysis)	4.000000e-20
GCST010266_3	Femoral neck bone mineral density and trunk fat mass adjusted by trunk lean mass	3.000000e-07
GCST010268_2	Femoral neck bone mineral density	5.000000e-08
GCST010696_2	Cortical thickness (min-P)	7.000000e-09
GCST010697_18	Cortical surface area (min-P)	9.000000e-09
GCST010698_50	Subcortical volume (min-P)	7.000000e-11
GCST010699_89	Brain morphology (min-P)	3.000000e-13
GCST010700_63	Cortical thickness (MOSTest)	2.000000e-09
GCST010701_82	Cortical surface area (MOSTest)	6.000000e-09
GCST010702_7	Subcortical volume (MOSTest)	4.000000e-08
GCST010703_332	Brain morphology (MOSTest)	2.000000e-10
GCST011743_83	HDL cholesterol levels in HIV infection	6.000000e-06

EFO canonical traits (10, from GWAS)

EFO ID	Trait name
EFO:0003892	pulmonary function measurement
EFO:0007701	spine bone mineral density
EFO:0007785	femoral neck bone mineral density
EFO:0009270	heel bone mineral density
EFO:0005323	post-operative sign or symptom
EFO:0009951	response to surgery
EFO:0006939	cup-to-disc ratio measurement
EFO:0004346	neuroimaging measurement
EFO:0004840	cortical thickness
EFO:0004612	high density lipoprotein cholesterol measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases methylation, affects cotreatment, increases expression	5
sodium arsenite	affects methylation, decreases expression, affects cotreatment, increases abundance	3
methylmercuric chloride	decreases expression, increases expression	2
bisphenol A	decreases expression, increases methylation	2
Air Pollutants	increases oxidation, decreases expression, affects cotreatment, increases abundance	2
Arsenic	affects methylation, affects cotreatment, decreases expression, increases abundance	2
Benzo(a)pyrene	affects methylation, decreases methylation	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Tretinoin	decreases expression, increases expression	2
aristolochic acid I	decreases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
propionaldehyde	increases expression	1
pirinixic acid	increases activity, affects binding, decreases expression	1
decabromobiphenyl ether	decreases expression	1
cobaltous chloride	decreases expression	1
tetrabromobisphenol A	decreases expression	1
manganese chloride	decreases expression, increases abundance, affects cotreatment	1
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	1
tetrachlorodian	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
entinostat	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	increases expression, affects cotreatment	1
ICG 001	decreases expression	1
dorsomorphin	affects cotreatment, increases expression	1
Decitabine	affects expression	1
Zoledronic Acid	decreases expression	1
Panobinostat	affects cotreatment, increases expression	1
Acrolein	affects cotreatment, increases oxidation, increases abundance	1
Atrazine	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_E2P8	HAP1 WLS (-) 1	Cancer cell line	Male
CVCL_E2P9	HAP1 WLS (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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