Is PRPF31 p.Ser445Phe (c.1334C>T) pathogenic?

PRPF31 p.Ser445Phe (c.1334C>T) is classified Uncertain significance in PRPF31 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-10-08). AlphaMissense: likely pathogenic (0.6404); Very rare (popmax 0.00212%, nfe); Associated with Inborn genetic diseases.

What condition is associated with PRPF31 p.Ser445Phe (c.1334C>T)?

PRPF31 p.Ser445Phe (c.1334C>T) is associated with Inborn genetic diseases (ClinVar).

How common is PRPF31 p.Ser445Phe (c.1334C>T) in the general population?

PRPF31 p.Ser445Phe (c.1334C>T) is very rare (popmax 0.00212%, nfe) (gnomAD).

What do computational predictors say about PRPF31 p.Ser445Phe (c.1334C>T)?

AlphaMissense predicts likely pathogenic (score 0.6404) — an in-silico prediction, not a clinical call.

PRPF31 p.Ser445Phe

c.1334C>T · VCV3425731

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.6404 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00212%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.6404	likely pathogenic
REVEL	0.458	indeterminate
SaProt	LLR -6.46	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.2, phastCons 1
Regional constraint	o/e 0.66	unconstrained · MANE · 7,893 bp · p 1.4e-13 · regional, not allelic
Overall
CADD	23.2	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 0.00212% European (non-Finnish) · 25/1,176,706 alleles

Filtering AF 0.00146% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00123%

Overall 0.00174% 28/1,605,106 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00212%	47,068
Admixed American	0.00169%	59,344
Remaining individualsnot grpmax-eligible	0.00161%	62,126
South Asian	0.00111%	89,960

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: PRPF31
Protein: p.Ser445Phe
Coding: c.1334C>T
MANE Select: NM_015629
Type: single nucleotide variant
Location: chr19:54129330 (GRCh38)
Gene constraint: LOEUF 0.347 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 77.69 · 30 PDB

Full PRPF31 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

PRPF31 p.Ala235Gly Uncertain significance ★★ ⚠ same condition
PRPF31 p.Ala254Thr Uncertain significance ★★ same condition
PRPF31 p.Arg357Cys Uncertain significance ★★ ⚠ same condition
PRPF31 p.Arg372Gln Uncertain significance ★★ ⚠ same condition
PRPF31 p.Arg442His Uncertain significance ★★ ⚠ same condition
PRPF31 p.Asn218Asp Uncertain significance ★★ ⚠ same condition
PRPF31 p.Asn240His Uncertain significance ★★ ⚠ same condition
PRPF31 p.Asp42Glu 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/prpf31-p-ser445phe (accessed [today's date]).

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