Is PRPF8 p.Pro133Ser (c.397C>T) pathogenic?

PRPF8 p.Pro133Ser (c.397C>T) is classified Uncertain significance in PRPF8 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-02-24). AlphaMissense: likely pathogenic (0.9067); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with PRPF8 p.Pro133Ser (c.397C>T)?

PRPF8 p.Pro133Ser (c.397C>T) is associated with Inborn genetic diseases (ClinVar).

How common is PRPF8 p.Pro133Ser (c.397C>T) in the general population?

PRPF8 p.Pro133Ser (c.397C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PRPF8 p.Pro133Ser (c.397C>T)?

AlphaMissense predicts likely pathogenic (score 0.9067) — an in-silico prediction, not a clinical call.

PRPF8 p.Pro133Ser

c.397C>T · VCV4840339

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9067 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9067	likely pathogenic
REVEL	0.598	indeterminate
SaProt	LLR -7.25	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 2.6, phastCons 1
Regional constraint	o/e 0.51	unconstrained · MANE · 1,760 bp · p 1.7e-11 · regional, not allelic
Overall
CADD	27.9	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.Pro133Ser
Coding: c.397C>T
MANE Select: NM_006445
Type: single nucleotide variant
Location: chr17:1682166 (GRCh38)
Gene constraint: LOEUF 0.26 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 85.20 · 100 PDB

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PRPF8 p.Ala201Thr Uncertain significance ★★ ⚠ same condition
PRPF8 p.Ala2275Thr Uncertain significance ★★ ⚠ same condition
PRPF8 p.Ala2299Val Uncertain significance ★★ ⚠ same condition
PRPF8 p.Arg1354His Uncertain significance ★★ ⚠ same condition
PRPF8 p.Arg153Gln Uncertain significance ★★ ⚠ same condition
PRPF8 p.Arg1667His Uncertain significance ★★ ⚠ same condition
PRPF8 p.Arg2287Trp Uncertain significance ★★ ⚠ same condition
PRPF8 p.Arg284Gln Uncertain significance ★★ 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/prpf8-p-pro133ser (accessed [today's date]).

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