Is PRPF6 p.Pro181Ala (c.541C>G) pathogenic?

PRPF6 p.Pro181Ala (c.541C>G) is classified Uncertain significance in PRPF6 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-09-23). AlphaMissense: ambiguous (0.5479); Very rare (popmax 0.000339%, nfe).

How common is PRPF6 p.Pro181Ala (c.541C>G) in the general population?

PRPF6 p.Pro181Ala (c.541C>G) is very rare (popmax 0.000339%, nfe) (gnomAD).

What do computational predictors say about PRPF6 p.Pro181Ala (c.541C>G)?

AlphaMissense predicts ambiguous (score 0.5479) — an in-silico prediction, not a clinical call.

PRPF6 p.Pro181Ala

c.541C>G · rs770072579 · VCV866999

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5479 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Computational evidence

Protein change
AlphaMissense	0.5479	ambiguous
REVEL	0.508	indeterminate
SaProt	LLR -7.66	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.7, phastCons 1
Regional constraint	o/e 0.79	unconstrained · MANE · 1,953 bp · p 0.021 · regional, not allelic
Overall
CADD	22.6	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 0.000339% European (non-Finnish) · 4/1,180,028 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000248% 4/1,614,144 alleles · very rare exomes 4/1,461,894 · genomes 0/152,250 · 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: PRPF6
Protein: p.Pro181Ala
Coding: c.541C>G
MANE Select: NM_012469
dbSNP: rs770072579
Type: single nucleotide variant
Location: chr20:63995018 (GRCh38)
Gene constraint: LOEUF 0.445 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 80.07 · 33 PDB
Residue 181: an α-helix

Full PRPF6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PRPF6 p.Pro181= Likely benign ★ same residue
PRPF6 c.2028+5G>A Uncertain significance ★★ same type
PRPF6 c.2205+5G>A Uncertain significance ★★ same type
PRPF6 c.439-19G>A Uncertain significance ★★ same type
PRPF6 p.Ala246Val Uncertain significance ★★ ⚠ same type
PRPF6 p.Ala380Thr Uncertain significance ★★ ⚠ same type
PRPF6 p.Ala564Thr Uncertain significance ★★ ⚠ same type
PRPF6 p.Ala65Thr 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/prpf6-p-pro181ala (accessed [today's date]).

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