DVL1

Chr 1AD

dishevelled segment polarity protein 1

Also known as: DRS2, DVL, DVL1L1

NCBI Gene: 1855 ENSG00000107404 UniProt: O14640 OMIM: 601365

DVL1 encodes a cytoplasmic phosphoprotein that participates in Wnt signaling pathways by binding to frizzled receptors and transducing signals to downstream effectors, and plays a role in neuromuscular junction formation through regulation of acetylcholine receptor clustering. Mutations cause autosomal dominant Robinow syndrome type 2, a skeletal dysplasia syndrome. The gene shows low constraint against loss-of-function variants (pLI near 0), suggesting tolerance to complete gene loss.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

GOFmechanismADLOEUF 0.731 OMIM phenotype

Clinical Summary— DVL1

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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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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint

0.73LOEUF

pLI 0.000

Z-score 2.69

OE 0.47 (0.31–0.73)

Tolerant

Typical tolerance to LoF variation

Missense Constraint

-1.13Z-score

OE missense 1.14 (1.07–1.23)

554 obs / 484.2 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios

LoF OE0.47 (0.31–0.73)

0≤0.351.4

Missense OE1.14 (1.07–1.23)

0≤0.61.4

Synonymous OE1.44

0≤1.21.6

LoF obs/exp: 14 / 29.9Missense obs/exp: 554 / 484.2Syn Z: -4.97

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveDVL1-related Robinow syndromeGOFAD

0.80top 25%

GOF

0.7126th %ile

LOF

0.4037th %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 · 1 literature citation

GOFprediction above median · 1 literature citation

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.

Literature Evidence

DNFurthermore, in contrast with the type of genetic alteration reported to cause WNT5A and ROR2 disease-associated mutations, variants in DVL1 seem to result in dominant-negative or gain-of-function proteins.PMID:25817016

GOFFurthermore, in contrast with the type of genetic alteration reported to cause WNT5A and ROR2 disease-associated mutations, variants in DVL1 seem to result in dominant-negative or gain-of-function proteins.PMID:25817016

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.