Is PRF1 p.Phe181Ser (c.542T>C) pathogenic?

PRF1 p.Phe181Ser (c.542T>C) is classified Uncertain significance in PRF1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-04-20). AlphaMissense: ambiguous (0.4395); Very rare (popmax 0.00988%, sas); Associated with Inborn genetic diseases.

What condition is associated with PRF1 p.Phe181Ser (c.542T>C)?

PRF1 p.Phe181Ser (c.542T>C) is associated with Inborn genetic diseases, familial hemophagocytic lymphohistiocytosis 2 (ClinVar).

How common is PRF1 p.Phe181Ser (c.542T>C) in the general population?

PRF1 p.Phe181Ser (c.542T>C) is very rare (popmax 0.00988%, sas) (gnomAD).

What do computational predictors say about PRF1 p.Phe181Ser (c.542T>C)?

AlphaMissense predicts ambiguous (score 0.4395) — an in-silico prediction, not a clinical call.

PRF1 p.Phe181Ser

c.542T>C · rs770131011 · VCV943778

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

ambiguous

0.4395 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00988%, sas)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4395	ambiguous
REVEL	0.388	indeterminate
SaProt	LLR -8.74	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.1	GERP -1, phastCons 0.041
Regional constraint	o/e 0.97	unconstrained · MANE · 2,846 bp · p 0.42 · regional, not allelic
Overall
CADD	13.47	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 0.00988% South Asian · 9/91,078 alleles

Filtering AF 0.00514% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00375%

Overall 0.000752% 11/1,461,832 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00988%	10,120
Remaining individualsnot grpmax-eligible	0.0032%	31,252

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.Phe181Ser
Coding: c.542T>C
MANE Select: NM_001083116
dbSNP: rs770131011
Type: single nucleotide variant
Location: chr10:70599179 (GRCh38)
Gene constraint: LOEUF 1.438 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 91.01
Residue 181: the macpf domain

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

Disease context

Inborn genetic diseases — 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-phe181ser (accessed [today's date]).

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