Is PRPF4 p.Arg231Trp (c.691C>T) pathogenic?

PRPF4 p.Arg231Trp (c.691C>T) is classified Uncertain significance in PRPF4 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-11-04). AlphaMissense: likely pathogenic (0.974); Very rare (popmax 0.000254%, nfe).

How common is PRPF4 p.Arg231Trp (c.691C>T) in the general population?

PRPF4 p.Arg231Trp (c.691C>T) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about PRPF4 p.Arg231Trp (c.691C>T)?

AlphaMissense predicts likely pathogenic (score 0.974) — an in-silico prediction, not a clinical call.

PRPF4 p.Arg231Trp

c.691C>T · VCV4904116

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.974 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.974	likely pathogenic
REVEL	0.89	moderately pathogenic-leaning
SaProt	LLR -14.42	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.40 · evaluated, not missing
Pangolin	Δ0.29	loss · gain 0.01 · SpliceAI below 0.2 · independent
Constraint at this position
Conservation	phyloP 4.9	GERP 2.4, phastCons 1
Regional constraint	o/e 0.73	unconstrained · MANE · 16 kb · p 6e-12 · regional, not allelic
Overall
CADD	33.0	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R232W vs ClinVar R231W) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000254% European (non-Finnish) · 3/1,179,288 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000186% 3/1,613,114 alleles · very rare exomes 2/1,461,010 · genomes 1/152,104 · 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: PRPF4
Protein: p.Arg231Trp
Coding: c.691C>T
MANE Select: NM_001244926
Type: single nucleotide variant
Location: chr9:113284331 (GRCh38)
Gene constraint: LOEUF 0.294 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 82.33 · 25 PDB

Full PRPF4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PRPF4 p.Pro314Leu Likely pathogenic ★★ same type
PRPF4 c.654+4A>T Uncertain significance ★★ same type
PRPF4 p.Ala195Thr Uncertain significance ★★ ⚠ same type
PRPF4 p.Ala299Val Uncertain significance ★★ ⚠ same type
PRPF4 p.Arg206Ser Uncertain significance ★★ ⚠ same type
PRPF4 p.Arg438Trp Uncertain significance ★★ ⚠ same type
PRPF4 p.Arg439Cys Uncertain significance ★★ ⚠ same type
PRPF4 p.Asn241Ser Uncertain significance ★★ ⚠ 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/prpf4-p-arg231trp (accessed [today's date]).

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