# NM_001083116.3(PRF1):c.46C>T (p.Pro16Ser)

https://sugi.bio/variant/prf1-p-pro16ser

## Summary

**PRF1 p.Pro16Ser (c.46C>T)** is classified **Uncertain significance** in PRF1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-06-04). AlphaMissense: likely benign (0.1115); Very rare (popmax 0.00448%, eas); Associated with familial hemophagocytic lymphohistiocytosis 2.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs1031606439 · 4 submitters · 1 linked condition · AlphaMissense likely benign · very rare (popmax 0.00448%, eas)

## For patients & families {#patients}

This is a change in the PRF1 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 4 submitters, 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.Pro16Ser |
| Coding change (HGVS c.) | c.46C>T |
| MANE Select transcript | [NM_001083116](https://www.ncbi.nlm.nih.gov/nuccore/NM_001083116) |
| dbSNP | [rs1031606439](https://www.ncbi.nlm.nih.gov/snp/rs1031606439/) |
| Variant type | single nucleotide variant |
| Location | chr10:70600857-70600857 (GRCh38) |
| ClinVar | [VCV1037362](https://www.ncbi.nlm.nih.gov/clinvar/variation/1037362/) |

**All HGVS expressions:** `LRG_94:g.6919C>T`, `NC_000010.10:g.72360613G>A`, `NC_000010.11:g.70600857G>A`, `NG_009615.1:g.6919C>T`, `NM_001083116.1:c.46C>T`, `NM_001083116.3:c.46C>T`, `NM_005041.6:c.46C>T`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.1115)
- REVEL 0.443 (indeterminate)
- SaProt LLR -8.656 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this tolerated; REVEL makes no call
- Conservation: phyloP 8.442, GERP 1.96, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 20.6**. 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 0.97** across the covering region of the MANE Select transcript (70,598,056–70,600,902), spanning 2,846 bp. Chi-square p 0.42. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (G>T, Δ0.40 acceptor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.00448%** (eas) · FAF95 0.000742% · FAF99 0.000278% · 2/44,674 in the highest group · 2/1,455,890 alleles overall — very rare (popmax 0.00448%, 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}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-06-04.

**Submitter consensus:** unanimous (4/4 Uncertain significance).

**Submission history:** 4 submissions (2020–2024); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | Uncertain significance | criteria provided, single submitter | clinical testing | 2020-01-22 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-06-04 |
| PreventionGenetics, part of Exact Sciences | Uncertain significance | no assertion criteria provided | clinical testing | 2024-01-03 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-11-27 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Familial hemophagocytic lymphohistiocytosis 2, See cases, PRF1-related disorder, not specified, AllHighlyPenetrant, PRF1-related condition, PRF1-Related Familial Hemophagocytic Lymphohistiocytosis (PRF1-fHLH).

## Similar variants {#similar}

Related PRF1 variant pages (same residue, condition, or type): [PRF1 p.Pro16Leu](/variant/prf1-p-pro16leu), [PRF1 p.Pro16Thr](/variant/prf1-p-pro16thr), [PRF1 p.Pro16=](/variant/prf1-p-pro16), [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).

### 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 1037362). 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.*