Is PRF1 p.Pro409Leu (c.1226C>T) pathogenic?

PRF1 p.Pro409Leu (c.1226C>T) is classified Uncertain significance in PRF1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-02-22). AlphaMissense: ambiguous (0.3848); Very rare (popmax 0.00133%, afr); Associated with autoinflammatory syndrome.

What condition is associated with PRF1 p.Pro409Leu (c.1226C>T)?

PRF1 p.Pro409Leu (c.1226C>T) is associated with autoinflammatory syndrome (ClinVar).

How common is PRF1 p.Pro409Leu (c.1226C>T) in the general population?

PRF1 p.Pro409Leu (c.1226C>T) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about PRF1 p.Pro409Leu (c.1226C>T)?

AlphaMissense predicts ambiguous (score 0.3848) — an in-silico prediction, not a clinical call.

PRF1 p.Pro409Leu

c.1226C>T · rs1278094424 · VCV1694124

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3848 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

autoinflammatory syndrome

Computational evidence

Protein change
AlphaMissense	0.3848	ambiguous
REVEL	0.863	moderately pathogenic-leaning
SaProt	LLR -11.31	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.2, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 2,846 bp · p 0.42 · regional, not allelic
Overall
CADD	28.7	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 0.00133% African / African-American · 1/74,930 alleles

Overall 6.2e-05% 1/1,613,406 alleles · very rare exomes 0/1,461,262 · genomes 1/152,144 · joint denominator

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.Pro409Leu
Coding: c.1226C>T
MANE Select: NM_001083116
dbSNP: rs1278094424
Type: single nucleotide variant
Location: chr10:70598495 (GRCh38)
Gene constraint: LOEUF 1.438 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 91.01
Residue 409: the c2 domain

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

Disease context

autoinflammatory syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PRF1 p.Arg225Trp Pathogenic ★★ ⚠ same condition
PRF1 p.Gly306Ser Pathogenic/Likely pathogenic ★★ ⚠ same condition
PRF1 p.Ser301Ter Pathogenic/Likely pathogenic ★★ same condition
PRF1 p.Trp374Ter Pathogenic ★★ same condition
PRF1 p.Ala401Val Uncertain significance ★★ ⚠ same condition
PRF1 p.Gly270Ser Uncertain significance ★★ ⚠ same condition
PRF1 p.Ile125Thr Uncertain significance ★★ ⚠ same condition
PRF1 p.Lys161Glu Uncertain significance ★★ 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-pro409leu (accessed [today's date]).

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