Is PRPF8 p.Pro22Ser (c.64C>T) pathogenic?

PRPF8 p.Pro22Ser (c.64C>T) is classified Uncertain significance in PRPF8 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-10-19). AlphaMissense: likely benign (0.1202); Very rare (popmax 0.00267%, afr); Associated with Inborn genetic diseases.

What condition is associated with PRPF8 p.Pro22Ser (c.64C>T)?

PRPF8 p.Pro22Ser (c.64C>T) is associated with Inborn genetic diseases (ClinVar).

How common is PRPF8 p.Pro22Ser (c.64C>T) in the general population?

PRPF8 p.Pro22Ser (c.64C>T) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about PRPF8 p.Pro22Ser (c.64C>T)?

AlphaMissense predicts likely benign (score 0.1202) — an in-silico prediction, not a clinical call.

PRPF8 p.Pro22Ser

c.64C>T · rs748142695 · VCV3011017

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1202 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1202	likely benign
REVEL	0.328	indeterminate
SaProt	LLR -7.76	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; 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 2.7, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 956 bp · p 0.37 · regional, not allelic
Overall
CADD	23.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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

Grpmax group 0.00267% African / African-American · 2/74,912 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000124% 2/1,612,552 alleles · very rare exomes 0/1,460,358 · genomes 2/152,194 · 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.Pro22Ser
Coding: c.64C>T
MANE Select: NM_006445
dbSNP: rs748142695
Type: single nucleotide variant
Location: chr17:1684508 (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.Pro22Leu Uncertain significance ★ ⚠ same residue
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

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-pro22ser (accessed [today's date]).

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