Is PRPF8 p.Arg474Ser (c.1420C>A) pathogenic?

PRPF8 p.Arg474Ser (c.1420C>A) is classified Uncertain significance in PRPF8 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-05). AlphaMissense: likely pathogenic (0.8301); Absent from gnomAD v4.1.

How common is PRPF8 p.Arg474Ser (c.1420C>A) in the general population?

PRPF8 p.Arg474Ser (c.1420C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PRPF8 p.Arg474Ser (c.1420C>A)?

AlphaMissense predicts likely pathogenic (score 0.8301) — an in-silico prediction, not a clinical call.

PRPF8 p.Arg474Ser

c.1420C>A · rs755296299 · VCV2115387

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8301 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8301	likely pathogenic
REVEL	0.749	pathogenic-leaning
SaProt	LLR -4.74	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.5	GERP 2.6, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 1,581 bp · p 0.057 · regional, not allelic
Overall
CADD	26.9	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: PRPF8
Protein: p.Arg474Ser
Coding: c.1420C>A
MANE Select: NM_006445
dbSNP: rs755296299
Type: single nucleotide variant
Location: chr17:1679196 (GRCh38)
Gene constraint: LOEUF 0.26 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 85.20 · 100 PDB
Residue 474: a turn

Full PRPF8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PRPF8 p.Arg474Cys Uncertain significance ★★ ⚠ same residue
PRPF8 p.Arg474= Likely benign ★★ same residue
PRPF8 p.Arg474Leu Uncertain significance ★ ⚠ same residue
PRPF8 p.Arg1935His Pathogenic/Likely pathogenic ★★ same type
PRPF8 p.Arg2310Gly Pathogenic/Likely pathogenic ★★ same type
PRPF8 p.Arg2310Lys Pathogenic ★★ ⚠ same type
PRPF8 p.Arg2310Ser Pathogenic ★★ ⚠ same type
PRPF8 p.Gln2321Ter Pathogenic/Likely pathogenic ★★ same type

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/prpf8-p-arg474ser (accessed [today's date]).

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