VWA1

Chr 1

von Willebrand factor A domain containing 1

Also known as: HMNMYO, HMNR7, WARP

NCBI Gene: 64856 ENSG00000179403 UniProt: Q6PCB0

VWA1 encodes a von Willebrand factor A domain-containing protein that promotes extracellular matrix assembly and is involved in skeletal muscle organization and neuromuscular junction formation. Mutations cause autosomal recessive distal hereditary motor neuronopathy type 7, which affects peripheral motor neurons and results in distal muscle weakness. The gene shows tolerance to loss-of-function variants (LOEUF 1.066), consistent with its recessive inheritance pattern.

ResearchSummary from RefSeq, OMIM, UniProt

VWA1 belongs to the von Willebrand factor (VWF; MIM 613160) A (VWFA) domain superfamily of extracellular matrix proteins and appears to play a role in cartilage structure and function (Fitzgerald et al., 2002 [PubMed 12062410]).[supplied by OMIM, Nov 2010]

ResearchGenerating clinical summary…

MultiplemechanismLOEUF 1.07

Clinical Summary— VWA1

⚡

Population Constraint (gnomAD)

Low constraint (pLI 0.01) — loss-of-function variants are relatively tolerated in the population.

📋

ClinVar Variants

18 unique Pathogenic / Likely Pathogenic· 127 VUS of 191 total submissions

Explore recent and relevant literature in Research Assistant →

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.07LOEUF

pLI 0.005

Z-score 1.43

OE 0.51 (0.26–1.07)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.15Z-score

OE missense 1.03 (0.92–1.15)

219 obs / 212.9 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.51 (0.26–1.07)

0≤0.351.4

Missense OE?1.03 (0.92–1.15)

0≤0.61.4

Synonymous OE?0.96

0≤1.21.6

LoF obs/exp: 5 / 9.9Missense obs/exp: 219 / 212.9Syn Z: 0.32

This gene — mechanism propensity

0.7326th %ile

GOF

0.83top 10%

LOF

0.2582th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). 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

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.

ClinVar Variant Classifications

191 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic4

Likely Pathogenic14

VUS127

Likely Benign23

Benign13

Conflicting6

Pathogenic

Likely Pathogenic

127

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	4	0	0	0	4
Likely Pathogenic	13	1	0	0	14
VUS	2	124	0	1	127
Likely Benign	0	9	1	13	23
Benign	0	4	5	4	13
Conflicting	—				6
Total	19	138	6	18	187

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

View in ClinVar →

131 pathogenic / likely-pathogenic (of 158) ClinVar copy-number / structural variants overlap VWA1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →