VWA3B

Chr 2AR

von Willebrand factor A domain containing 3B

Also known as: SCAR22

NCBI Gene: 200403 ENSG00000168658 UniProt: Q502W6 OMIM: 614884

The protein contains a von Willebrand factor type A domain and functions in cellular processes including transcription, DNA repair, ribosomal transport, membrane transport, and proteasome activity. Mutations cause spinocerebellar ataxia, autosomal recessive 22, which follows autosomal recessive inheritance. The gene shows very low constraint against loss-of-function variants (pLI near zero), consistent with its recessive disease pattern.

OMIM ResearchSummary from RefSeq, OMIM

This gene encodes an intracellular protein that contains a von Willebrand factor type A domain. Intracellular proteins with VWA domains are thought to function in transcription, DNA repair, ribosomal and membrane transport and the proteasome. Mutations in this gene are associated with Spinocerebellar ataxia, autosomal recessive 22. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, May 2017]

OMIM ResearchGenerating clinical summary…

MultiplemechanismARLOEUF 0.941 OMIM phenotype

Clinical Summary— VWA3B

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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

11 unique Pathogenic / Likely Pathogenic· 196 VUS of 295 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.94LOEUF

pLI 0.000

Z-score 1.97

OE 0.75 (0.60–0.94)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.26Z-score

OE missense 0.97 (0.91–1.04)

678 obs / 697.2 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.75 (0.60–0.94)

0≤0.351.4

Missense OE?0.97 (0.91–1.04)

0≤0.61.4

Synonymous OE?0.97

0≤1.21.6

LoF obs/exp: 52 / 69.7Missense obs/exp: 678 / 697.2Syn Z: 0.34

This gene — mechanism propensity

0.6065th %ile

GOF

0.6540th %ile

LOF

0.4037th %ile

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

LOF91% of P/LP variants are LoF

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

295 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic1

Likely Pathogenic10

VUS196

Likely Benign48

Benign20

Conflicting4

Pathogenic

Likely Pathogenic

196

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	1	0	0	1
Likely Pathogenic	10	0	0	0	10
VUS	10	182	4	0	196
Likely Benign	1	25	4	18	48
Benign	2	8	5	5	20
Conflicting	—				4
Total	23	216	13	23	279

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

View in ClinVar →

14 pathogenic / likely-pathogenic (of 20) ClinVar copy-number / structural variants overlap VWA3B — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →