Is PRPF8 p.Ser2189Pro (c.6565T>C) pathogenic?

PRPF8 p.Ser2189Pro (c.6565T>C) is classified Uncertain significance in PRPF8 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-13). AlphaMissense: likely benign (0.2586); Very rare (popmax 0.000169%, nfe); Associated with retinitis pigmentosa.

What condition is associated with PRPF8 p.Ser2189Pro (c.6565T>C)?

PRPF8 p.Ser2189Pro (c.6565T>C) is associated with retinitis pigmentosa (ClinVar).

How common is PRPF8 p.Ser2189Pro (c.6565T>C) in the general population?

PRPF8 p.Ser2189Pro (c.6565T>C) is very rare (popmax 0.000169%, nfe) (gnomAD).

How is Retinitis pigmentosa inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about PRPF8 p.Ser2189Pro (c.6565T>C)?

AlphaMissense predicts likely benign (score 0.2586) — an in-silico prediction, not a clinical call.

PRPF8 p.Ser2189Pro

c.6565T>C · rs929492529 · VCV889694

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2586 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

retinitis pigmentosa

Computational evidence

Protein change
AlphaMissense	0.2586	likely benign
REVEL	0.646	pathogenic-leaning
SaProt	LLR -11.24	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 11	GERP 2.3, phastCons 1
Regional constraint	o/e 0.43	unconstrained · MANE · 3,063 bp · p 2.1e-28 · regional, not allelic
Overall
CADD	22.7	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 0.000169% European (non-Finnish) · 2/1,180,022 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,614,156 alleles · very rare exomes 2/1,461,864 · genomes 0/152,292 · 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: PRPF8
Protein: p.Ser2189Pro
Coding: c.6565T>C
MANE Select: NM_006445
dbSNP: rs929492529
Type: single nucleotide variant
Location: chr17:1651499 (GRCh38)
Gene constraint: LOEUF 0.26 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 85.20 · 100 PDB
Residue 2189: the mpn domain

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

Disease context

retinitis pigmentosa — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Retinitis pigmentosa (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, Mitochondrial inheritance
Onset: Adolescent, Adult, Childhood
Prevalence: 1-5 / 10 000 (Europe)

Similar variants

PRPF8 p.Arg1935His Pathogenic/Likely pathogenic ★★ same condition
PRPF8 p.Arg2310Gly Pathogenic/Likely pathogenic ★★ same condition
PRPF8 c.1719+4A>G Uncertain significance ★★ same condition
PRPF8 p.Arg309His Uncertain significance ★★ ⚠ same condition
PRPF8 p.Asp1598Asn Uncertain significance ★★ ⚠ same condition
PRPF8 p.Thr1102Lys Uncertain significance ★★ same condition
PRPF8 p.Thr2195Ser Uncertain significance ★★ ⚠ same condition
PRPF8 c.101-3C>T Benign ★★ 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-ser2189pro (accessed [today's date]).

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