VANGL2

Chr 1AD

VANGL planar cell polarity protein 2

Also known as: LPP1, LTAP, STB1, STBM, STBM1

NCBI Gene: 57216 ENSG00000162738 UniProt: Q9ULK5 OMIM: 600533

The protein encoded by this gene is a membrane protein involved in the regulation of planar cell polarity, especially in the stereociliary bundles of the cochlea. The encoded protein transmits directional signals to individual cells or groups of cells in epithelial sheets. This protein is also involved in the development of the neural plate. [provided by RefSeq, Sep 2011]

OMIM Research

OMIM ResearchGenerating clinical summary…

MultiplemechanismADLOEUF 0.391 OMIM phenotype

Clinical Summary— VANGL2

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Population Constraint (gnomAD)

Moderately constrained gene (pLI 0.84) — some intolerance to loss-of-function variants.

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ClinVar Variants

55 VUS of 77 total submissions

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Clinical Trials

3 active or recruiting trials — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.39LOEUF

pLI 0.843

Z-score 3.75

OE 0.17 (0.08–0.39)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.43Z-score

OE missense 0.78 (0.70–0.86)

253 obs / 325.8 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.17 (0.08–0.39)

0≤0.351.4

Missense OE?0.78 (0.70–0.86)

0≤0.61.4

Synonymous OE?1.00

0≤1.21.6

LoF obs/exp: 4 / 23.7Missense obs/exp: 253 / 325.8Syn Z: 0.00

This gene — mechanism propensity

0.5477th %ile

GOF

0.6345th %ile

LOF

0.61top 25%

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and loss-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median

LOFLOEUF 0.39

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

77 submitted variants in ClinVar

ClinVar

Classification Summary

VUS55

Likely Benign6

Benign5

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0
Likely Pathogenic	0	0	0	0
VUS	54	1	0	55
Likely Benign	1	1	4	6
Benign	3	0	2	5
Total	58	2	6	66

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

View in ClinVar →

10 pathogenic / likely-pathogenic (of 15) ClinVar copy-number / structural variants overlap VANGL2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →