# NM_000377.3(WAS):c.383T>C (p.Phe128Ser)

https://sugi.bio/variant/was-p-phe128ser

## Summary

**WAS p.Phe128Ser (c.383T>C)** is classified **Pathogenic/Likely pathogenic** in WAS (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-09-18). AlphaMissense: likely pathogenic (0.9969); Absent from gnomAD v4.1; Associated with thrombocytopenia 1.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs2519280746 · 2 submitters · 3 linked conditions · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the WAS gene that is considered likely disease-causing, submitted by 2 submitters, and is linked to thrombocytopenia 1.

*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.*

|  |  |
| --- | --- |
| Clinical trials | 22 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0005176/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.Phe128Ser |
| Coding change (HGVS c.) | c.383T>C |
| MANE Select transcript | [NM_000377](https://www.ncbi.nlm.nih.gov/nuccore/NM_000377) |
| dbSNP | [rs2519280746](https://www.ncbi.nlm.nih.gov/snp/rs2519280746/) |
| Variant type | single nucleotide variant |
| Location | chrX:48685756-48685756 (GRCh38) |
| ClinVar | [VCV1810240](https://www.ncbi.nlm.nih.gov/clinvar/variation/1810240/) |

**All HGVS expressions:** `LRG_125:g.6960T>C`, `LRG_125t1:c.383T>C`, `NC_000023.10:g.48544145T>C`, `NC_000023.11:g.48685756T>C`, `NG_007877.1:g.6960T>C`, `NM_000377.3:c.383T>C`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- AlphaMissense **likely pathogenic** (0.9969) — concordant with the pathogenic call
- REVEL 0.952 (strongly pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -15.557 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- SpliceAI predicts **acceptor loss** (Δ 0.28) — consistent with the pathogenic call
- Conservation: phyloP 7.841, GERP 1.56, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 2%** most-pathogenic-predicted substitutions in WAS (of 2,915 modeled).
- CADD: **PHRED 25.8**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- Regional missense constraint: **o/e 0.52** across the covering region of the MANE Select transcript (48,683,854–48,685,827), spanning 1,973 bp. Chi-square p 1.3e-07. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.28**, donor loss **0.00**, acceptor gain **0.02**, donor gain **0.00**. Largest is acceptor loss.
- SpliceAI deltas (masked): acceptor loss **0.28**, donor loss **0.00**, acceptor gain **0.02**, donor gain **0.00**.
- Population frequency: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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}

Residue **128** lies in the wh1 domain.

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. p.Phe128Ser falls in the wh1 domain. 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/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2023-09-18.

**Submitter consensus:** conflicting (1 Likely pathogenic, 1 Pathogenic).

**Submission history:** 2 submissions (2022–2023); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Dubai Health Genomic Medicine Center, Dubai Health | Likely pathogenic | criteria provided, single submitter | clinical testing | 2022-12-17 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2023-09-18 |

## Associated conditions {#conditions}

[thrombocytopenia 1](https://sugi.bio/atlas/disease/thrombocytopenia-1/), [X-linked severe congenital neutropenia](https://sugi.bio/atlas/disease/x-linked-severe-congenital-neutropenia/), [Wiskott-Aldrich syndrome](https://sugi.bio/atlas/disease/wiskott-aldrich-syndrome/).

**Reported phenotype names (ClinVar):** Thrombocytopenia 1, not provided, Wiskott-Aldrich syndrome, X-linked severe congenital neutropenia, THROMBOCYTOPENIA, X-LINKED, 1, X-linked thrombocytopenia with normal platelets, X-Linked Thrombocytopenia (XLT), ALDRICH SYNDROME, IMMUNODEFICIENCY 2, WISKOTT-ALDRICH SYNDROME 1.

## Same-residue context {#hotspot}

Residue **128** carries **2 other pathogenic ClinVar variants** — a recurrently-mutated position: [WAS p.Phe128Leu](/variant/was-p-phe128leu), [WAS p.Phe128Cys](/variant/was-p-phe128cys). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related WAS variant pages (same residue, condition, or type): [WAS p.Phe128Cys](/variant/was-p-phe128cys), [WAS p.Phe128Leu](/variant/was-p-phe128leu), [WAS c.1339-2A>G](/variant/was-c-1339-minus-2a-g), [WAS c.1453+2T>C](/variant/was-c-1453-plus-2t-c), [WAS c.273+1G>A](/variant/was-c-273-plus-1g-a), [WAS c.360+1G>A](/variant/was-c-360-plus-1g-a), [WAS c.559+5G>A](/variant/was-c-559-plus-5g-a), [WAS c.777+1G>A](/variant/was-c-777-plus-1g-a).

### 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 1810240). 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.*