Is PRICKLE2 p.Cys198= (c.594C>T) pathogenic?

PRICKLE2 p.Cys198= (c.594C>T) is classified Conflicting classifications of pathogenicity in PRICKLE2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-11-03). Ultra-rare (popmax 0.0227%, afr); Associated with Progressive myoclonic epilepsy type 5.

What condition is associated with PRICKLE2 p.Cys198= (c.594C>T)?

PRICKLE2 p.Cys198= (c.594C>T) is associated with Progressive myoclonic epilepsy type 5, progressive myoclonus epilepsy (ClinVar).

How common is PRICKLE2 p.Cys198= (c.594C>T) in the general population?

PRICKLE2 p.Cys198= (c.594C>T) is ultra-rare (popmax 0.0227%, afr) (gnomAD).

PRICKLE2 p.Cys198=

c.594C>T · rs367680077 · VCV448123

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0227%, afr)

Conditions

Progressive myoclonic epilepsy type 5

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -3.5	GERP -4.3
Overall
CADD	1.756	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0227% African / African-American · 17/74,932 alleles

Filtering AF 0.0144% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0118%

Overall 0.00837% 135/1,613,816 alleles · ultra-rare exomes 118/1,461,568 · genomes 17/152,248 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0227%	4,408
Remaining individualsnot grpmax-eligible	0.0128%	7,808
European (non-Finnish)	0.00924%	10,824
South Asian	0.0011%	91,070

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.Cys198=
Coding: c.594C>T
MANE Select: NM_198859
dbSNP: rs367680077
Type: single nucleotide variant
Location: chr3:64157168 (GRCh38)
Gene constraint: LOEUF 0.34 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 56.41
Residue 198: the lim zinc-binding 2 domain

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

Also linked: progressive myoclonus epilepsy

Similar variants

PRICKLE2 c.*4330A>T Uncertain significance ★★ same condition
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-cys198 (accessed [today's date]).

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