Is PRICKLE2 p.Arg680Pro (c.2039G>C) pathogenic?

PRICKLE2 p.Arg680Pro (c.2039G>C) is classified Uncertain significance in PRICKLE2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-10-14). AlphaMissense: likely benign (0.1918); Absent from gnomAD v4.1; Associated with Progressive myoclonic epilepsy type 5.

What condition is associated with PRICKLE2 p.Arg680Pro (c.2039G>C)?

PRICKLE2 p.Arg680Pro (c.2039G>C) is associated with Progressive myoclonic epilepsy type 5 (ClinVar).

How common is PRICKLE2 p.Arg680Pro (c.2039G>C) in the general population?

PRICKLE2 p.Arg680Pro (c.2039G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PRICKLE2 p.Arg680Pro (c.2039G>C)?

AlphaMissense predicts likely benign (score 0.1918) — an in-silico prediction, not a clinical call.

PRICKLE2 p.Arg680Pro

c.2039G>C · rs1308230146 · VCV1489152

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1918 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Progressive myoclonic epilepsy type 5

Computational evidence

Protein change
AlphaMissense	0.1918	likely benign
REVEL	0.296	indeterminate
SaProt	LLR -6.93	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 0.97, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 49 kb · p 0.078 · regional, not allelic
Overall
CADD	22.1	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: PRICKLE2
Protein: p.Arg680Pro
Coding: c.2039G>C
MANE Select: NM_198859
dbSNP: rs1308230146
Type: single nucleotide variant
Location: chr3:64099547 (GRCh38)
Gene constraint: LOEUF 0.34 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 56.41
Residue 680: the 'disordered' region

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.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
PRICKLE2 p.Ala650Val Uncertain significance ★★ ⚠ same condition
PRICKLE2 p.Ala707Thr 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-arg680pro (accessed [today's date]).

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