# NM_004484.4(GPC3):c.332del (p.Phe111fs)

https://sugi.bio/variant/gpc3-p-phe111fs

## Summary

**GPC3 p.Phe111fs (c.332del)** is classified **Pathogenic** in GPC3 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-29). No gnomAD frequency available for this variant; Associated with Wilms tumor 1.

**At a glance:** Pathogenic · review: Single submitter · rsID rs2521895087 · 1 submitter · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the GPC3 gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to Wilms tumor 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 | 6 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0015124/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [GPC3](https://sugi.bio/atlas/gene/GPC3/) |
| Protein change (HGVS p.) | p.Phe111fs |
| Coding change (HGVS c.) | c.332del |
| MANE Select transcript | [NM_004484](https://www.ncbi.nlm.nih.gov/nuccore/NM_004484) |
| dbSNP | [rs2521895087](https://www.ncbi.nlm.nih.gov/snp/rs2521895087/) |
| Variant type | Deletion |
| Location | chrX:133953055-133953055 (GRCh38) |
| ClinVar | [VCV2027782](https://www.ncbi.nlm.nih.gov/clinvar/variation/2027782/) |

**All HGVS expressions:** `LRG_505:g.37585del`, `LRG_505t1:c.329del`, `NC_000023.10:g.133087085del`, `NC_000023.11:g.133953058del`, `NG_009286.1:g.37585del`, `NM_001164617.2:c.332del`, `NM_001164618.2:c.289+43del`, `NM_001164619.2:c.175+32220del`, `NM_004484.4:c.332del`

## Computational & population evidence {#evidence}

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

- **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 7.336, GERP 2.35, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. ClinGen curates **sufficient evidence for haploinsufficiency** in this gene, supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 2 of 8**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion 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}

**GPC3** 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):

- **Simpson-Golabi-Behmel syndrome** — Definitive (XL)

## Protein context {#protein}

Residue **111** lies in an α-helix.

AlphaFold model confidence (whole protein): pLDDT 75.60, 54% of residues very-high.

**4 experimental structure(s)** (PDB): [7ZA1](https://www.rcsb.org/structure/7ZA1), [7ZAW](https://www.rcsb.org/structure/7ZAW), [9NTQ](https://www.rcsb.org/structure/9NTQ), [9NTT](https://www.rcsb.org/structure/9NTT).

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

*Describes the biological roles of GPC3 (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:** GPC3's established molecular role includes peptidyl-dipeptidase inhibitor activity. In Reactome, GPC3 is annotated in disease pathway(s) including **Defective B3GALT6 causes EDSP2 and SEMDJL1**, **Defective B3GAT3 causes JDSSDHD**.

**Disease mechanism (Reactome):** GPC3 loss or alteration is curated in [Defective B3GALT6 causes EDSP2 and SEMDJL1](https://reactome.org/content/detail/R-HSA-4420332), [Defective B3GAT3 causes JDSSDHD](https://reactome.org/content/detail/R-HSA-3560801), [Defective B4GALT7 causes EDS, progeroid type](https://reactome.org/content/detail/R-HSA-3560783).

### Pathways affected {#pathways}

GPC3 participates in **18 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective B3GALT6 causes EDSP2 and SEMDJL1](https://reactome.org/content/detail/R-HSA-4420332) | curated |
| ⚕ [Defective B3GAT3 causes JDSSDHD](https://reactome.org/content/detail/R-HSA-3560801) | curated |
| ⚕ [Defective B4GALT7 causes EDS, progeroid type](https://reactome.org/content/detail/R-HSA-3560783) | curated |
| ⚕ [Defective EXT1 causes exostoses 1, TRPS2 and CHDS](https://reactome.org/content/detail/R-HSA-3656253) | curated |
| ⚕ [Defective EXT2 causes exostoses 2](https://reactome.org/content/detail/R-HSA-3656237) | curated |
| ⚕ [Dengue Virus Attachment and Entry](https://reactome.org/content/detail/R-HSA-9918485) | curated |
| ⚕ [Dengue Virus-Host Interactions](https://reactome.org/content/detail/R-HSA-9918481) | curated |
| ⚕ [RSV-host interactions](https://reactome.org/content/detail/R-HSA-9833110) | curated |
| ⚕ [Respiratory syncytial virus (RSV) attachment and entry](https://reactome.org/content/detail/R-HSA-9820960) | curated |
| ⚕ [Attachment and Entry](https://reactome.org/content/detail/R-HSA-9694614) | electronic |
| [Glycosaminoglycan-protein linkage region biosynthesis](https://reactome.org/content/detail/R-HSA-1971475) | curated |
| [HS-GAG degradation](https://reactome.org/content/detail/R-HSA-2024096) | curated |
| [Initiation of coagulation cascade](https://reactome.org/content/detail/R-HSA-9769735) | curated |
| [Post-translational protein phosphorylation](https://reactome.org/content/detail/R-HSA-8957275) | curated |
| [Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)](https://reactome.org/content/detail/R-HSA-381426) | curated |
| [Regulation of clotting cascade](https://reactome.org/content/detail/R-HSA-9769739) | curated |
| [Retinoid metabolism and transport](https://reactome.org/content/detail/R-HSA-975634) | curated |
| [HS-GAG biosynthesis](https://reactome.org/content/detail/R-HSA-2022928) | electronic |

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

**Molecular function:** peptidyl-dipeptidase inhibitor activity.

**Biological process:** regulation of canonical Wnt signaling pathway, positive regulation of canonical Wnt signaling pathway, regulation of non-canonical Wnt signaling pathway.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-08-29.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2022-08-29 |

## Associated conditions {#conditions}

[Wilms tumor 1](https://sugi.bio/atlas/disease/wilms-tumor-1/).

**Reported phenotype names (ClinVar):** Wilms tumor 1, Wilms tumor, somatic.

## Similar variants {#similar}

Related GPC3 variant pages (same residue, condition, or type): [GPC3 p.Gln91fs](/variant/gpc3-p-gln91fs), [GPC3 c.338-5del](/variant/gpc3-c-338-minus-5del), [GPC3 c.338-7_338-5del](/variant/gpc3-c-338-minus-7-338-minus-5del), [GPC3 c.1574-?_*379+?del](/variant/gpc3-c-1574-minus-star-379-plus-del), [GPC3 p.Ala13fs](/variant/gpc3-p-ala13fs), [GPC3 p.Ala436fs](/variant/gpc3-p-ala436fs), [GPC3 p.Ala524fs](/variant/gpc3-p-ala524fs), [GPC3 p.Arg203fs](/variant/gpc3-p-arg203fs).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-06); 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 2027782). 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.*