# NM_000377.3(WAS):c.389ACGAGG[3] (p.130DE[3])

https://sugi.bio/variant/was-p-130de-3

## Summary

**WAS p.130DE[3] (c.389ACGAGG[3])** is classified **Pathogenic** in WAS (ClinVar, No assertion criteria, 1 submitter; last evaluated 2001-07-17). No gnomAD frequency available for this variant; Associated with Wiskott-Aldrich syndrome.

**At a glance:** Pathogenic · review: No assertion criteria · rsID rs587776743 · 1 submitter · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the WAS gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to Wiskott-Aldrich syndrome.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal dominant, Autosomal recessive, Not applicable |
| Age of onset (of this condition) | Infancy, Neonatal |
| Prevalence | 1-9 / 1 000 000 (Europe) |
| Clinical trials | 34 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | WAS is a diagnostic-grade gene on 11 Genomics England panels |

**Commonly reported features of Wiskott-Aldrich syndrome** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Sinusitis — Very frequent (99-80%)
- Otitis media — Very frequent (99-80%)
- Chronic otitis media — Very frequent (99-80%)
- Bruising susceptibility — Very frequent (99-80%)
- Thrombocytopenia — Very frequent (99-80%)
- Lymphopenia — Very frequent (99-80%)
- Fever — Very frequent (99-80%)
- Chronic diarrhea — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0007895/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [WAS](https://sugi.bio/atlas/gene/WAS/) |
| Protein change (HGVS p.) | p.130DE[3] |
| Coding change (HGVS c.) | c.389ACGAGG[3] |
| MANE Select transcript | [NM_000377](https://www.ncbi.nlm.nih.gov/nuccore/NM_000377) |
| dbSNP | [rs587776743](https://www.ncbi.nlm.nih.gov/snp/rs587776743/) |
| Variant type | Microsatellite |
| Location | chrX:48685760-48685761 (GRCh38) |
| ClinVar | [VCV11121](https://www.ncbi.nlm.nih.gov/clinvar/variation/11121/) |

**All HGVS expressions:** `LRG_125:g.6966ACGAGG[3]`, `NC_000023.10:g.48544151ACGAGG[3]`, `NC_000023.11:g.48685762ACGAGG[3]`, `NG_007877.1:g.6966ACGAGG[3]`, `NM_000377.2:c.395_400dup`, `NM_000377.3:c.389ACGAGG[3]`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP -0.515, GERP -3.13 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no microsatellite variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**WAS** population constraint: ClinGen dosage — haploinsufficiency 3/3, triplosensitivity 0/3. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **X-linked severe congenital neutropenia** — Definitive (XL)
- **Wiskott-Aldrich syndrome** — Definitive (XL)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 70.84, 26% of residues very-high.

**7 experimental structure(s)** (PDB): [1CEE](https://www.rcsb.org/structure/1CEE), [1EJ5](https://www.rcsb.org/structure/1EJ5), [1T84](https://www.rcsb.org/structure/1T84), [2A3Z](https://www.rcsb.org/structure/2A3Z), [2K42](https://www.rcsb.org/structure/2K42), [2OT0](https://www.rcsb.org/structure/2OT0).

## What this gene does {#gene-function}

*Describes the biological roles of WAS (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** WAS's established molecular role includes SH3 domain binding. In Reactome, WAS is annotated in disease pathway(s) including **FCGR3A-mediated phagocytosis**.

**Disease mechanism (Reactome):** WAS loss or alteration is curated in [FCGR3A-mediated phagocytosis](https://reactome.org/content/detail/R-HSA-9664422).

### Pathways affected {#pathways}

WAS participates in **7 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [FCGR3A-mediated phagocytosis](https://reactome.org/content/detail/R-HSA-9664422) | electronic |
| [CDC42 GTPase cycle](https://reactome.org/content/detail/R-HSA-9013148) | curated |
| [Generation of second messenger molecules](https://reactome.org/content/detail/R-HSA-202433) | curated |
| [RAC1 GTPase cycle](https://reactome.org/content/detail/R-HSA-9013149) | curated |
| [RHOJ GTPase cycle](https://reactome.org/content/detail/R-HSA-9013409) | curated |
| [RHO GTPases Activate WASPs and WAVEs](https://reactome.org/content/detail/R-HSA-5663213) | electronic |
| [Regulation of actin dynamics for phagocytic cup formation](https://reactome.org/content/detail/R-HSA-2029482) | electronic |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** SH3 domain binding, protein kinase binding, small GTPase binding, identical protein binding, phospholipase binding.

**Biological process:** regulation of T cell antigen processing and presentation, immune response, regulation of actin polymerization or depolymerization, regulation of lamellipodium assembly, actin filament polymerization, Cdc42 protein signal transduction.

## Clinical significance {#significance}

**Pathogenic** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 2001-07-17.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 2001-07-17 |

## Associated conditions {#conditions}

[Wiskott-Aldrich syndrome](https://sugi.bio/atlas/disease/wiskott-aldrich-syndrome/).

**Reported phenotype names (ClinVar):** Wiskott-Aldrich syndrome, ALDRICH SYNDROME, IMMUNODEFICIENCY 2, WISKOTT-ALDRICH SYNDROME 1, Wiskott-aldrich syndrome, somatic.

## Similar variants {#similar}

Related WAS variant pages (same residue, condition, or type): [WAS p.Pro404_Ser405insProProPro](/variant/was-p-pro404-ser405inspropropro), [WAS p.Lys232del](/variant/was-p-lys232del), [WAS c.509_510del](/variant/was-c-509-510del), [WAS c.560-3_560-2del](/variant/was-c-560-minus-3-560-minus-2del), [WAS p.Arg151fs](/variant/was-p-arg151fs), [WAS p.Leu35_Phe36insTer](/variant/was-p-leu35-phe36inster), [WAS p.494ED[1]](/variant/was-p-494ed-1), [WAS p.Gly323del](/variant/was-p-gly323del).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 11121). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*