Is PRF1 p.Phe421Cys (c.1262T>G) pathogenic?

PRF1 p.Phe421Cys (c.1262T>G) is classified Conflicting classifications of pathogenicity in PRF1 (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2026-02-02). AlphaMissense: likely benign (0.267); Rare (popmax 0.116%, mid); Associated with aplastic anemia.

What condition is associated with PRF1 p.Phe421Cys (c.1262T>G)?

PRF1 p.Phe421Cys (c.1262T>G) is associated with aplastic anemia, familial hemophagocytic lymphohistiocytosis 2, lymphoma, non-Hodgkin, familial (ClinVar).

How common is PRF1 p.Phe421Cys (c.1262T>G) in the general population?

PRF1 p.Phe421Cys (c.1262T>G) is rare (popmax 0.116%, mid) (gnomAD).

What do computational predictors say about PRF1 p.Phe421Cys (c.1262T>G)?

AlphaMissense predicts likely benign (score 0.267) — an in-silico prediction, not a clinical call.

PRF1 p.Phe421Cys

c.1262T>G · rs200534908 · VCV639509

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.267 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.116%, mid)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

aplastic anemia

Computational evidence

Protein change
AlphaMissense	0.267	likely benign
REVEL	0.353	indeterminate
SaProt	LLR -11.36	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.05	GERP -4.3
Regional constraint	o/e 0.97	unconstrained · MANE · 2,846 bp · p 0.42 · regional, not allelic
Overall
CADD	5.107	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 0.116% Middle Eastern · 7/6,060 alleles

Filtering AF 0.0648% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0583%

Overall 0.0108% 174/1,613,704 alleles · rare exomes 153/1,461,464 · genomes 21/152,240 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.116%	866
Admixed American	0.0833%	1,201
Ashkenazi Jewishnot grpmax-eligible	0.0338%	2,961
African / African-American	0.0293%	3,410
Remaining individualsnot grpmax-eligible	0.0288%	3,473
European (non-Finnish)	0.00551%	18,154
East Asian	0.00223%	44,854
South Asian	0.0011%	91,084

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.Phe421Cys
Coding: c.1262T>G
MANE Select: NM_001083116
dbSNP: rs200534908
Type: single nucleotide variant
Location: chr10:70598459 (GRCh38)
Gene constraint: LOEUF 1.438 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 91.01
Residue 421: the c2 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

Similar variants

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
PRF1 p.Arg410Pro 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-phe421cys (accessed [today's date]).

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