Is PRICKLE2 p.Glu253= (c.759A>G) pathogenic?

PRICKLE2 p.Glu253= (c.759A>G) is classified Likely benign in PRICKLE2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-02-02). Very rare (popmax 0.00223%, eas); Associated with Progressive myoclonic epilepsy type 5.

What condition is associated with PRICKLE2 p.Glu253= (c.759A>G)?

PRICKLE2 p.Glu253= (c.759A>G) is associated with Progressive myoclonic epilepsy type 5 (ClinVar).

How common is PRICKLE2 p.Glu253= (c.759A>G) in the general population?

PRICKLE2 p.Glu253= (c.759A>G) is very rare (popmax 0.00223%, eas) (gnomAD).

PRICKLE2 p.Glu253=

c.759A>G · rs1422015238 · VCV1530790

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

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	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.45	GERP -1.2, phastCons 0.14
Overall
CADD	7.857	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,886 alleles

Filtering AF 0.000615% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000474%

Overall 0.000991% 16/1,614,258 alleles · very rare exomes 16/1,461,882 · genomes 0/152,376 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,886
Remaining individualsnot grpmax-eligible	0.0016%	62,508
African / African-American	0.00133%	75,074
European (non-Finnish)	0.0011%	90,773

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.Glu253=
Coding: c.759A>G
MANE Select: NM_198859
dbSNP: rs1422015238
Type: single nucleotide variant
Location: chr3:64153210 (GRCh38)
Gene constraint: LOEUF 0.34 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 56.41
Residue 253: the lim zinc-binding 2 domain; the lim zinc-binding 3 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

Similar variants

PRICKLE2 p.Glu253Val 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-glu253 (accessed [today's date]).

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