Is PRPF6 p.Pro228Ser (c.682C>T) pathogenic?

PRPF6 p.Pro228Ser (c.682C>T) is classified Uncertain significance in PRPF6 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-10-08). AlphaMissense: likely benign (0.1299); Very rare (popmax 0.00134%, afr).

How common is PRPF6 p.Pro228Ser (c.682C>T) in the general population?

PRPF6 p.Pro228Ser (c.682C>T) is very rare (popmax 0.00134%, afr) (gnomAD).

What do computational predictors say about PRPF6 p.Pro228Ser (c.682C>T)?

AlphaMissense predicts likely benign (score 0.1299) — an in-silico prediction, not a clinical call.

PRPF6 p.Pro228Ser

c.682C>T · VCV4945907

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1299 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.1299	likely benign
REVEL	0.32	indeterminate
SaProt	LLR -9.87	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 5.9	GERP 1.5, phastCons 1
Regional constraint	o/e 0.79	unconstrained · MANE · 1,953 bp · p 0.021 · regional, not allelic
Overall
CADD	21.9	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.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00134% African / African-American · 1/74,892 alleles

Filtering AF 0.0005% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000366%

Overall 0.000744% 12/1,613,972 alleles · very rare exomes 11/1,461,870 · genomes 1/152,102 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00134%	74,892
European (non-Finnish)	0.000932%	107,275

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.Pro228Ser
Coding: c.682C>T
MANE Select: NM_012469
Type: single nucleotide variant
Location: chr20:63995393 (GRCh38)
Gene constraint: LOEUF 0.445 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 80.07 · 33 PDB

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

Similar variants

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
PRPF6 p.Ala675Thr 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-pro228ser (accessed [today's date]).

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