Is PRF1 p.Arg96= (c.286C>A) pathogenic?

PRF1 p.Arg96= (c.286C>A) is classified Conflicting classifications of pathogenicity in PRF1 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-01-25). Rare (popmax 0.196%, afr); Associated with autoinflammatory syndrome.

What condition is associated with PRF1 p.Arg96= (c.286C>A)?

PRF1 p.Arg96= (c.286C>A) is associated with autoinflammatory syndrome, familial hemophagocytic lymphohistiocytosis 2 (ClinVar).

How common is PRF1 p.Arg96= (c.286C>A) in the general population?

PRF1 p.Arg96= (c.286C>A) is rare (popmax 0.196%, afr) (gnomAD).

PRF1 p.Arg96=

c.286C>A · rs144024245 · VCV300334

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

rare (popmax 0.196%, afr)

Conditions

autoinflammatory syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.5	GERP -0.21, phastCons 1
Overall
CADD	5.707	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.196% African / African-American · 147/75,040 alleles

Filtering AF 0.17% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.16%

Overall 0.00973% 157/1,613,080 alleles · rare exomes 59/1,460,736 · genomes 98/152,344 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.196%	510
Remaining individualsnot grpmax-eligible	0.00801%	12,487
Admixed American	0.005%	19,997
European (non-Finnish)	0.00017%	589,713

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.Arg96=
Coding: c.286C>A
MANE Select: NM_001083116
dbSNP: rs144024245
Type: single nucleotide variant
Location: chr10:70600617 (GRCh38)
Gene constraint: LOEUF 1.438 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 91.01
Residue 96: the macpf domain

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

Disease context

autoinflammatory syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: familial hemophagocytic lymphohistiocytosis 2

Similar variants

PRF1 p.Arg96Trp Uncertain significance ★★ ⚠ same residue
PRF1 p.Arg96Gln Uncertain significance ★ ⚠ same residue
PRF1 c.539+2T>A Pathogenic/Likely pathogenic ★★ same condition
PRF1 p.Arg225Trp Pathogenic ★★ ⚠ same condition
PRF1 p.Arg232Cys Pathogenic/Likely pathogenic ★★ ⚠ same condition
PRF1 p.Arg299Cys Pathogenic/Likely pathogenic ★★ same condition
PRF1 p.Arg356Trp Pathogenic/Likely pathogenic ★★ ⚠ same condition
PRF1 p.Arg361Trp 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-arg96 (accessed [today's date]).

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