Is PRPF8 p.Ala754Pro (c.2260G>C) pathogenic?

PRPF8 p.Ala754Pro (c.2260G>C) is classified Uncertain significance in PRPF8 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-03). AlphaMissense: likely pathogenic (0.9993); Absent from gnomAD v4.1.

How common is PRPF8 p.Ala754Pro (c.2260G>C) in the general population?

PRPF8 p.Ala754Pro (c.2260G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PRPF8 p.Ala754Pro (c.2260G>C)?

AlphaMissense predicts likely pathogenic (score 0.9993) — an in-silico prediction, not a clinical call.

PRPF8 p.Ala754Pro

c.2260G>C · VCV4932538

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9993 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9993	likely pathogenic · top 3% in PRPF8
REVEL	0.898	moderately pathogenic-leaning
SaProt	LLR -15.28	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 5.9	GERP 2.6, phastCons 1
Regional constraint	o/e 0.26	constrained · MANE · 1,029 bp · p 7.7e-35 · regional, not allelic
Overall
CADD	27.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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.Ala754Pro
Coding: c.2260G>C
MANE Select: NM_006445
Type: single nucleotide variant
Location: chr17:1676633 (GRCh38)
Gene constraint: LOEUF 0.26 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 85.20 · 100 PDB
Residue 754: an α-helix

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

Similar variants

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
PRPF8 p.His2309Arg Pathogenic ★★ ⚠ same type
PRPF8 p.His2309Pro Pathogenic/Likely pathogenic ★★ same type
PRPF8 p.His2313Pro 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-ala754pro (accessed [today's date]).

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