DVL2

Chr 17

dishevelled segment polarity protein 2

NCBI Gene: 1856 ENSG00000004975 UniProt: O14641 OMIM: 602151

This protein functions as a cytoplasmic signal transducer in Wnt signaling pathways, binding to frizzled receptors and transmitting signals to downstream effectors in both canonical and non-canonical pathways. Mutations cause autosomal dominant neurodevelopmental disorders characterized by intellectual disability, autism spectrum disorder, and brain malformations. The gene is moderately constrained against loss-of-function variants, consistent with its essential role in early brain development.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a member of the dishevelled (dsh) protein family. The vertebrate dsh proteins have approximately 40% amino acid sequence similarity with Drosophila dsh. This gene encodes a 90-kD protein that undergoes posttranslational phosphorylation to form a 95-kD cytoplasmic protein, which may play a role in the signal transduction pathway mediated by multiple Wnt proteins. The mechanisms of dishevelled function in Wnt signaling are likely to be conserved among metazoans. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.66

Clinical Summary— DVL2

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Population Constraint (gnomAD)

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

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ClinVar Variants

4 unique Pathogenic / Likely Pathogenic· 107 VUS of 143 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.66LOEUF

pLI 0.000

Z-score 3.10

OE 0.42 (0.28–0.66)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.32Z-score

OE missense 0.96 (0.89–1.04)

447 obs / 466.6 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.42 (0.28–0.66)

0≤0.351.4

Missense OE?0.96 (0.89–1.04)

0≤0.61.4

Synonymous OE?1.11

0≤1.21.6

LoF obs/exp: 14 / 33.3Missense obs/exp: 447 / 466.6Syn Z: -1.14

This gene — mechanism propensity

0.7326th %ile

GOF

0.6639th %ile

LOF

0.4332th %ile

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

DNprediction above median

GOFprediction above median

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.

ClinVar Variant Classifications

143 submitted variants in ClinVar

ClinVar

Classification Summary

Likely Pathogenic4

VUS107

Likely Benign12

Benign10

Likely Pathogenic

107

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0	0
Likely Pathogenic	2	2	0	0	4
VUS	0	107	0	0	107
Likely Benign	0	4	4	4	12
Benign	0	2	4	4	10
Total	2	115	8	8	133

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

View in ClinVar →

30 pathogenic / likely-pathogenic (of 41) ClinVar copy-number / structural variants overlap DVL2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →