Is PRF1 p.Gln481Pro (c.1442A>C) pathogenic?

PRF1 p.Gln481Pro (c.1442A>C) is classified Conflicting classifications of pathogenicity in PRF1 (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2025-11-05). AlphaMissense: likely pathogenic (0.8964); Very rare (popmax 0.00667%, amr); Associated with PRF1-related disorder.

What condition is associated with PRF1 p.Gln481Pro (c.1442A>C)?

PRF1 p.Gln481Pro (c.1442A>C) is associated with PRF1-related disorder, familial hemophagocytic lymphohistiocytosis 2, hereditary hemophagocytic lymphohistiocytosis (ClinVar).

How common is PRF1 p.Gln481Pro (c.1442A>C) in the general population?

PRF1 p.Gln481Pro (c.1442A>C) is very rare (popmax 0.00667%, amr) (gnomAD).

What do computational predictors say about PRF1 p.Gln481Pro (c.1442A>C)?

AlphaMissense predicts likely pathogenic (score 0.8964) — an in-silico prediction, not a clinical call.

PRF1 p.Gln481Pro

c.1442A>C · rs764596094 · VCV1331382

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 8 submitters

AlphaMissense

likely pathogenic

0.8964 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00667%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

PRF1-related disorder

Computational evidence

Protein change
AlphaMissense	0.8964	likely pathogenic · top 3% in PRF1
REVEL	0.727	pathogenic-leaning
SaProt	LLR -15.39	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.1	GERP 2.2, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 2,846 bp · p 0.42 · regional, not allelic
Overall
CADD	28.1	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 0.00667% Admixed American · 4/60,014 alleles

Filtering AF 0.00226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00135%

Overall 0.00031% 5/1,614,080 alleles · very rare exomes 3/1,461,894 · genomes 2/152,186 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00667%	15,004
European (non-Finnish)	8.47e-05%	1,180,027

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.Gln481Pro
Coding: c.1442A>C
MANE Select: NM_001083116
dbSNP: rs764596094
Type: single nucleotide variant
Location: chr10:70598279 (GRCh38)
Gene constraint: LOEUF 1.438 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 91.01
Residue 481: the c2 domain

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

Disease context

PRF1-related disorder

Also linked: familial hemophagocytic lymphohistiocytosis 2 hereditary hemophagocytic lymphohistiocytosis aplastic anemia

Similar variants

PRF1 p.Gln481= 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
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-gln481pro (accessed [today's date]).

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