Is PRF1 p.Pro187Ser (c.559C>T) pathogenic?

PRF1 p.Pro187Ser (c.559C>T) is classified Uncertain significance in PRF1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-03-01). AlphaMissense: ambiguous (0.4369); Ultra-rare (popmax 0.0373%, sas); Associated with familial hemophagocytic lymphohistiocytosis 2.

What condition is associated with PRF1 p.Pro187Ser (c.559C>T)?

PRF1 p.Pro187Ser (c.559C>T) is associated with familial hemophagocytic lymphohistiocytosis 2 (ClinVar).

How common is PRF1 p.Pro187Ser (c.559C>T) in the general population?

PRF1 p.Pro187Ser (c.559C>T) is ultra-rare (popmax 0.0373%, sas) (gnomAD).

How is Familial hemophagocytic lymphohistiocytosis inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about PRF1 p.Pro187Ser (c.559C>T)?

AlphaMissense predicts ambiguous (score 0.4369) — an in-silico prediction, not a clinical call.

PRF1 p.Pro187Ser

c.559C>T · rs780042742 · VCV1343516

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

ambiguous

0.4369 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0373%, sas)

Conditions

familial hemophagocytic lymphohistiocytosis 2

Computational evidence

Protein change
AlphaMissense	0.4369	ambiguous
REVEL	0.608	indeterminate
SaProt	LLR -11.06	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.1, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 2,846 bp · p 0.42 · regional, not allelic
Overall
CADD	23.4	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 0.0373% South Asian · 34/91,092 alleles

Filtering AF 0.0274% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.024%

Overall 0.00235% 38/1,614,086 alleles · ultra-rare exomes 36/1,461,856 · genomes 2/152,230 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0373%	2,679
African / African-American	0.00267%	37,471
East Asian	0.00223%	44,892
Admixed American	0.00167%	60,012

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.Pro187Ser
Coding: c.559C>T
MANE Select: NM_001083116
dbSNP: rs780042742
Type: single nucleotide variant
Location: chr10:70599162 (GRCh38)
Gene constraint: LOEUF 1.438 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 91.01
Residue 187: the macpf domain

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

Disease context

familial hemophagocytic lymphohistiocytosis 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Familial hemophagocytic lymphohistiocytosis (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Infancy
Prevalence: 1-9 / 100 000 (Sweden)

Similar variants

PRF1 p.Pro187Leu Uncertain significance ★ 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-pro187ser (accessed [today's date]).

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