Is PRF1 p.Arg33Cys (c.97C>T) pathogenic?

PRF1 p.Arg33Cys (c.97C>T) is classified Uncertain significance in PRF1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-09-26). AlphaMissense: ambiguous (0.3532); Ultra-rare (popmax 0.0165%, mid); Associated with aplastic anemia.

What condition is associated with PRF1 p.Arg33Cys (c.97C>T)?

PRF1 p.Arg33Cys (c.97C>T) is associated with aplastic anemia, familial hemophagocytic lymphohistiocytosis 2 (ClinVar).

How common is PRF1 p.Arg33Cys (c.97C>T) in the general population?

PRF1 p.Arg33Cys (c.97C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about PRF1 p.Arg33Cys (c.97C>T)?

AlphaMissense predicts ambiguous (score 0.3532) — an in-silico prediction, not a clinical call.

PRF1 p.Arg33Cys

c.97C>T · rs777782785 · VCV997654

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.3532 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

aplastic anemia

Computational evidence

Protein change
AlphaMissense	0.3532	ambiguous
REVEL	0.271	benign-leaning
SaProt	LLR -12.44	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.17	GERP -2.9
Regional constraint	o/e 0.97	unconstrained · MANE · 2,846 bp · p 0.42 · regional, not allelic
Overall
CADD	16.22	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 0.0165% Middle Eastern · 1/6,048 alleles

Filtering AF 0.00429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00296%

Overall 0.00124% 20/1,611,900 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,048
Admixed American	0.01%	9,978
East Asian	0.00892%	11,212
African / African-American	0.00667%	14,988
South Asian	0.0022%	45,428
European (non-Finnish)	0.00017%	589,431

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.Arg33Cys
Coding: c.97C>T
MANE Select: NM_001083116
dbSNP: rs777782785
Type: single nucleotide variant
Location: chr10:70600806 (GRCh38)
Gene constraint: LOEUF 1.438 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 91.01
Residue 33: 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

Similar variants

PRF1 p.Arg33His 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
PRF1 p.Arg390Ter 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-arg33cys (accessed [today's date]).

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