# NM_002641.4(PIGA):c.329dup (p.Pro111fs)

https://sugi.bio/variant/piga-p-pro111fs

## Summary

**PIGA p.Pro111fs (c.329dup)** is classified **Likely pathogenic** in PIGA (ClinVar, No assertion criteria, 1 submitter; last evaluated 2022-12-05). No gnomAD frequency available for this variant; Associated with paroxysmal nocturnal hemoglobinuria 1.

**At a glance:** Likely pathogenic · review: No assertion criteria · rsID rs2519331657 · 1 submitter · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the PIGA gene that is considered likely disease-causing, submitted by 1 submitter, and is linked to paroxysmal nocturnal hemoglobinuria 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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Not applicable |
| Age of onset (of this condition) | All ages |
| Prevalence | 1-9 / 1 000 000 (United Kingdom) |
| Diagnostic panels | PIGA is a diagnostic-grade gene on 13 Genomics England panels |

**Commonly reported features of Paroxysmal nocturnal hemoglobinuria** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Abnormal erythrocyte enzyme activity — Obligate (100%)
- Hemolytic anemia — Very frequent (99-80%)
- Anemia — Very frequent (99-80%)
- Hemoglobinuria — Very frequent (99-80%)
- Asthenia — Very frequent (99-80%)
- Thromboembolism — Frequent (79-30%)
- Reticulocytosis — Frequent (79-30%)
- Dyspnea — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0024726/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [PIGA](https://sugi.bio/atlas/gene/PIGA/) |
| Protein change (HGVS p.) | p.Pro111fs |
| Coding change (HGVS c.) | c.329dup |
| MANE Select transcript | [NM_002641](https://www.ncbi.nlm.nih.gov/nuccore/NM_002641) |
| dbSNP | [rs2519331657](https://www.ncbi.nlm.nih.gov/snp/rs2519331657/) |
| Variant type | Duplication |
| Location | chrX:15331601-15331602 (GRCh38) |
| ClinVar | [VCV2502426](https://www.ncbi.nlm.nih.gov/clinvar/variation/2502426/) |

**All HGVS expressions:** `LRG_160:g.8937dup`, `LRG_160t1:c.329dup`, `NC_000023.10:g.15349724dup`, `NC_000023.11:g.15331602dup`, `NG_009786.1:g.8937dup`, `NM_002641.4:c.329dup`, `NM_020473.3:c.13+3899dup`, `NR_033835.1:n.445dup`

## 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 2.181, GERP 0.076, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 2 of 6**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no duplication 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}

**PIGA** population constraint: ClinGen dosage — haploinsufficiency 1/3, 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):

- **complex neurodevelopmental disorder** — Definitive (XL)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 86.22, 70% of residues very-high.

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

*Describes the biological roles of PIGA (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.*


### Pathways affected {#pathways}

PIGA participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Synthesis of glycosylphosphatidylinositol (GPI)](https://reactome.org/content/detail/R-HSA-162710) | other |

## Clinical significance {#significance}

**Likely pathogenic** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 2022-12-05.

**Submitter consensus:** unanimous (1/1 Likely pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Pangenia Genomics, Pangenia Inc. | Likely pathogenic | no assertion criteria provided | research | 2022-12-05 |

## Associated conditions {#conditions}

[paroxysmal nocturnal hemoglobinuria 1](https://sugi.bio/atlas/disease/paroxysmal-nocturnal-hemoglobinuria-1/).

**Reported phenotype names (ClinVar):** Paroxysmal nocturnal hemoglobinuria 1.

## Similar variants {#similar}

Related PIGA variant pages (same residue, condition, or type): [PIGA p.Pro111Leu](/variant/piga-p-pro111leu), [PIGA p.Pro111=](/variant/piga-p-pro111), [PIGA p.Arg119Trp](/variant/piga-p-arg119trp), [PIGA p.Met37Val](/variant/piga-p-met37val), [PIGA p.Val329Ala](/variant/piga-p-val329ala), [PIGA p.Val49Met](/variant/piga-p-val49met), [PIGA p.Pro350Ser](/variant/piga-p-pro350ser), [PIGA p.Leu175=](/variant/piga-p-leu175).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 2502426). 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.*