Is PRF1 p.Arg232Cys (c.694C>T) pathogenic?

PRF1 p.Arg232Cys (c.694C>T) is classified Pathogenic/Likely pathogenic in PRF1 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-09-08). AlphaMissense: likely benign (0.2667); Very rare (popmax 0.00659%, sas); Associated with aplastic anemia.

What condition is associated with PRF1 p.Arg232Cys (c.694C>T)?

PRF1 p.Arg232Cys (c.694C>T) is associated with aplastic anemia, familial hemophagocytic lymphohistiocytosis 2, lymphoma, non-Hodgkin, familial (ClinVar).

How common is PRF1 p.Arg232Cys (c.694C>T) in the general population?

PRF1 p.Arg232Cys (c.694C>T) is very rare (popmax 0.00659%, sas) (gnomAD).

What do computational predictors say about PRF1 p.Arg232Cys (c.694C>T)?

AlphaMissense predicts likely benign (score 0.2667) — an in-silico prediction, not a clinical call.

PRF1 p.Arg232Cys

c.694C>T · rs550073023 · VCV2678052

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.2667 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00659%, sas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

aplastic anemia

Computational evidence

Protein change
AlphaMissense	0.2667	likely benign ⚠ discordant with ClinVar
REVEL	0.661	pathogenic-leaning
SaProt	LLR -13.68	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.1	GERP 1.1, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 2,846 bp · p 0.42 · regional, not allelic
Overall
CADD	27.2	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 0.00659% South Asian · 6/91,068 alleles

Filtering AF 0.00286% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00195%

Overall 0.00112% 18/1,613,592 alleles · very rare exomes 17/1,461,262 · genomes 1/152,330 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00659%	15,178
Remaining individualsnot grpmax-eligible	0.0032%	31,248
European (non-Finnish)	0.000848%	117,959

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.Arg232Cys
Coding: c.694C>T
MANE Select: NM_001083116
dbSNP: rs550073023
Type: single nucleotide variant
Location: chr10:70599027 (GRCh38)
Gene constraint: LOEUF 1.438 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 91.01
Residue 232: 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 hereditary hemophagocytic lymphohistiocytosis

Similar variants

PRF1 p.Arg232His Conflicting classifications of pathogenicity ★ ⚠ same residue
PRF1 p.Arg232= Likely benign ★ same residue
PRF1 c.539+2T>A Pathogenic/Likely pathogenic ★★ same condition
PRF1 p.Arg225Trp 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-arg232cys (accessed [today's date]).

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