Is PRF1 p.Pro477fs (c.1428dup) pathogenic?

PRF1 p.Pro477fs (c.1428dup) is classified Pathogenic in PRF1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-23). Very rare (popmax 0.0011%, sas); Associated with familial hemophagocytic lymphohistiocytosis 2.

What condition is associated with PRF1 p.Pro477fs (c.1428dup)?

PRF1 p.Pro477fs (c.1428dup) is associated with familial hemophagocytic lymphohistiocytosis 2 (ClinVar).

How common is PRF1 p.Pro477fs (c.1428dup) in the general population?

PRF1 p.Pro477fs (c.1428dup) is very rare (popmax 0.0011%, sas) (gnomAD).

How is Familial hemophagocytic lymphohistiocytosis inherited?

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

PRF1 p.Pro477fs

c.1428dup · rs748926167 · VCV2088310

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

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	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 1.7	GERP -1.3, phastCons 0.98

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/91,084 alleles

Overall 0.000137% 2/1,461,886 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	91,084
European (non-Finnish)	8.47e-05%	1,180,025

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.Pro477fs
Coding: c.1428dup
MANE Select: NM_001083116
dbSNP: rs748926167
Type: Duplication
Location: chr10:70598292 (GRCh38)
Gene constraint: LOEUF 1.438 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 91.01
Residue 477: the c2 domain

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.Pro477_Leu478insTer Pathogenic/Likely pathogenic ★★ same residue
PRF1 p.Pro477Thr Uncertain significance ★★ ⚠ same residue
PRF1 p.Pro477Ala Uncertain significance ★ ⚠ same residue
PRF1 p.Pro477Leu Uncertain significance ★ ⚠ 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

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-pro477fs (accessed [today's date]).

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