DVL3

Chr 3AD

dishevelled segment polarity protein 3

Also known as: DRS3

NCBI Gene: 1857 ENSG00000161202 UniProt: Q92997 OMIM: 601368

The protein is involved in Wnt signaling pathways that regulate cell proliferation and development. Mutations cause autosomal dominant Robinow syndrome type 3, characterized by distinctive facial features, short stature, and skeletal abnormalities. The gene shows high constraint against loss-of-function variants (LOEUF 0.422), suggesting intolerance to protein disruption.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene is a member of a multi-gene family which shares strong similarity with the Drosophila dishevelled gene, dsh. The Drosophila dishevelled gene encodes a cytoplasmic phosphoprotein that regulates cell proliferation. [provided by RefSeq, Jul 2008]

GeneReviews OMIM ResearchGenerating clinical summary…

DNmechanismADLOEUF 0.421 OMIM phenotype

Clinical Summary— DVL3

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.22) despite low pLI — interpret in context.

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ClinVar Variants

20 unique Pathogenic / Likely Pathogenic· 212 VUS of 469 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — DVL3

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.42LOEUF

pLI 0.385

Z-score 4.01

OE 0.22 (0.13–0.42)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

2.32Z-score

OE missense 0.70 (0.65–0.77)

345 obs / 489.4 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.22 (0.13–0.42)

0≤0.351.4

Missense OE?0.70 (0.65–0.77)

0≤0.61.4

Synonymous OE?0.95

0≤1.21.6

LoF obs/exp: 7 / 31.2Missense obs/exp: 345 / 489.4Syn Z: 0.60

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveDVL3-related Robinow syndromeDNAD

This gene — mechanism propensity

0.7033th %ile

GOF

0.6346th %ile

LOF

0.52top 25%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and dominant-negative). The Badonyi & Marsh model scores dominant-negative highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports loss-of-function (haploinsufficiency). Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOF95% of P/LP variants are LoF · LOEUF 0.42

DNprediction 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. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

469 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic9

Likely Pathogenic11

VUS212

Likely Benign168

Benign34

Conflicting22

Pathogenic

Likely Pathogenic

212

VUS

168

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	9	0	0	0	9
Likely Pathogenic	10	1	0	0	11
VUS	14	193	4	1	212
Likely Benign	2	21	40	105	168
Benign	0	12	17	5	34
Conflicting	—				22
Total	35	227	61	111	456

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

View in ClinVar →

40 pathogenic / likely-pathogenic (of 46) ClinVar copy-number / structural variants overlap DVL3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →