Is PRF1 p.Glu545fs (c.1628dup) pathogenic?

PRF1 p.Glu545fs (c.1628dup) is classified Conflicting classifications of pathogenicity in PRF1 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2024-10-28). Very rare (popmax 0.000339%, nfe); Associated with hereditary hemophagocytic lymphohistiocytosis.

What condition is associated with PRF1 p.Glu545fs (c.1628dup)?

PRF1 p.Glu545fs (c.1628dup) is associated with hereditary hemophagocytic lymphohistiocytosis, familial hemophagocytic lymphohistiocytosis 2, lymphoma, non-Hodgkin, familial (ClinVar).

How common is PRF1 p.Glu545fs (c.1628dup) in the general population?

PRF1 p.Glu545fs (c.1628dup) is very rare (popmax 0.000339%, nfe) (gnomAD).

How is Familial hemophagocytic lymphohistiocytosis inherited?

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

PRF1 p.Glu545fs

c.1628dup · rs1564723449 · VCV1020734

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Conditions

hereditary hemophagocytic lymphohistiocytosis

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	escapes	premature termination codon in the last exon (3 of 3) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -3.4	GERP -3.7
Overall
CADD	23.9	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000339% European (non-Finnish) · 4/1,180,046 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.00192% 31/1,613,946 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0844%	1,184
Remaining individualsnot grpmax-eligible	0.0032%	31,245
European (non-Finnish)grpmax	0.000339%	295,011

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. 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.

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: PRF1
Protein: p.Glu545fs
Coding: c.1628dup
MANE Select: NM_001083116
dbSNP: rs1564723449
Type: Duplication
Location: chr10:70598092 (GRCh38)
Gene constraint: LOEUF 1.438 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 91.01

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

Disease context

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

Also linked: familial hemophagocytic lymphohistiocytosis 2 lymphoma, non-Hodgkin, familial aplastic anemia

For Familial hemophagocytic lymphohistiocytosis (Orphanet):

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

Similar variants

PRF1 p.Leu189fs Pathogenic/Likely pathogenic ★★ same condition
PRF1 p.Thr114delinsMetTer Likely pathogenic ★★ same condition
PRF1 p.Trp425fs Pathogenic ★★ same condition
PRF1 p.Val329fs Likely pathogenic ★★ same condition
PRF1 p.Arg195fs Likely pathogenic ★ same condition
PRF1 p.Arg371Ter Pathogenic ★ same condition
PRF1 p.Asn78fs Likely pathogenic ★ same condition
PRF1 p.Cys23fs 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-glu545fs (accessed [today's date]).

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