WDR81

Chr 17AR

WD repeat domain 81

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 (PubMed:26783301). 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 (PubMed:27126989). 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 (PubMed:28404643). May also be involved in maintenance of normal mitochondrial structure and organization (By similarity)

Primary Disease Associations & Inheritance

Cerebellar ataxia, impaired intellectual development, and dysquilibrium syndrome 2MIM #610185

Hydrocephalus, congenital, 3, with brain anomaliesMIM #617967

ClinVar variants

Pathogenic / LP

0.00

pLI score

Active trials

Clinical Summary— WDR81

⚡

Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

Some data sources returned errors (2)

ncbi: Error: NCBI fetch failed: 429 https://eutils.ncbi.nlm.nih.gov/entrez/eutils/esearch.fcgi

clinvarCount: Error: NCBI fetch failed: 429 https://eutils.ncbi.nlm.nih.gov/entrez/eutils/esearch.fcgi

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.

0.53LOEUF

pLI 0.000

Z-score 4.57

OE 0.38 (0.27–0.53)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.

2.11Z-score

OE missense 0.83 (0.79–0.87)

1000 obs / 1206.3 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.

LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.38 (0.27–0.53)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.83 (0.79–0.87)

0≤0.61.4

Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.91

0≤1.21.6

LoF obs/exp: 24 / 63.2Missense obs/exp: 1000 / 1206.3Syn Z: 1.60