Is PRF1 p.Arg28Cys (c.82C>T) pathogenic?

PRF1 p.Arg28Cys (c.82C>T) is classified Conflicting classifications of pathogenicity in PRF1 (ClinVar, Conflicting submitters, 9 submitters; last evaluated 2026-02-02). AlphaMissense: likely benign (0.3238); Rare (popmax 0.533%, sas); Associated with aplastic anemia.

What condition is associated with PRF1 p.Arg28Cys (c.82C>T)?

PRF1 p.Arg28Cys (c.82C>T) is associated with aplastic anemia, familial hemophagocytic lymphohistiocytosis 2, lymphoma, non-Hodgkin, familial (ClinVar).

How common is PRF1 p.Arg28Cys (c.82C>T) in the general population?

PRF1 p.Arg28Cys (c.82C>T) is rare (popmax 0.533%, sas) (gnomAD).

What do computational predictors say about PRF1 p.Arg28Cys (c.82C>T)?

AlphaMissense predicts likely benign (score 0.3238) — an in-silico prediction, not a clinical call.

PRF1 p.Arg28Cys

c.82C>T · rs141660796 · VCV598223

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 9 submitters

AlphaMissense

likely benign

0.3238 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.533%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

aplastic anemia

Computational evidence

Protein change
AlphaMissense	0.3238	likely benign
REVEL	0.351	indeterminate
SaProt	LLR -11.57	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2	GERP -4, phastCons 0.016
Regional constraint	o/e 0.97	unconstrained · MANE · 2,846 bp · p 0.42 · regional, not allelic
Overall
CADD	23.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.533% South Asian · 484/90,824 alleles

Filtering AF 0.494% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.478%

Overall 0.083% 1,339/1,612,538 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.533%	188
Finnishnot grpmax-eligible	0.159%	630
European (non-Finnish)	0.0599%	1,668
Remaining individualsnot grpmax-eligible	0.0529%	1,891
Middle Eastern	0.0332%	3,008
African / African-American	0.00933%	10,723
Admixed American	0.00835%	11,973

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.Arg28Cys
Coding: c.82C>T
MANE Select: NM_001083116
dbSNP: rs141660796
Type: single nucleotide variant
Location: chr10:70600821 (GRCh38)
Gene constraint: LOEUF 1.438 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 91.01
Residue 28: a disulfide bond; the macpf domain

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

Disease context

aplastic anemia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: familial hemophagocytic lymphohistiocytosis 2 lymphoma, non-Hodgkin, familial autoinflammatory syndrome

Similar variants

PRF1 p.Arg28His Uncertain significance ★★ ⚠ same residue
PRF1 p.Arg28Gly 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-arg28cys (accessed [today's date]).

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