Is PRPF4 p.Pro458Ser (c.1372C>T) pathogenic?

PRPF4 p.Pro458Ser (c.1372C>T) is classified Uncertain significance in PRPF4 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-22). AlphaMissense: likely benign (0.1972); Very rare (popmax 0.00204%, nfe).

How common is PRPF4 p.Pro458Ser (c.1372C>T) in the general population?

PRPF4 p.Pro458Ser (c.1372C>T) is very rare (popmax 0.00204%, nfe) (gnomAD).

What do computational predictors say about PRPF4 p.Pro458Ser (c.1372C>T)?

AlphaMissense predicts likely benign (score 0.1972) — an in-silico prediction, not a clinical call.

PRPF4 p.Pro458Ser

c.1372C>T · rs768775315 · VCV1913304

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1972 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00204%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.1972	likely benign
REVEL	0.353	indeterminate
SaProt	LLR -9.40	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.5, phastCons 1
Regional constraint	o/e 0.73	unconstrained · MANE · 16 kb · p 6e-12 · regional, not allelic
Overall
CADD	26.0	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P459S vs ClinVar P458S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00204% European (non-Finnish) · 24/1,176,092 alleles

Filtering AF 0.00138% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00116%

Overall 0.00168% 27/1,609,666 alleles · very rare exomes 25/1,457,490 · genomes 2/152,176 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00204%	49,004
Finnishnot grpmax-eligible	0.00156%	64,004
African / African-American	0.00134%	74,800
South Asian	0.0011%	91,002

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.Pro458Ser
Coding: c.1372C>T
MANE Select: NM_001244926
dbSNP: rs768775315
Type: single nucleotide variant
Location: chr9:113291016 (GRCh38)
Gene constraint: LOEUF 0.294 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 82.33 · 25 PDB
Residue 459 UniProt numbering: a β-strand

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

Similar variants

PRPF4 p.Pro458Thr Uncertain significance ★ ⚠ same residue
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

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-pro458ser (accessed [today's date]).

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