WDR81

Summary

WDR81 (WD repeat domain 81, HGNC:26600) is a protein-coding gene on chromosome 17p13.3, encoding WD repeat-containing protein 81 (Q562E7). Functions as a negative regulator of the PI3 kinase/PI3K activity associated with endosomal membranes via BECN1, a core subunit of the PI3K complex.

This gene encodes a multi-domain transmembrane protein which is predominantly expressed in the brain and is thought to play a role in endolysosomal trafficking. Mutations in this gene are associated with an autosomal recessive form of a syndrome exhibiting cerebellar ataxia, cognitive disability, and disequilibrium (CAMRQ2). Alternatively spliced transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 124997 — RefSeq curated summary.

At a glance

• Gene–disease (curated): cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 2 (Strong, GenCC) — +2 more curated relationships
• GWAS associations: 10
• Clinical variants (ClinVar): 652 total — 10 pathogenic, 24 likely-pathogenic
• Phenotypes (HPO): 55
• MANE Select transcript: NM_001163809

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:26600
Approved symbol	WDR81
Name	WD repeat domain 81
Location	17p13.3
Locus type	gene with protein product
Status	Approved
Aliases	FLJ33817, PPP1R166, CAMRQ2, SORF-2
Ensembl gene	ENSG00000167716
Ensembl biotype	protein_coding
OMIM	614218
Entrez	124997

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 9 protein_coding, 4 retained_intron, 1 nonsense_mediated_decay

ENST00000309182, ENST00000409644, ENST00000418841, ENST00000419248, ENST00000437219, ENST00000446363, ENST00000455636, ENST00000464528, ENST00000468539, ENST00000474958, ENST00000479966, ENST00000492901, ENST00000495411, ENST00000575206

RefSeq mRNA: 4 — MANE Select: NM_001163809 NM_001163673, NM_001163809, NM_001163811, NM_152348

CCDS: CCDS54061, CCDS54062, CCDS54063

Canonical transcript exons

ENST00000409644 — 10 exons

Exon	Start	End
ENSE00001250309	1736039	1736218
ENSE00001357227	1735572	1735717
ENSE00001577361	1737365	1738585
ENSE00001589588	1724704	1728626
ENSE00003477337	1730380	1730487
ENSE00003506294	1731068	1731258
ENSE00003509419	1730755	1730945
ENSE00003587313	1733527	1734216
ENSE00003626694	1732325	1732490
ENSE00003651158	1732666	1732831

Expression profiles

Bgee: expression breadth ubiquitous, 138 present calls, max score 91.96.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 14.1003 / max 138.0322, expressed in 1798 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
158743	12.7893	1797
158742	0.6144	317
158745	0.3687	185
158744	0.2890	146
208024	0.0389	7

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	91.96	gold quality
left ovary	UBERON:0002119	91.57	gold quality
right ovary	UBERON:0002118	91.33	gold quality
sural nerve	UBERON:0015488	90.74	gold quality
right lobe of liver	UBERON:0001114	90.63	gold quality
ovary	UBERON:0000992	90.56	gold quality
spleen	UBERON:0002106	90.35	gold quality
left uterine tube	UBERON:0001303	90.31	gold quality
endocervix	UBERON:0000458	89.92	gold quality
body of uterus	UBERON:0009853	89.82	gold quality
myometrium	UBERON:0001296	89.16	gold quality
ectocervix	UBERON:0012249	88.51	gold quality
subcutaneous adipose tissue	UBERON:0002190	88.46	gold quality
small intestine Peyer’s patch	UBERON:0003454	88.36	gold quality
apex of heart	UBERON:0002098	88.34	gold quality
right adrenal gland cortex	UBERON:0035827	87.94	gold quality
adipose tissue	UBERON:0001013	87.74	gold quality
mucosa of stomach	UBERON:0001199	87.70	gold quality
tibial nerve	UBERON:0001323	87.62	gold quality
right adrenal gland	UBERON:0001233	87.61	gold quality
blood	UBERON:0000178	87.60	gold quality
uterine cervix	UBERON:0000002	87.59	gold quality
skin of leg	UBERON:0001511	87.44	gold quality
monocyte	CL:0000576	87.32	gold quality
leukocyte	CL:0000738	87.32	gold quality
gastrocnemius	UBERON:0001388	87.24	gold quality
liver	UBERON:0002107	87.07	gold quality
small intestine	UBERON:0002108	87.05	gold quality
prostate gland	UBERON:0002367	87.01	gold quality
zone of skin	UBERON:0000014	86.92	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.13

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

35 targeting WDR81, 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-548AW	99.99	72.57	3559
HSA-MIR-1236-3P	99.94	68.04	1695
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-605-3P	99.88	69.22	1833
HSA-MIR-518A-5P	99.70	69.01	2209
HSA-MIR-527	99.70	69.01	2209
HSA-MIR-3175	99.65	66.30	2031
HSA-MIR-7150	99.62	66.80	1322
HSA-MIR-1207-5P	99.49	69.11	2983
HSA-MIR-6722-3P	99.45	67.62	1919
HSA-MIR-5582-5P	99.27	71.42	1879
HSA-MIR-4685-5P	99.25	65.99	1563
HSA-MIR-6868-5P	99.06	65.69	1284
HSA-MIR-1909-3P	99.03	66.56	1662
HSA-MIR-3127-3P	98.94	67.34	1055
HSA-MIR-6756-3P	98.94	66.79	1104
HSA-MIR-760	98.81	66.65	1392
HSA-MIR-4700-5P	98.63	67.43	1915
HSA-MIR-3184-5P	98.56	67.13	1491
HSA-MIR-6757-5P	98.08	65.50	724
HSA-MIR-4736	97.96	65.89	1287
HSA-MIR-6893-3P	97.79	64.91	1238
HSA-MIR-8089	97.74	66.21	1698
HSA-MIR-8057	97.64	66.54	897
HSA-MIR-4667-5P	97.61	66.67	1683
HSA-MIR-4308	97.56	67.13	1385
HSA-MIR-6802-3P	97.29	65.42	613
HSA-MIR-6748-3P	97.20	65.66	836
HSA-MIR-370-3P	97.09	64.92	1221
HSA-MIR-339-5P	96.73	66.01	820

Literature-anchored findings (GeneRIF, showing 8)

• The neuro-ophthalmic examination in CAMRQ2 revealed downbeat nystagmus in all patients, and temporal disc pallor and macular atrophy in two patients. (PMID:22686558)
• WDR81 mutation is associated with dysequilibrium syndrome type 2 and sensorineural hearing loss. (PMID:26437881)
• suggest a role for the WDR81-WDR91 complex in the fusion of endolysosomal compartments and the absence of WDR81 leads to impaired receptor trafficking and degradation (PMID:27126989)
• The WDR81 interacts with LC3C through canonical LC3-interacting regions in the BEACH domain, promoting LC3C recruitment to ubiquitinated proteins. (PMID:28404643)
• Recessive mutations in WDR81, previously linked to cerebellar ataxia, mental retardation, and disequilibrium syndrome 2, cause severe congenital hydrocephalus. (PMID:28556411)
• The results of this study suggest that the WDR81 might have a role in mitosis that is conserved between Drosophila and humans. (PMID:28969387)
• WDR81 Gene Silencing Can Reduce Exosome Levels in Human U87-MG Glioblastoma Cells. (PMID:33954857)
• Fetal brain arrest broadens the spectrum of WDR81-related developmental brain malformations. (PMID:34338917)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	wdr81	ENSDARG00000079702
mus_musculus	Wdr81	ENSMUSG00000045374
rattus_norvegicus	Wdr81	ENSRNOG00000003243
drosophila_melanogaster	Wdr81	FBGN0032395

Paralogs (26): PAFAH1B1 (ENSG00000007168), SNRNP40 (ENSG00000060688), WDR62 (ENSG00000075702), WDR7 (ENSG00000091157), TBL2 (ENSG00000106638), PAK1IP1 (ENSG00000111845), WDR75 (ENSG00000115368), DCAF4 (ENSG00000119599), DAW1 (ENSG00000123977), TEP1 (ENSG00000129566), AHI1 (ENSG00000135541), WDR38 (ENSG00000136918), MAPKBP1 (ENSG00000137802), POC1B (ENSG00000139323), NEDD1 (ENSG00000139350), COP1 (ENSG00000143207), WDR17 (ENSG00000150627), WDR43 (ENSG00000163811), POC1A (ENSG00000164087), WDR88 (ENSG00000166359), DCAF4L2 (ENSG00000176566), DCAF4L1 (ENSG00000182308), WDR27 (ENSG00000184465), NWD1 (ENSG00000188039), WDR5 (ENSG00000196363), WDR5B (ENSG00000196981)

Protein

Protein identifiers

WD repeat-containing protein 81 — Q562E7 (reviewed: Q562E7)

All UniProt accessions (7): C9JCF9, Q562E7, C9JD20, E9PDG3, I3L1G2, I3L3U7, K7ELV8

UniProt curated annotations — full annotation on UniProt →

Function. Functions as a negative regulator of the PI3 kinase/PI3K activity associated with endosomal membranes via BECN1, a core subunit of the PI3K complex. By modifying the phosphatidylinositol 3-phosphate/PtdInsP3 content of endosomal membranes may regulate endosome fusion, recycling, sorting and early to late endosome transport. It is for instance, required for the delivery of cargos like BST2/tetherin from early to late endosome and thereby participates indirectly to their degradation by the lysosome. May also play a role in aggrephagy, the macroautophagic degradation of ubiquitinated protein aggregates. In this process, may regulate the interaction of SQSTM1 with ubiquitinated proteins and also recruit MAP1LC3C. May also be involved in maintenance of normal mitochondrial structure and organization.

Subunit / interactions. Interacts with WDR91; involved in early to late endosome cargo transport. Interacts with BECN1; negatively regulates the PI3 kinase/PI3K activity associated with endosomal membranes. Interacts with SQSTM1; the interaction is direct and regulates the interaction of SQSTM1 with ubiquitinated proteins. Interacts with MAP1LC3C; recruits MAP1LC3C to ubiquitinated protein aggregates in the aggrephagy process.

Subcellular location. Early endosome membrane. Late endosome membrane. Lysosome membrane. Cytoplasmic vesicle. Autophagosome membrane. Mitochondrion. Cytoplasm. Cytosol.

Tissue specificity. Widely expressed. In the brain, highest levels in cerebellum and corpus callosum.

Disease relevance. Cerebellar ataxia, impaired intellectual development, and dysequilibrium syndrome 2 (CAMRQ2) [MIM:610185] An autosomal recessive, congenital cerebellar ataxia associated with cerebellar hypoplasia, intellectual disability, and inability to walk bipedally, resulting in quadrupedal locomotion as a functional adaptation. Additional findings include generalized brain atrophy and mild hypoplasia of the corpus callosum. The disease is caused by variants affecting the gene represented in this entry. Hydrocephalus, congenital, 3, with brain anomalies (HYC3) [MIM:617967] A form of congenital hydrocephalus, a disease characterized by onset in utero of enlarged ventricles due to accumulation of ventricular cerebrospinal fluid. HYC3 features include enlarged ventricles, hypoplastic or absent cerebellum, holoprosencephaly and Dandy-Walker malformation. Most patients die in utero or shortly after birth. HYC3 inheritance is autosomal recessive. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the WD repeat WDR81 family.

Isoforms (6)

UniProt ID	Names	Canonical?
Q562E7-1	1	yes
Q562E7-2	2
Q562E7-3	3
Q562E7-4	4
Q562E7-5	5
Q562E7-6	6

RefSeq proteins (4): NP_001157145, NP_001157281, NP_001157283, NP_689561 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000409	BEACH_dom	Domain
IPR001680	WD40_rpt	Repeat
IPR011009	Kinase-like_dom_sf	Homologous_superfamily
IPR015943	WD40/YVTN_repeat-like_dom_sf	Homologous_superfamily
IPR036322	WD40_repeat_dom_sf	Homologous_superfamily
IPR036372	BEACH_dom_sf	Homologous_superfamily
IPR052651	WDR81	Family

Pfam: PF00400, PF02138

UniProt features (44 total): region of interest 8, sequence conflict 8, repeat 7, splice variant 6, sequence variant 5, mutagenesis site 5, compositionally biased region 3, chain 1, domain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q562E7-F1	69.23	0.13

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Mutagenesis-validated functional residues (5):

Position	Phenotype
544	loss of interaction with map1lc3c; when associated with a-547.
547	loss of interaction with map1lc3c; when associated with a-544.
577	loss of interaction with map1lc3c; when associated with a-578 and a-581.
578	loss of interaction with map1lc3c; when associated with a-577 and a-581.
581	loss of interaction with map1lc3c; when associated with a-577 and a-578.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-9013148	CDC42 GTPase cycle

MSigDB gene sets: 325 (showing top): RNGTGGGC_UNKNOWN, FXR_IR1_Q6, AP1_01, PAX4_01, GOCC_VACUOLAR_MEMBRANE, GCANCTGNY_MYOD_Q6, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, TGACCTY_ERR1_Q2, GOBP_VESICLE_MEDIATED_TRANSPORT, TAL1ALPHAE47_01, GGGTGGRR_PAX4_03, CAGCTG_AP4_Q5, SP1_Q2_01, EFC_Q6, CEBPB_01

GO Biological Process (5): ubiquitin-dependent protein catabolic process (GO:0006511), mitochondrion organization (GO:0007005), aggrephagy (GO:0035973), early endosome to late endosome transport (GO:0045022), protein stabilization (GO:0050821)

GO Molecular Function (4): phosphatidylinositol 3-kinase regulator activity (GO:0035014), K63-linked polyubiquitin modification-dependent protein binding (GO:0070530), phosphatidylinositol 3-kinase inhibitor activity (GO:0141039), protein binding (GO:0005515)

GO Cellular Component (12): autophagosome membrane (GO:0000421), mitochondrion (GO:0005739), lysosomal membrane (GO:0005765), cytosol (GO:0005829), endosome membrane (GO:0010008), early endosome membrane (GO:0031901), late endosome membrane (GO:0031902), cytoplasm (GO:0005737), lysosome (GO:0005764), endosome (GO:0005768), membrane (GO:0016020), cytoplasmic vesicle (GO:0031410)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
RHO GTPase cycle	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cytoplasm	4
cellular anatomical structure	3
endosome membrane	2
protein ubiquitination	1
modification-dependent protein catabolic process	1
organelle organization	1
macroautophagy	1
vesicle-mediated transport between endosomal compartments	1
regulation of protein stability	1
kinase regulator activity	1
phosphatidylinositol 3-kinase catalytic subunit binding	1
polyubiquitin modification-dependent protein binding	1
phosphatidylinositol 3-kinase regulator activity	1
binding	1
vacuolar membrane	1
autophagosome	1
intracellular membrane-bounded organelle	1
lysosome	1
lytic vacuole membrane	1
endosome	1
cytoplasmic vesicle membrane	1
bounding membrane of organelle	1
early endosome	1
late endosome	1
intracellular anatomical structure	1
lytic vacuole	1
endomembrane system	1
cytoplasmic vesicle	1
intracellular vesicle	1

Protein interactions and networks

STRING

1310 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
WDR81	WDR91	A4D1P6	916
WDR81	MAP1LC3C	Q9BXW4	728
WDR81	PIK3C3	Q8NEB9	705
WDR81	ATP8A2	Q9NTI2	641
WDR81	CCZ1B	P86790	626
WDR81	VLDLR	P98155	580
WDR81	COMMD2	Q86X83	572
WDR81	TLCD2	A6NGC4	502
WDR81	ATP6V0B	Q99437	500
WDR81	VPS18	Q9P253	496
WDR81	WRAP73	Q9P2S5	484
WDR81	FGD4	Q96M96	484
WDR81	ATP6AP1	Q15904	466
WDR81	GABARAP	O95166	462
WDR81	MON1A	Q86VX9	459

IntAct

48 interactions, top by confidence:

A	B	Type	Score
RCCD1	SPAG9	psi-mi:“MI:0914”(association)	0.640
RAB8A	WDR91	psi-mi:“MI:0914”(association)	0.600
WDR81	WDR91	psi-mi:“MI:0915”(physical association)	0.590
WDR91	WDR81	psi-mi:“MI:0915”(physical association)	0.590
HSPB8	VWA8	psi-mi:“MI:0914”(association)	0.530
NAPA	NBAS	psi-mi:“MI:0914”(association)	0.530
DNAJB8	DNAJB6	psi-mi:“MI:0914”(association)	0.530
WDR81	PPP1CA	psi-mi:“MI:0407”(direct interaction)	0.440
bec-1	WDR81	psi-mi:“MI:0915”(physical association)	0.400
NUDC	WDR81	psi-mi:“MI:0915”(physical association)	0.400
Xpo1	IFT56	psi-mi:“MI:0914”(association)	0.350
UTP4	MASP1	psi-mi:“MI:0914”(association)	0.350
CUL3	PXDNL	psi-mi:“MI:0914”(association)	0.350
BECN1	WDR91	psi-mi:“MI:0914”(association)	0.350
BECN1	WDR81	psi-mi:“MI:0914”(association)	0.350
WFDC2	WDR91	psi-mi:“MI:0914”(association)	0.350
CEP135	WDR91	psi-mi:“MI:0914”(association)	0.350
CCT2	WDR91	psi-mi:“MI:0914”(association)	0.350
NPAS1	CIBAR1	psi-mi:“MI:0914”(association)	0.350
INF2	PIPSL	psi-mi:“MI:0914”(association)	0.350
PLEKHG7	MROH6	psi-mi:“MI:0914”(association)	0.350
EEF1AKMT3	SMCHD1	psi-mi:“MI:0914”(association)	0.350
UBXN6	ZSWIM8	psi-mi:“MI:0914”(association)	0.350

BioGRID (46): WDR81 (Affinity Capture-RNA), WDR81 (Affinity Capture-RNA), WDR81 (Affinity Capture-RNA), WDR81 (Affinity Capture-RNA), WDR81 (Affinity Capture-MS), WDR81 (Proximity Label-MS), WDR81 (Affinity Capture-MS), WDR81 (Affinity Capture-MS), WDR81 (Affinity Capture-Western), SQSTM1 (Affinity Capture-Western), WDR81 (Affinity Capture-Western), MAP1LC3C (Affinity Capture-Western), WDR81 (Affinity Capture-Western), UBC (Co-localization), WDR91 (Co-localization)

ESM2 similar proteins: A0JN53, A0PJX8, A1L1L2, A1L3T7, A4FV45, B0BMG8, E2JF22, G3HQ82, O15360, O43299, O70491, P60330, Q0KL00, Q0V8E7, Q17Q97, Q24JP3, Q3U829, Q49LS3, Q4QR83, Q562E7, Q5ND34, Q5R7B4, Q5T1A1, Q5XG04, Q6NUQ4, Q6PH58, Q6UX68, Q7L4E1, Q7Z412, Q8BGI5, Q8BM55, Q8BSD4, Q8BXV2, Q8C3R1, Q8C7B8, Q8IXR5, Q8K0R6, Q8N6S5, Q8R115, Q8VCA6

Diamond homologs: A8XSV3, D4A929, E7FAW3, E9Q2M9, F4HZB2, F4IG73, F4JD14, F4JHT3, O35242, P0C6P0, P25356, P50851, P97412, Q19317, Q54PP7, Q54RQ8, Q55AV3, Q55DM1, Q562E7, Q5ND34, Q6VNB8, Q6ZNJ1, Q6ZQA0, Q6ZS30, Q6ZS81, Q7LKZ7, Q86JF2, Q8IZQ1, Q8NFP9, Q92636, Q99698, Q9DDD5, Q9EPN1, Q9ESE1, Q9TTK4, Q9W060, Q9W4E2, E7FEV0, F4JY12, Q10122

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	10
Likely pathogenic	24
Uncertain significance	403
Likely benign	132
Benign	34

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1687637	NM_001163809.2(WDR81):c.218del (p.Leu73fs)	Pathogenic
1700900	NM_001163809.2(WDR81):c.2836_2839del (p.Phe946fs)	Pathogenic
191291	NM_001163809.2(WDR81):c.3286C>T (p.Gln1096Ter)	Pathogenic
2070117	NM_001163809.2(WDR81):c.1666A>T (p.Lys556Ter)	Pathogenic
3233622	NM_001163809.2(WDR81):c.2698G>T (p.Glu900Ter)	Pathogenic
392796	NM_001163809.2(WDR81):c.1564C>T (p.Gln522Ter)	Pathogenic
423034	NM_001163809.2(WDR81):c.3557del (p.Thr1186fs)	Pathogenic
635849	NM_001163809.2(WDR81):c.4668_4669del (p.Gly1557fs)	Pathogenic
816552	GRCh37/hg19 17p13.3(chr17:1204863-1751418)x3	Pathogenic
984714	NM_001163809.2(WDR81):c.5335C>T (p.Arg1779Ter)	Pathogenic
1301585	NM_001163809.2(WDR81):c.5326-1G>A	Likely pathogenic
1339955	NM_001163809.2(WDR81):c.1585C>T (p.Arg529Ter)	Likely pathogenic
1696176	NM_001163809.2(WDR81):c.1358dup (p.Tyr453Ter)	Likely pathogenic
1702659	NM_001163809.2(WDR81):c.2074_2077del (p.Phe692fs)	Likely pathogenic
183290	NM_001163809.2(WDR81):c.845G>A (p.Gly282Glu)	Likely pathogenic
2500760	NM_001163809.2(WDR81):c.5411G>T (p.Gly1804Val)	Likely pathogenic
2627973	NM_001163809.2(WDR81):c.2410C>T (p.Arg804Ter)	Likely pathogenic
2663364	NM_001163809.2(WDR81):c.5325+5G>A	Likely pathogenic
3055081	NM_001163809.2(WDR81):c.4910_4934del (p.His1637fs)	Likely pathogenic
3252613	NM_001163809.2(WDR81):c.1734C>G (p.Tyr578Ter)	Likely pathogenic
3255116	NM_001163809.2(WDR81):c.5672T>C (p.Ile1891Thr)	Likely pathogenic
3340764	NM_001163809.2(WDR81):c.2292_2309del (p.Gln764_Asp770delinsHis)	Likely pathogenic
3362491	NM_001163809.2(WDR81):c.1285dup (p.Ala429fs)	Likely pathogenic
3362717	NM_001163809.2(WDR81):c.850_851del (p.Leu284fs)	Likely pathogenic
3381150	NM_001163809.2(WDR81):c.459dup (p.Ala154fs)	Likely pathogenic
3381151	NM_001163809.2(WDR81):c.1154G>A (p.Trp385Ter)	Likely pathogenic
3780802	NM_001163809.2(WDR81):c.1213del (p.Arg405fs)	Likely pathogenic
3780803	NM_001163809.2(WDR81):c.1521del (p.Asp508fs)	Likely pathogenic
3780804	NM_001163809.2(WDR81):c.4489+1G>A	Likely pathogenic
4849337	NM_001163809.2(WDR81):c.1297G>T (p.Glu433Ter)	Likely pathogenic

SpliceAI

1730 predictions. Top by Δscore:

Variant	Effect	Δscore
17:1730378:A:AG	acceptor_gain	1.0000
17:1730379:G:GA	acceptor_gain	1.0000
17:1730484:GTTG:G	donor_gain	1.0000
17:1730488:G:GC	donor_loss	1.0000
17:1730488:G:GG	donor_gain	1.0000
17:1730489:T:G	donor_loss	1.0000
17:1730749:T:TA	acceptor_gain	1.0000
17:1730921:G:GG	donor_gain	1.0000
17:1730939:C:G	donor_gain	1.0000
17:1730946:G:GG	donor_gain	1.0000
17:1731256:GGG:G	donor_gain	1.0000
17:1731257:GG:G	donor_gain	1.0000
17:1731257:GGG:G	donor_gain	1.0000
17:1731257:GGGTA:G	donor_loss	1.0000
17:1731258:GG:G	donor_gain	1.0000
17:1731259:G:GG	donor_gain	1.0000
17:1732322:CA:C	acceptor_loss	1.0000
17:1732323:A:AG	acceptor_gain	1.0000
17:1732323:AG:A	acceptor_gain	1.0000
17:1732324:G:GG	acceptor_gain	1.0000
17:1732324:GG:G	acceptor_gain	1.0000
17:1732488:CAG:C	donor_loss	1.0000
17:1732489:AG:A	donor_loss	1.0000
17:1732490:GG:G	donor_loss	1.0000
17:1732491:G:T	donor_loss	1.0000
17:1732806:C:CG	donor_gain	1.0000
17:1732828:T:G	donor_gain	1.0000
17:1735702:G:GT	donor_gain	1.0000
17:1735724:G:T	donor_gain	1.0000
17:1736037:A:AG	acceptor_gain	1.0000

AlphaMissense

12538 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:1726359:T:A	V467D	1.000
17:1726370:T:A	W471R	1.000
17:1726370:T:C	W471R	1.000
17:1726372:G:C	W471C	1.000
17:1726372:G:T	W471C	1.000
17:1734030:A:C	S1665R	1.000
17:1734032:C:A	S1665R	1.000
17:1734032:C:G	S1665R	1.000
17:1734177:A:C	S1714R	1.000
17:1734179:C:A	S1714R	1.000
17:1734179:C:G	S1714R	1.000
17:1737389:A:C	S1844R	1.000
17:1737391:C:A	S1844R	1.000
17:1737391:C:G	S1844R	1.000
17:1726112:T:A	W385R	0.999
17:1726112:T:C	W385R	0.999
17:1726169:T:C	F404L	0.999
17:1726170:T:C	F404S	0.999
17:1726171:C:A	F404L	0.999
17:1726171:C:G	F404L	0.999
17:1726183:G:C	K408N	0.999
17:1726183:G:T	K408N	0.999
17:1726197:T:C	L413P	0.999
17:1726203:T:C	F415S	0.999
17:1726296:C:T	S446F	0.999
17:1726302:T:A	I448N	0.999
17:1726371:G:C	W471S	0.999
17:1726385:T:C	Y476H	0.999
17:1726386:A:G	Y476C	0.999
17:1726415:T:A	W486R	0.999

dbSNP variants (sampled 300 via entrez): RS1000073610 (17:1716125 C>G), RS1000140507 (17:1717177 G>A), RS1000223608 (17:1722874 T>C), RS1000480296 (17:1726740 G>A,C), RS1000560320 (17:1734558 A>G), RS1000622696 (17:1736286 AG>A), RS1000631440 (17:1715013 C>T), RS1000833904 (17:1731474 T>C), RS1000925495 (17:1736452 G>A), RS1001159262 (17:1734810 T>C), RS1001167051 (17:1729001 C>T), RS1001261826 (17:1729215 C>T), RS1001404752 (17:1723248 G>A), RS1001413126 (17:1734117 A>G), RS1001587850 (17:1717243 G>C)

Disease associations

OMIM: gene MIM:614218 | disease phenotypes: MIM:610185, MIM:617967, MIM:258040, MIM:617667

GenCC curated gene-disease

Disease	Classification	Inheritance
cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 2	Strong	Autosomal recessive
hydrocephalus, congenital, 3, with brain anomalies	Strong	Autosomal recessive
cerebellar ataxia, intellectual disability, and dysequilibrium	Supportive	Autosomal recessive

Mondo (10): cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 2 (MONDO:0012430), hydrocephalus, congenital, 3, with brain anomalies (MONDO:0054794), hydranencephaly (MONDO:0016344), cerebellar ataxia (MONDO:0000437), exstrophy-epispadias complex (MONDO:0017919), intellectual disability (MONDO:0001071), microlissencephaly (MONDO:0015204), microcephaly (MONDO:0001149), Fraser syndrome 3 (MONDO:0054739), cerebellar ataxia, intellectual disability, and dysequilibrium (MONDO:0009133)

Orphanet (7): Dysequilibrium syndrome (Orphanet:1766), Hydranencephaly (Orphanet:2177), Rare ataxia (Orphanet:102002), Exstrophy-epispadias complex (Orphanet:322), Cloacal exstrophy (Orphanet:93929), Microlissencephaly (Orphanet:1083), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

55 total (30 of 55 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000238	Hydrocephalus
HP:0000280	Coarse facial features
HP:0000407	Sensorineural hearing impairment
HP:0000464	Abnormality of the neck
HP:0000478	Abnormality of the eye
HP:0000486	Strabismus
HP:0000504	Abnormality of vision
HP:0000518	Cataract
HP:0000750	Delayed speech and language development
HP:0001007	Hirsutism
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001260	Dysarthria
HP:0001263	Global developmental delay
HP:0001265	Hyporeflexia
HP:0001272	Cerebellar atrophy
HP:0001288	Gait disturbance
HP:0001305	Dandy-Walker malformation
HP:0001310	Dysmetria
HP:0001321	Cerebellar hypoplasia
HP:0001337	Tremor
HP:0001347	Hyperreflexia
HP:0001360	Holoprosencephaly
HP:0001561	Polyhydramnios
HP:0001773	Short foot
HP:0001999	Abnormal facial shape
HP:0002066	Gait ataxia

GWAS associations

10 associations (top):

Study	Trait	p-value
GCST000769_6	Calcium levels	7.000000e-07
GCST001699_15	Serum albumin levels	7.000000e-13
GCST001699_6	Serum albumin levels	1.000000e-14
GCST002201_12	Calcium levels	2.000000e-06
GCST009640_26	Urinary albumin-to-creatinine ratio	2.000000e-08
GCST010243_133	Apolipoprotein B levels	4.000000e-09
GCST010244_125	Triglyceride levels	1.000000e-13
GCST90011900_146	Serum alkaline phosphatase levels	2.000000e-33
GCST90013406_270	Liver enzyme levels (alkaline phosphatase)	1.000000e-24
GCST90020029_816	Waist circumference adjusted for body mass index	2.000000e-10

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0004838	calcium measurement
EFO:0007778	urinary albumin to creatinine ratio
EFO:0004615	apolipoprotein B measurement
EFO:0004530	triglyceride measurement
EFO:0004533	alkaline phosphatase measurement
EFO:0007789	BMI-adjusted waist circumference

MeSH disease descriptors (6)

Descriptor	Name	Tree numbers
D002524	Cerebellar Ataxia	C10.228.140.252.190; C10.597.350.090.500; C23.888.592.350.090.200
D006832	Hydranencephaly	C10.500.450; C16.131.666.450
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500
C567656	Cerebellar Ataxia, Mental Retardation, And Dysequilibrium Syndrome 2 (supp.)
C535731	Dysequilibrium syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression, decreases methylation, increases expression	3
Arsenic	increases expression, affects methylation, increases abundance	2
aristolochic acid I	increases expression	1
FR900359	affects phosphorylation	1
dicrotophos	increases expression	1
2,4,6-tribromophenol	increases expression	1
triphenyl phosphate	affects expression	1
sodium arsenite	increases abundance, increases expression	1
tetrabromobisphenol A	increases expression	1
coumarin	decreases phosphorylation	1
muconaldehyde	decreases expression	1
2-palmitoylglycerol	increases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
hexabrominated diphenyl ether 153	decreases expression	1
jinfukang	affects cotreatment, increases expression	1
Sunitinib	increases expression	1
Fulvestrant	increases methylation	1
Acetaminophen	decreases expression	1
Air Pollutants	decreases expression, increases abundance	1
Benzo(a)pyrene	affects methylation	1
Chelating Agents	affects binding, decreases expression	1
Cisplatin	affects cotreatment, increases expression	1
Copper	decreases expression, affects binding	1
Doxorubicin	decreases expression	1
Gallic Acid	increases expression	1
Ibuprofen	increases expression	1
Ivermectin	increases expression	1
Oxygen	decreases expression	1
Smoke	decreases expression	1
Urethane	decreases expression	1

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_TX95	HAP1 WDR81 (-)	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00950196	PHASE4	COMPLETED	Amantadine for Improving Neurologic Symptoms in Ataxia-Telangiectasia
NCT04107740	PHASE4	COMPLETED	C-Trelin Orally Disintegrated(OD) Tablet 5mg in Ataxia Due to Spinocerebellar Degeneration
NCT04760028	PHASE4	COMPLETED	Study on the Influencing Factors of Electroencephalogram Parameters Under Anesthesia
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT01970098	PHASE3	COMPLETED	A Confirmatory Study of KPS-0373 in Patients With Spinocerebellar Degeneration (SCD)
NCT01970111	PHASE3	COMPLETED	An Extension Study of KPS-0373 in Patients With Spinocerebellar Degeneration (SCD)
NCT01970124	PHASE3	COMPLETED	A Long-Term Study of KPS-0373 in Patients With Spinocerebellar Degeneration (SCD)
NCT01970137	PHASE3	COMPLETED	A 24-week Open-label Study of KPS-0373 in Patients With Spinocerebellar Degeneration (SCD)
NCT02889302	PHASE3	COMPLETED	An Additional Confirmatory Study of KPS-0373 in Patients With Spinocerebellar Degeneration (SCD)
NCT03408080	PHASE3	ACTIVE_NOT_RECRUITING	Open Pilot Trial of BHV-4157
NCT03701399	PHASE3	ACTIVE_NOT_RECRUITING	Troriluzole in Adult Participants With Spinocerebellar Ataxia
NCT03901638	PHASE3	TERMINATED	Tllsh2910 for Ataxia and Gut Microbiota Alteration in Patients of Multiple System Atrophy
NCT07040137	PHASE3	RECRUITING	Confirmatory Study 3 of KPS-0373 in Patients With Spinocerebellar Degeneration
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT00034242	PHASE2	COMPLETED	High-Dose Intravenous Immunoglobulin to Treat Cerebellar Degeneration
NCT00202397	PHASE2	COMPLETED	Effect of Riluzole as a Symptomatic Approach in Patients With Chronic Cerebellar Ataxia
NCT00863538	PHASE2	COMPLETED	Phase II Study of KPS-0373 in Patients With Spinocerebellar Degeneration (SCD)
NCT01004016	PHASE2	COMPLETED	A Study of KPS-0373 in Patients With Spinocerebellar Degeneration (SCD)
NCT01350440	PHASE2	COMPLETED	Safety and Efficacy of Intravenous Immune Globulin in Treating Spinocerebellar Ataxia
NCT02540655	PHASE2	COMPLETED	Efficacy and Safety Study of Stemchymal® in Polyglutamine Spinocerebellar Ataxia
NCT03932669	PHASE2	COMPLETED	Effect of Nilotinib in Cerebellar Ataxia Patients
NCT04301284	PHASE2	WITHDRAWN	Study of CAD-1883 for Spinocerebellar Ataxia
NCT05125666	PHASE2	UNKNOWN	Efficacy of Dual Task Training on Children With Ataxia After Medulloblastoma Resection
NCT06397274	PHASE2	NOT_YET_RECRUITING	Stemchymal® for Polyglutamine Spinocerebellar Ataxia
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT00683943	PHASE1	COMPLETED	Lithium Treatment for Patients With Spinocerebellar Ataxia Type I
NCT02287064	PHASE1	UNKNOWN	An Open-label Trial of Intravenous Immune Globulin (IVIG)in Treating Spinocerebellar Ataxias
NCT05157802	PHASE1	ACTIVE_NOT_RECRUITING	Promoting Physical Activity Engagement for People With Early-stage Cerebellar Ataxia
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT06366230	PHASE1/PHASE2	RECRUITING	Adding Urea to the Final Dialysis Fluid