Is PRF1 p.Pro345Arg (c.1034C>G) pathogenic?

PRF1 p.Pro345Arg (c.1034C>G) is classified Conflicting classifications of pathogenicity in PRF1 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-07-11). AlphaMissense: likely pathogenic (0.8754); Very rare (popmax 0.00267%, afr); Associated with hereditary hemophagocytic lymphohistiocytosis.

What condition is associated with PRF1 p.Pro345Arg (c.1034C>G)?

PRF1 p.Pro345Arg (c.1034C>G) is associated with hereditary hemophagocytic lymphohistiocytosis, familial hemophagocytic lymphohistiocytosis 2 (ClinVar).

How common is PRF1 p.Pro345Arg (c.1034C>G) in the general population?

PRF1 p.Pro345Arg (c.1034C>G) is very rare (popmax 0.00267%, afr) (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.Pro345Arg (c.1034C>G)?

AlphaMissense predicts likely pathogenic (score 0.8754) — an in-silico prediction, not a clinical call.

PRF1 p.Pro345Arg

c.1034C>G · rs28933374 · VCV2136870

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.8754 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary hemophagocytic lymphohistiocytosis

Computational evidence

Protein change
AlphaMissense	0.8754	likely pathogenic · top 4% in PRF1
REVEL	0.872	moderately pathogenic-leaning
SaProt	LLR -17.25	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 2,846 bp · p 0.42 · regional, not allelic
Overall
CADD	25.4	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 0.00267% African / African-American · 2/74,940 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000124% 2/1,613,982 alleles · very rare exomes 1/1,461,746 · genomes 1/152,236 · 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.Pro345Arg
Coding: c.1034C>G
MANE Select: NM_001083116
dbSNP: rs28933374
Type: single nucleotide variant
Location: chr10:70598687 (GRCh38)
Gene constraint: LOEUF 1.438 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 91.01
Residue 345: the macpf domain; a UniProt-annotated variant site (in fhl2)

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

Disease context

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

Also linked: familial hemophagocytic lymphohistiocytosis 2

For Familial hemophagocytic lymphohistiocytosis (Orphanet):

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

Similar variants

PRF1 p.Pro345Leu Uncertain significance ★ ⚠ same residue
PRF1 p.Pro345Thr 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

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-pro345arg (accessed [today's date]).

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