Is PRICKLE2 p.Arg563His (c.1688G>A) pathogenic?

PRICKLE2 p.Arg563His (c.1688G>A) is classified Uncertain significance in PRICKLE2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-04). AlphaMissense: likely benign (0.1848); Ultra-rare (popmax 0.0133%, amr); Associated with Progressive myoclonic epilepsy type 5.

What condition is associated with PRICKLE2 p.Arg563His (c.1688G>A)?

PRICKLE2 p.Arg563His (c.1688G>A) is associated with Progressive myoclonic epilepsy type 5 (ClinVar).

How common is PRICKLE2 p.Arg563His (c.1688G>A) in the general population?

PRICKLE2 p.Arg563His (c.1688G>A) is ultra-rare (popmax 0.0133%, amr) (gnomAD).

What do computational predictors say about PRICKLE2 p.Arg563His (c.1688G>A)?

AlphaMissense predicts likely benign (score 0.1848) — an in-silico prediction, not a clinical call.

PRICKLE2 p.Arg563His

c.1688G>A · rs375448087 · VCV1401438

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1848 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0133%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Progressive myoclonic epilepsy type 5

Computational evidence

Protein change
AlphaMissense	0.1848	likely benign
REVEL	0.043	moderately benign-leaning
SaProt	LLR -7.05	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 4.5, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 49 kb · p 0.078 · regional, not allelic
Overall
CADD	23.8	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 0.0133% Admixed American · 8/60,036 alleles

Filtering AF 0.00661% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00482%

Overall 0.00359% 58/1,614,150 alleles · ultra-rare exomes 51/1,461,856 · genomes 7/152,294 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0133%	7,505
Remaining individualsnot grpmax-eligible	0.0048%	20,835
European (non-Finnish)	0.00373%	26,819
South Asian	0.0022%	45,537
African / African-American	0.00133%	75,040

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.Arg563His
Coding: c.1688G>A
MANE Select: NM_198859
dbSNP: rs375448087
Type: single nucleotide variant
Location: chr3:64099898 (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.Arg563Cys 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
PRICKLE2 p.Ala650Val 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-arg563his (accessed [today's date]).

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