Is PRF1 p.Val131Phe (c.391G>T) pathogenic?

PRF1 p.Val131Phe (c.391G>T) is classified Uncertain significance in PRF1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-07-08). AlphaMissense: likely benign (0.1351); Very rare (popmax 0.00223%, eas); Associated with autoinflammatory syndrome.

What condition is associated with PRF1 p.Val131Phe (c.391G>T)?

PRF1 p.Val131Phe (c.391G>T) is associated with autoinflammatory syndrome, familial hemophagocytic lymphohistiocytosis 2 (ClinVar).

How common is PRF1 p.Val131Phe (c.391G>T) in the general population?

PRF1 p.Val131Phe (c.391G>T) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about PRF1 p.Val131Phe (c.391G>T)?

AlphaMissense predicts likely benign (score 0.1351) — an in-silico prediction, not a clinical call.

PRF1 p.Val131Phe

c.391G>T · rs761941942 · VCV1694129

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1351 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

autoinflammatory syndrome

Computational evidence

Protein change
AlphaMissense	0.1351	likely benign
REVEL	0.392	indeterminate
SaProt	LLR -9.05	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.9	GERP 1
Regional constraint	o/e 0.97	unconstrained · MANE · 2,846 bp · p 0.42 · regional, not allelic
Overall
CADD	15.16	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,888 alleles

Overall 6.2e-05% 1/1,614,072 alleles · very rare exomes 0/1,461,866 · genomes 1/152,206 · 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.Val131Phe
Coding: c.391G>T
MANE Select: NM_001083116
dbSNP: rs761941942
Type: single nucleotide variant
Location: chr10:70600512 (GRCh38)
Gene constraint: LOEUF 1.438 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 91.01
Residue 131: the macpf 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

Also linked: familial hemophagocytic lymphohistiocytosis 2

Similar variants

PRF1 p.Val131= 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-val131phe (accessed [today's date]).

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