# NM_001083116.3(PRF1):c.65del (p.Pro22fs)

https://sugi.bio/variant/prf1-p-pro22fs

## Summary

**PRF1 p.Pro22fs (c.65del)** is classified **Pathogenic** in PRF1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-07-14). Very rare (popmax 0.00446%, eas); Associated with aplastic anemia.

**At a glance:** Pathogenic · review: Multiple submitters · rsID rs761651233 · 4 submitters · 2 linked conditions · very rare (popmax 0.00446%, eas)

## For patients & families {#patients}

This is a change in the PRF1 gene that is considered disease-causing, submitted by 4 submitters, and is linked to aplastic anemia.

*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 | 232 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0020234/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [PRF1](https://sugi.bio/atlas/gene/PRF1/) |
| Protein change (HGVS p.) | p.Pro22fs |
| Coding change (HGVS c.) | c.65del |
| MANE Select transcript | [NM_001083116](https://www.ncbi.nlm.nih.gov/nuccore/NM_001083116) |
| dbSNP | [rs761651233](https://www.ncbi.nlm.nih.gov/snp/rs761651233/) |
| Variant type | Deletion |
| Location | chr10:70600838-70600838 (GRCh38) |
| ClinVar | [VCV2442794](https://www.ncbi.nlm.nih.gov/clinvar/variation/2442794/) |

**All HGVS expressions:** `LRG_94:g.6938del`, `LRG_94t1:c.65del`, `NC_000010.10:g.72360597del`, `NC_000010.11:g.70600841del`, `NG_009615.1:g.6938del`, `NM_001083116.1:c.62delC`, `NM_001083116.3:c.65del`, `NM_005041.6:c.65del`

## 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 0.838, GERP -3.75, phastCons 0.999 — weakly conserved position
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.438, pLI 0.00029003. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 2 of 3**, 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.
- Repeat context: **simple_repeat** ((GCAGGA)n). The alignment of this deletion is ambiguous inside a repeating unit, so the same change can be written several ways and a frequency lookup keyed on one representation can miss another. *A qualifier on how reliably this variant can be called and counted — not a pathogenicity signal.*
- Population frequency (gnomAD v4.1): grpmax **0.00446%** (eas) · FAF95 0.000739% · FAF99 0.000277% · 2/44,830 in the highest group · 2/1,459,702 alleles overall — very rare (popmax 0.00446%, eas).

*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}

**PRF1** population constraint: LOEUF 1.438, pLI 0.00029003, missense-Z 0.6948; ClinGen dosage — haploinsufficiency 30, triplosensitivity Not yet evaluated (0–3 scale). *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):

- **familial hemophagocytic lymphohistiocytosis 2** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 91.01, 78% of residues very-high.

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

*Describes the biological roles of PRF1 (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:** PRF1's established molecular role includes wide pore channel activity. In Reactome, PRF1 is annotated in disease pathway(s) including **Nuclear events stimulated by ALK signaling in cancer**.

**Disease mechanism (Reactome):** PRF1 loss or alteration is curated in [Nuclear events stimulated by ALK signaling in cancer](https://reactome.org/content/detail/R-HSA-9725371).

### Pathways affected {#pathways}

PRF1 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Nuclear events stimulated by ALK signaling in cancer](https://reactome.org/content/detail/R-HSA-9725371) | curated |

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

**Molecular function:** wide pore channel activity, identical protein binding.

**Biological process:** immunological synapse formation, protein import, protein homooligomerization, positive regulation of killing of cells of another organism, protein transmembrane transport.

## Clinical significance {#significance}

**Pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-07-14.

**Submitter consensus:** unanimous (4/4 Pathogenic).

**Submission history:** 4 submissions (2023–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Diagnostic Genetics, Severance Hospital, Yonsei University College of Medicine | Pathogenic | criteria provided, single submitter | clinical testing | 2023-01-03 |
| Baylor Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2023-07-01 |
| Myriad Genetics, Inc. | Pathogenic | criteria provided, single submitter | clinical testing | 2025-04-10 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-07-14 |

## Associated conditions {#conditions}

[aplastic anemia](https://sugi.bio/atlas/disease/aplastic-anemia/), [familial hemophagocytic lymphohistiocytosis 2](https://sugi.bio/atlas/disease/familial-hemophagocytic-lymphohistiocytosis-2/).

**Reported phenotype names (ClinVar):** Aplastic anemia, Familial hemophagocytic lymphohistiocytosis 2, PRF1-Related Familial Hemophagocytic Lymphohistiocytosis (PRF1-fHLH).

## Similar variants {#similar}

Related PRF1 variant pages (same residue, condition, or type): [PRF1 p.Pro22Leu](/variant/prf1-p-pro22leu), [PRF1 p.Pro22=](/variant/prf1-p-pro22), [PRF1 p.Pro22Ser](/variant/prf1-p-pro22ser), [PRF1 p.Asp484fs](/variant/prf1-p-asp484fs), [PRF1 p.Asp62fs](/variant/prf1-p-asp62fs), [PRF1 p.Cys73fs](/variant/prf1-p-cys73fs), [PRF1 p.Glu323fs](/variant/prf1-p-glu323fs), [PRF1 p.His308fs](/variant/prf1-p-his308fs).

### 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 2442794). 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.*