Is PRPF8 p.Pro2149= (c.6447G>A) pathogenic?

PRPF8 p.Pro2149= (c.6447G>A) is classified Conflicting classifications of pathogenicity in PRPF8 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-09-08). Ultra-rare (popmax 0.0187%, afr); Associated with retinitis pigmentosa.

What condition is associated with PRPF8 p.Pro2149= (c.6447G>A)?

PRPF8 p.Pro2149= (c.6447G>A) is associated with retinitis pigmentosa (ClinVar).

How common is PRPF8 p.Pro2149= (c.6447G>A) in the general population?

PRPF8 p.Pro2149= (c.6447G>A) is ultra-rare (popmax 0.0187%, afr) (gnomAD).

How is Retinitis pigmentosa inherited?

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

PRPF8 p.Pro2149=

c.6447G>A · rs140315637 · VCV889696

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0187%, afr)

Conditions

retinitis pigmentosa

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2.6	GERP -4.6
Overall
CADD	3.865	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0187% African / African-American · 14/75,022 alleles

Filtering AF 0.0112% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00903%

Overall 0.00223% 36/1,614,148 alleles · ultra-rare exomes 27/1,461,858 · genomes 9/152,290 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0187%	5,359
South Asian	0.00878%	11,386
East Asian	0.00223%	44,892
Remaining individualsnot grpmax-eligible	0.0016%	62,506
Finnishnot grpmax-eligible	0.00156%	63,996
European (non-Finnish)	0.000932%	107,277

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.Pro2149=
Coding: c.6447G>A
MANE Select: NM_006445
dbSNP: rs140315637
Type: single nucleotide variant
Location: chr17:1651711 (GRCh38)
Gene constraint: LOEUF 0.26 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 85.20 · 100 PDB
Residue 2149: the mpn domain; a β-strand

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.Pro2149Leu Uncertain significance ★ ⚠ same residue
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.Pro2149_Gln2150insThr Uncertain significance ★★ same residue
PRPF8 p.Thr1102Lys 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-pro2149 (accessed [today's date]).

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