Is PRICKLE2 p.Arg364Pro (c.1091G>C) pathogenic?

PRICKLE2 p.Arg364Pro (c.1091G>C) is classified Uncertain significance in PRICKLE2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-16). AlphaMissense: ambiguous (0.4541); Very rare (popmax 8.47e-05%, nfe); Associated with Progressive myoclonic epilepsy type 5.

What condition is associated with PRICKLE2 p.Arg364Pro (c.1091G>C)?

PRICKLE2 p.Arg364Pro (c.1091G>C) is associated with Progressive myoclonic epilepsy type 5 (ClinVar).

How common is PRICKLE2 p.Arg364Pro (c.1091G>C) in the general population?

PRICKLE2 p.Arg364Pro (c.1091G>C) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about PRICKLE2 p.Arg364Pro (c.1091G>C)?

AlphaMissense predicts ambiguous (score 0.4541) — an in-silico prediction, not a clinical call.

PRICKLE2 p.Arg364Pro

c.1091G>C · rs372367565 · VCV2831700

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4541 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Conditions

Progressive myoclonic epilepsy type 5

Computational evidence

Protein change
AlphaMissense	0.4541	ambiguous
REVEL	0.318	indeterminate
SaProt	LLR -6.79	tolerated
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 6.2	GERP 4.1, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 49 kb · p 0.078 · regional, not allelic
Overall
CADD	23.5	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 8.47e-05% European (non-Finnish) · 1/1,180,042 alleles

Overall 6.19e-05% 1/1,614,242 alleles · very rare exomes 1/1,461,890 · genomes 0/152,352 · 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: PRICKLE2
Protein: p.Arg364Pro
Coding: c.1091G>C
MANE Select: NM_198859
dbSNP: rs372367565
Type: single nucleotide variant
Location: chr3:64147399 (GRCh38)
Gene constraint: LOEUF 0.34 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 56.41

Full PRICKLE2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Progressive myoclonic epilepsy type 5 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PRICKLE2 p.Arg364Gln Uncertain significance ★★ ⚠ same residue
PRICKLE2 p.Arg364Trp Uncertain significance ★★ ⚠ same residue
PRICKLE2 p.Ala143Thr Uncertain significance ★★ ⚠ same condition
PRICKLE2 p.Ala146Val Uncertain significance ★★ ⚠ same condition
PRICKLE2 p.Ala149Ser Uncertain significance ★★ same condition
PRICKLE2 p.Ala309Gly Uncertain significance ★★ ⚠ same condition
PRICKLE2 p.Ala33Ser Uncertain significance ★★ ⚠ same condition
PRICKLE2 p.Ala548Thr 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/prickle2-p-arg364pro (accessed [today's date]).

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