Is PRF1 p.Arg4His (c.11G>A) pathogenic?

PRF1 p.Arg4His (c.11G>A) is classified Benign/Likely benign in PRF1 (ClinVar, Multiple submitters, 12 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.1018); Common (popmax 8.26%, afr) — too common for a highly-penetrant pathogenic allele; Associated with familial hemophagocytic lymphohistiocytosis 2.

What condition is associated with PRF1 p.Arg4His (c.11G>A)?

PRF1 p.Arg4His (c.11G>A) is associated with familial hemophagocytic lymphohistiocytosis 2, aplastic anemia, autoinflammatory syndrome (ClinVar).

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.Arg4His (c.11G>A)?

AlphaMissense predicts likely benign (score 0.1018) — an in-silico prediction, not a clinical call.

PRF1 p.Arg4His

Q: How common is PRF1 p.Arg4His (c.11G>A) in the general population?

PRF1 p.Arg4His (c.11G>A) is common (popmax 8.26%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.11G>A · rs35418374 · VCV13720

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 12 submitters

AlphaMissense

likely benign

0.1018 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 8.26%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

familial hemophagocytic lymphohistiocytosis 2

Computational evidence

Protein change
AlphaMissense	0.1018	likely benign
REVEL	0.216	benign-leaning
SaProt	LLR -7.77	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -11	GERP -4
Regional constraint	o/e 0.97	unconstrained · MANE · 2,846 bp · p 0.42 · regional, not allelic
Overall
CADD	12.56	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 8.26% African / African-American · 6,181/74,844 alleles

Filtering AF 8.09% ClinGen BA1/BS1 input FAF95, joint · FAF99 8.02%

Overall 0.444% 7,067/1,590,208 alleles · common exomes 3,439/1,437,964 · genomes 3,628/152,244 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	8.26%	12
Admixed American	0.603%	166
Remaining individualsnot grpmax-eligible	0.59%	170
Middle Eastern	0.401%	249
South Asian	0.025%	4,002
European (non-Finnish)	0.0125%	8,011

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.Arg4His
Coding: c.11G>A
MANE Select: NM_001083116
dbSNP: rs35418374
Type: single nucleotide variant
Location: chr10:70600892 (GRCh38)
Gene constraint: LOEUF 1.438 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 91.01
Residue 4: a UniProt-annotated variant site (in)

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

Also linked: aplastic anemia autoinflammatory syndrome

For Familial hemophagocytic lymphohistiocytosis (Orphanet):

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

Similar variants

PRF1 p.Arg4Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
PRF1 p.Arg4= Likely benign ★ 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-arg4his (accessed [today's date]).

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