WIPI2

Chr 7AR

WD repeat domain, phosphoinositide interacting 2

Also known as: ATG18B, Atg21, CGI-50, IDDSSA, WIPI-2

NCBI Gene: 26100ENSG00000157954UniProt: Q9Y4P8

WD40 repeat proteins are key components of many essential biologic functions. They regulate the assembly of multiprotein complexes by presenting a beta-propeller platform for simultaneous and reversible protein-protein interactions. Members of the WIPI subfamily of WD40 repeat proteins, such as WIPI2, have a 7-bladed propeller structure and contain a conserved motif for interaction with phospholipids (Proikas-Cezanne et al., 2004 [PubMed 15602573]).[supplied by OMIM, Mar 2008]

Primary Disease Associations & Inheritance

?Intellectual developmental disorder with short stature and variable skeletal anomaliesMIM #618453
AR
136
ClinVar variants
42
Pathogenic / LP
0.01
pLI score
0
Active trials
Clinical Summary— WIPI2
⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.34) despite low pLI — interpret in context.
📋
ClinVar Variants
42 Pathogenic / Likely Pathogenic· 65 VUS of 136 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
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.
0.62LOEUF
pLI 0.006
Z-score 2.94
OE 0.34 (0.20–0.62)
Tolerant

Typical tolerance to LoF variation

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.
1.66Z-score
OE missense 0.72 (0.64–0.81)
204 obs / 282.6 exp
Tolerant

Mild missense constraint

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.0.34 (0.20–0.62)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.72 (0.64–0.81)
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.1.11
0≤1.21.6
LoF obs/exp: 8 / 23.3Missense obs/exp: 204 / 282.6Syn Z: -0.99

ClinVar Variant Classifications

136 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic39
Likely Pathogenic3
VUS65
Likely Benign16
Benign12
Conflicting1
39
Pathogenic
3
Likely Pathogenic
65
VUS
16
Likely Benign
12
Benign
1
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
2
37
0
39
Likely Pathogenic
0
0
3
0
3
VUS
1
51
13
0
65
Likely Benign
0
4
1
11
16
Benign
0
2
3
7
12
Conflicting
—1
Total1595718136

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

WIPI2 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

WIPI2-related neurodevelopmental disorder with white matter loss and hypoplasia of vermis and corpus callosum

moderate
ARLoss Of FunctionAltered Gene Product Structure
Dev. Disorders
G2P ↗
missense variant

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

?Intellectual developmental disorder with short stature and variable skeletal anomalies

MIM #618453

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Autophagy in the physiological endometrium and cancer.
Devis-Jauregui L et al.·Autophagy
2021Review
Autozygome and high throughput confirmation of disease genes candidacy.
Maddirevula S et al.·Genet Med
2019
Targeted proteomics addresses selectivity and complexity of protein degradation by autophagy.
Leytens A et al.·Autophagy
2025
DNA-dependent protein kinase regulates lysosomal AMP-dependent protein kinase activation and autophagy.
Puustinen P et al.·Autophagy
2020
A mutation in the major autophagy gene, WIPI2, associated with global developmental abnormalities.
Jelani M et al.·Brain
2019
A genome-wide CRISPR screen identifies the TNRC18 gene locus as a regulator of inflammatory signaling.
Rahimov F et al.·Nat Commun
2025
WIPI2 links LC3 conjugation with PI3P, autophagosome formation, and pathogen clearance by recruiting Atg12-5-16L1.
Dooley HC et al.·Mol Cell
2014
Evaluation of urinary autophagy transcripts expression in diabetic kidney disease.
Matboli M et al.·J Diabetes Complications
2017
Correlation of autophagy-related genes for predicting clinical prognosis in colorectal cancer.
Liu L et al.·Biomark Med
2021
Excess sphingomyelin disturbs ATG9A trafficking and autophagosome closure.
Corcelle-Termeau E et al.·Autophagy
2016
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools