Is PRF1 p.Ala154= (c.462A>G) pathogenic?

PRF1 p.Ala154= (c.462A>G) is classified Benign/Likely benign in PRF1 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-02-04). Low-frequency (popmax 3.23%, afr); Associated with autoinflammatory syndrome.

What condition is associated with PRF1 p.Ala154= (c.462A>G)?

PRF1 p.Ala154= (c.462A>G) is associated with autoinflammatory syndrome, familial hemophagocytic lymphohistiocytosis 2 (ClinVar).

How common is PRF1 p.Ala154= (c.462A>G) in the general population?

PRF1 p.Ala154= (c.462A>G) is low-frequency (popmax 3.23%, afr) (gnomAD).

PRF1 p.Ala154=

c.462A>G · rs116554195 · VCV257402

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

gnomAD v4.1

Rare

low-frequency (popmax 3.23%, afr)

Conditions

autoinflammatory syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -8.5	GERP -4
Overall
CADD	1.807	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 3.23% African / African-American · 2,422/75,066 alleles

Filtering AF 3.12% ClinGen BA1/BS1 input FAF95, joint · FAF99 3.08%

Overall 0.762% 12,297/1,614,242 alleles · low-frequency

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	12.3%	8
African / African-Americangrpmax	3.23%	31
Remaining individualsnot grpmax-eligible	0.79%	127
Admixed American	0.78%	128
European (non-Finnish)	0.696%	144
Middle Eastern	0.676%	148
South Asian	0.543%	184
Finnishnot grpmax-eligible	0.0734%	1,363
Ashkenazi Jewishnot grpmax-eligible	0.0101%	9,869

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ala154=
Coding: c.462A>G
MANE Select: NM_001083116
dbSNP: rs116554195
Type: single nucleotide variant
Location: chr10:70600441 (GRCh38)
Gene constraint: LOEUF 1.438 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 91.01
Residue 154: a disulfide bond; 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 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-ala154 (accessed [today's date]).

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