Is PRF1 p.Ala415Pro (c.1243G>C) pathogenic?

PRF1 p.Ala415Pro (c.1243G>C) is classified Likely pathogenic in PRF1 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-07-15). AlphaMissense: likely pathogenic (0.8302); Absent from gnomAD v4.1; Associated with Haemophagocytic syndrome with absent perforin expression.

What condition is associated with PRF1 p.Ala415Pro (c.1243G>C)?

PRF1 p.Ala415Pro (c.1243G>C) is associated with Haemophagocytic syndrome with absent perforin expression (ClinVar).

How common is PRF1 p.Ala415Pro (c.1243G>C) in the general population?

PRF1 p.Ala415Pro (c.1243G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PRF1 p.Ala415Pro (c.1243G>C)?

AlphaMissense predicts likely pathogenic (score 0.8302) — an in-silico prediction, not a clinical call.

PRF1 p.Ala415Pro

c.1243G>C · VCV4890850

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8302 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Haemophagocytic syndrome with absent perforin expression

Computational evidence

Protein change
AlphaMissense	0.8302	likely pathogenic ✓ concordant with ClinVar · top 7% in PRF1
REVEL	0.902	moderately pathogenic-leaning
SaProt	LLR -16.26	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 7.6	GERP 1.2, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 2,846 bp · p 0.42 · regional, not allelic
Overall
CADD	28.0	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: PRF1
Protein: p.Ala415Pro
Coding: c.1243G>C
MANE Select: NM_001083116
Type: single nucleotide variant
Location: chr10:70598478 (GRCh38)
Gene constraint: LOEUF 1.438 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 91.01
Residue 415: the c2 domain

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

Disease context

Haemophagocytic syndrome with absent perforin expression

Similar variants

PRF1 p.Ala415Gly Uncertain significance ★ ⚠ same residue
PRF1 p.His222Gln Pathogenic/Likely pathogenic ★★ same condition
PRF1 p.Met1Ile Pathogenic/Likely pathogenic ★★ same condition
PRF1 p.Trp374Ter Pathogenic ★★ same condition
PRF1 p.Ala235Val Uncertain significance ★★ ⚠ same condition
PRF1 p.Arg54His Uncertain significance ★★ ⚠ same condition
PRF1 p.Gly71Ser Uncertain significance ★★ ⚠ same condition
PRF1 p.Cys408Ter 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-ala415pro (accessed [today's date]).

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