WASF1

Chr 6AD

WASP family member 1

Also known as: NEDALVS, SCAR1, WAVE, WAVE-1, WAVE1

NCBI Gene: 8936 ENSG00000112290 UniProt: Q92558 OMIM: 605035

This protein regulates actin cytoskeleton dynamics by promoting actin filament formation as part of the WAVE complex and is involved in BDNF-NTRK2 endocytic trafficking and mitochondrial dynamics. Mutations cause neurodevelopmental disorder with absent language and variable seizures with autosomal dominant inheritance. The gene is highly constrained against loss-of-function variants (pLI 0.998, LOEUF 0.215), indicating intolerance to protein disruption.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene, a member of the Wiskott-Aldrich syndrome protein (WASP)-family, plays a critical role downstream of Rac, a Rho-family small GTPase, in regulating the actin cytoskeleton required for membrane ruffling. It has been shown to associate with an actin nucleation core Arp2/3 complex while enhancing actin polymerization in vitro. Wiskott-Aldrich syndrome is a disease of the immune system, likely due to defects in regulation of actin cytoskeleton. Multiple alternatively spliced transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 0.211 OMIM phenotype

Clinical Summary— WASF1

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

13 unique Pathogenic / Likely Pathogenic· 97 VUS of 143 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.21LOEUF

pLI 0.998

Z-score 4.15

OE 0.05 (0.01–0.21)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

2.55Z-score

OE missense 0.59 (0.52–0.66)

175 obs / 298.9 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.05 (0.01–0.21)

0≤0.351.4

Missense OE?0.59 (0.52–0.66)

0≤0.61.4

Synonymous OE?0.84

0≤1.21.6

LoF obs/exp: 1 / 22.1Missense obs/exp: 175 / 298.9Syn Z: 1.32

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

limitedWASF1-related neurodevelopmental disorderLOFAD

moderateWASF1-related intellectual disability with seizuresLOFAD

This gene — mechanism propensity

0.2598th %ile

GOF

0.4183th %ile

LOF

0.78top 5%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · 77% of P/LP variants are LoF · LOEUF 0.21

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

143 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic8

Likely Pathogenic5

VUS97

Likely Benign20

Benign1

Conflicting3

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	7	1	0	0	8
Likely Pathogenic	3	2	0	0	5
VUS	6	87	4	0	97
Likely Benign	0	10	2	8	20
Benign	0	1	0	0	1
Conflicting	—				3
Total	16	101	6	8	134

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

View in ClinVar →

17 pathogenic / likely-pathogenic (of 28) ClinVar copy-number / structural variants overlap WASF1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →