Is PRF1 p.Gln366Arg (c.1097A>G) pathogenic?

PRF1 p.Gln366Arg (c.1097A>G) is classified Uncertain significance in PRF1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-09-02). AlphaMissense: likely benign (0.065); Very rare (popmax 0.005%, amr); Associated with Inborn genetic diseases.

What condition is associated with PRF1 p.Gln366Arg (c.1097A>G)?

PRF1 p.Gln366Arg (c.1097A>G) is associated with Inborn genetic diseases, familial hemophagocytic lymphohistiocytosis 2, lymphoma, non-Hodgkin, familial (ClinVar).

How common is PRF1 p.Gln366Arg (c.1097A>G) in the general population?

PRF1 p.Gln366Arg (c.1097A>G) is very rare (popmax 0.005%, amr) (gnomAD).

What do computational predictors say about PRF1 p.Gln366Arg (c.1097A>G)?

AlphaMissense predicts likely benign (score 0.065) — an in-silico prediction, not a clinical call.

PRF1 p.Gln366Arg

c.1097A>G · rs957245579 · VCV802581

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.065 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.065	likely benign
REVEL	0.177	moderately benign-leaning
SaProt	LLR -7.41	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.6	GERP -2.8, phastCons 0.48
Regional constraint	o/e 0.97	unconstrained · MANE · 2,846 bp · p 0.42 · regional, not allelic
Overall
CADD	13.6	PHRED · no single calibrated threshold — expert panels disagree

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

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.005% Admixed American · 3/59,992 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000668%

Overall 0.000558% 9/1,612,986 alleles · very rare exomes 8/1,460,798 · genomes 1/152,188 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.005%	19,997
Remaining individualsnot grpmax-eligible	0.0016%	62,442
European (non-Finnish)	0.000424%	235,982

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.Gln366Arg
Coding: c.1097A>G
MANE Select: NM_001083116
dbSNP: rs957245579
Type: single nucleotide variant
Location: chr10:70598624 (GRCh38)
Gene constraint: LOEUF 1.438 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 91.01
Residue 366: the macpf domain

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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

Similar variants

PRF1 p.Gln366Ter Pathogenic/Likely pathogenic ★★ same residue
PRF1 p.Gln366= Likely benign ★ 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-gln366arg (accessed [today's date]).

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