Is PRF1 p.Pro501Ser (c.1501C>T) pathogenic?

PRF1 p.Pro501Ser (c.1501C>T) is classified Uncertain significance in PRF1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-12). AlphaMissense: likely benign (0.3302); Ultra-rare (popmax 0.0493%, mid); Associated with familial hemophagocytic lymphohistiocytosis 2.

What condition is associated with PRF1 p.Pro501Ser (c.1501C>T)?

PRF1 p.Pro501Ser (c.1501C>T) is associated with familial hemophagocytic lymphohistiocytosis 2 (ClinVar).

How common is PRF1 p.Pro501Ser (c.1501C>T) in the general population?

PRF1 p.Pro501Ser (c.1501C>T) is ultra-rare (popmax 0.0493%, mid) (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.Pro501Ser (c.1501C>T)?

AlphaMissense predicts likely benign (score 0.3302) — an in-silico prediction, not a clinical call.

PRF1 p.Pro501Ser

c.1501C>T · rs200589152 · VCV948356

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3302 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0493%, mid)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

familial hemophagocytic lymphohistiocytosis 2

Computational evidence

Protein change
AlphaMissense	0.3302	likely benign
REVEL	0.39	indeterminate
SaProt	LLR -10.55	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.2	GERP -1.4, phastCons 0.34
Regional constraint	o/e 0.97	unconstrained · MANE · 2,846 bp · p 0.42 · regional, not allelic
Overall
CADD	7.66	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 0.0493% Middle Eastern · 3/6,084 alleles

Filtering AF 0.0134% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00715%

Overall 0.00112% 18/1,614,082 alleles · ultra-rare exomes 16/1,461,894 · genomes 2/152,188 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0493%	2,028
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,606
Remaining individualsnot grpmax-eligible	0.0032%	31,245
European (non-Finnish)	0.00102%	98,337

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.Pro501Ser
Coding: c.1501C>T
MANE Select: NM_001083116
dbSNP: rs200589152
Type: single nucleotide variant
Location: chr10:70598220 (GRCh38)
Gene constraint: LOEUF 1.438 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 91.01
Residue 501: the c2 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 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-pro501ser (accessed [today's date]).

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