Is PRF1 p.Cys23fs (c.65dup) pathogenic?

PRF1 p.Cys23fs (c.65dup) is classified Pathogenic in PRF1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-19). Ultra-rare (gnomAD MAF 1.429e-06); Associated with familial hemophagocytic lymphohistiocytosis 2.

What condition is associated with PRF1 p.Cys23fs (c.65dup)?

PRF1 p.Cys23fs (c.65dup) is associated with familial hemophagocytic lymphohistiocytosis 2 (ClinVar).

How common is PRF1 p.Cys23fs (c.65dup) in the general population?

PRF1 p.Cys23fs (c.65dup) is ultra-rare (gnomAD MAF 1.429e-06) (gnomAD).

How is Familial hemophagocytic lymphohistiocytosis inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

PRF1 p.Cys23fs

c.65dup · rs761651233 · VCV2832650

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

ultra-rare (gnomAD MAF 1.429e-06)

Conditions

familial hemophagocytic lymphohistiocytosis 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 2 of 3
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.84	GERP -3.8, phastCons 1
Region caveats
Repeat context	tandem	(GCAGGA)n simple repeat · ambiguous alignment · confidence, not pathogenicity

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

dbSNP / gnomAD

Global frequency 0.000143% via dbSNP · ultra-rare

No ancestry breakdown or filtering allele frequency is available for this variant, so BA1/BS1 cannot be assessed from this figure alone.

Variant & gene context

Gene: PRF1
Protein: p.Cys23fs
Coding: c.65dup
MANE Select: NM_001083116
dbSNP: rs761651233
Type: Duplication
Location: chr10:70600837 (GRCh38)
Gene constraint: LOEUF 1.438 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 91.01
Residue 23: a disulfide bond

Full PRF1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

familial hemophagocytic lymphohistiocytosis 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Familial hemophagocytic lymphohistiocytosis (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Infancy
Prevalence: 1-9 / 100 000 (Sweden)

Similar variants

PRF1 p.Cys23= Likely benign ★ same residue
PRF1 p.Leu189fs Pathogenic/Likely pathogenic ★★ same condition
PRF1 p.Thr114delinsMetTer Likely pathogenic ★★ same condition
PRF1 p.Trp425fs Pathogenic ★★ same condition
PRF1 p.Arg371Ter Pathogenic ★ same condition
PRF1 p.Pro477fs Pathogenic ★ same condition
PRF1 p.Glu545fs Conflicting classifications of pathogenicity ★ same condition
PRF1 c.539+2T>A Pathogenic/Likely pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/prf1-p-cys23fs (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown