# NM_001083116.3(PRF1):c.393C>A (p.Val131=)

https://sugi.bio/variant/prf1-p-val131

## Summary

**PRF1 p.Val131= (c.393C>A)** is classified **Likely benign** in PRF1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-28). Very rare (popmax 0.00167%, amr); Associated with familial hemophagocytic lymphohistiocytosis 2.

**At a glance:** Likely benign · review: Single submitter · rsID rs374948681 · 1 submitter · 1 linked condition · very rare (popmax 0.00167%, amr)

## For patients & families {#patients}

This is a change in the PRF1 gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to familial hemophagocytic lymphohistiocytosis 2.

*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 recessive |
| Age of onset (of this condition) | Adolescent, Infancy |
| Prevalence | 1-9 / 100 000 (Sweden) |
| Diagnostic panels | PRF1 is a diagnostic-grade gene on 6 Genomics England panels |

**Commonly reported features of Familial hemophagocytic lymphohistiocytosis** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Thrombocytopenia — Very frequent (99-80%)
- Anemia — Very frequent (99-80%)
- Fever — Very frequent (99-80%)
- Elevated circulating hepatic transaminase concentration — Very frequent (99-80%)
- Immune dysregulation — Very frequent (99-80%)
- Hypoalbuminemia — Very frequent (99-80%)
- Increased circulating ferritin concentration — Very frequent (99-80%)
- Abnormality of serum cytokine level — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0009922/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.Val131= |
| Coding change (HGVS c.) | c.393C>A |
| MANE Select transcript | [NM_001083116](https://www.ncbi.nlm.nih.gov/nuccore/NM_001083116) |
| dbSNP | [rs374948681](https://www.ncbi.nlm.nih.gov/snp/rs374948681/) |
| Variant type | single nucleotide variant |
| Location | chr10:70600510-70600510 (GRCh38) |
| ClinVar | [VCV1536584](https://www.ncbi.nlm.nih.gov/clinvar/variation/1536584/) |

**All HGVS expressions:** `LRG_94:g.7266C>A`, `NC_000010.10:g.72360266G>T`, `NC_000010.11:g.70600510G>T`, `NG_009615.1:g.7266C>A`, `NM_001083116.3:c.393C>A`, `NM_005041.6:c.393C>A`

## 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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **donor gain** (Δ 0.20) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP -3.852, GERP -4.05 — fast-evolving / accelerated position
- CADD: **PHRED 0.512**. 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.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.20**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.20**.
- Population frequency (gnomAD v4.1): grpmax **0.00167%** (amr) · FAF95 0.000359% · FAF99 0.00026% · 1/59,996 in the highest group · 13/1,614,022 alleles overall — very rare (popmax 0.00167%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Finnish (not grpmax-eligible) | 0.00312% | 32,002 |
| Admixed American (grpmax) | 0.00167% | 59,996 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,484 |
| European (non-Finnish) | 0.000763% | 131,116 |

Finnish shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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 gene assoc. with recessive phenotype, triplosensitivity Not yet evaluated/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):

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

## Protein context {#protein}

Residue **131** lies in the macpf domain.

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. p.Val131= falls in the macpf domain. 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}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-05-28.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-05-28 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** 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.Val131Phe](/variant/prf1-p-val131phe), [PRF1 c.539+2T>A](/variant/prf1-c-539-plus-2t-a), [PRF1 p.Arg225Trp](/variant/prf1-p-arg225trp), [PRF1 p.Arg232Cys](/variant/prf1-p-arg232cys), [PRF1 p.Arg299Cys](/variant/prf1-p-arg299cys), [PRF1 p.Arg356Trp](/variant/prf1-p-arg356trp), [PRF1 p.Arg361Trp](/variant/prf1-p-arg361trp), [PRF1 p.Arg390Ter](/variant/prf1-p-arg390ter).

### 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 1536584). 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.*