Is PRF1 p.Pro201Thr (c.601C>A) pathogenic?

PRF1 p.Pro201Thr (c.601C>A) is classified Likely pathogenic in PRF1 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-02-09). AlphaMissense: ambiguous (0.4877); Very rare (popmax 0.000339%, nfe); Associated with hereditary hemophagocytic lymphohistiocytosis.

What condition is associated with PRF1 p.Pro201Thr (c.601C>A)?

PRF1 p.Pro201Thr (c.601C>A) is associated with hereditary hemophagocytic lymphohistiocytosis (ClinVar).

How common is PRF1 p.Pro201Thr (c.601C>A) in the general population?

PRF1 p.Pro201Thr (c.601C>A) is very rare (popmax 0.000339%, nfe) (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.Pro201Thr (c.601C>A)?

AlphaMissense predicts ambiguous (score 0.4877) — an in-silico prediction, not a clinical call.

PRF1 p.Pro201Thr

c.601C>A · VCV4847951

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4877 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

hereditary hemophagocytic lymphohistiocytosis

Computational evidence

Protein change
AlphaMissense	0.4877	ambiguous
REVEL	0.948	strongly pathogenic-leaning
SaProt	LLR -13.45	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.7	GERP 2.1, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 2,846 bp · p 0.42 · regional, not allelic
Overall
CADD	25.5	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 0.000339% European (non-Finnish) · 4/1,180,004 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000248% 4/1,614,144 alleles · very rare exomes 4/1,461,798 · genomes 0/152,346 · 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.Pro201Thr
Coding: c.601C>A
MANE Select: NM_001083116
Type: single nucleotide variant
Location: chr10:70599120 (GRCh38)
Gene constraint: LOEUF 1.438 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 91.01
Residue 201: the macpf domain

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

For Familial hemophagocytic lymphohistiocytosis (Orphanet):

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

Similar variants

PRF1 p.Pro201Leu Uncertain significance ★ ⚠ same residue
PRF1 p.Arg225Trp Pathogenic ★★ ⚠ same condition
PRF1 p.Arg232Cys Pathogenic/Likely pathogenic ★★ ⚠ same condition
PRF1 p.Arg299Cys Pathogenic/Likely pathogenic ★★ same condition
PRF1 p.Arg410Pro Pathogenic/Likely pathogenic ★★ same condition
PRF1 p.Arg410Trp Pathogenic/Likely pathogenic ★★ ⚠ same condition
PRF1 p.Arg54Cys Pathogenic/Likely pathogenic ★★ ⚠ same condition
PRF1 p.Asp340Asn 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-pro201thr (accessed [today's date]).

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