Is PRPF19 p.Ala487Thr (c.1459G>A) pathogenic?

PRPF19 p.Ala487Thr (c.1459G>A) is classified Uncertain significance in PRPF19 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-09). AlphaMissense: likely pathogenic (0.7952); Rare (popmax 0.138%, afr); Associated with Inborn genetic diseases.

What condition is associated with PRPF19 p.Ala487Thr (c.1459G>A)?

PRPF19 p.Ala487Thr (c.1459G>A) is associated with Inborn genetic diseases (ClinVar).

How common is PRPF19 p.Ala487Thr (c.1459G>A) in the general population?

PRPF19 p.Ala487Thr (c.1459G>A) is rare (popmax 0.138%, afr) (gnomAD).

What do computational predictors say about PRPF19 p.Ala487Thr (c.1459G>A)?

AlphaMissense predicts likely pathogenic (score 0.7952) — an in-silico prediction, not a clinical call.

PRPF19 p.Ala487Thr

c.1459G>A · VCV4144952

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7952 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.138%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.7952	likely pathogenic
REVEL	0.24	benign-leaning
SaProt	LLR -11.76	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.5	GERP 1.8, phastCons 1
Regional constraint	o/e 0.50	unconstrained · MANE · 6,957 bp · p 1e-06 · regional, not allelic
Overall
CADD	27.6	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 0.138% African / African-American · 103/74,836 alleles

Filtering AF 0.116% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.108%

Overall 0.0171% 276/1,612,558 alleles · rare exomes 218/1,460,704 · genomes 58/151,854 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.138%	727
Admixed American	0.0234%	4,280
Remaining individualsnot grpmax-eligible	0.016%	6,244
European (non-Finnish)	0.0126%	7,916

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: PRPF19
Protein: p.Ala487Thr
Coding: c.1459G>A
MANE Select: NM_014502
Type: single nucleotide variant
Location: chr11:60891222 (GRCh38)
Gene constraint: LOEUF 0.099 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 89.35 · 27 PDB
Residue 487: an α-helix

Full PRPF19 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

PRPF19 p.Ile172Ser Likely pathogenic ★ same condition
PRPF19 p.Ala35Val Uncertain significance ★ ⚠ same condition
PRPF19 p.Ala491Thr Uncertain significance ★ ⚠ same condition
PRPF19 p.Arg100Gly Uncertain significance ★ ⚠ same condition
PRPF19 p.Arg303Gln Uncertain significance ★ ⚠ same condition
PRPF19 p.Asn434Asp Uncertain significance ★ ⚠ same condition
PRPF19 p.Asn434Ile Uncertain significance ★ ⚠ same condition
PRPF19 p.Asn434Lys 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/prpf19-p-ala487thr (accessed [today's date]).

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