Is PRICKLE2 p.Pro350Ser (c.1048C>T) pathogenic?

PRICKLE2 p.Pro350Ser (c.1048C>T) is classified Conflicting classifications of pathogenicity in PRICKLE2 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-09-08). AlphaMissense: likely benign (0.0675); Ultra-rare (popmax 0.0716%, amr); Associated with progressive myoclonus epilepsy.

What condition is associated with PRICKLE2 p.Pro350Ser (c.1048C>T)?

PRICKLE2 p.Pro350Ser (c.1048C>T) is associated with progressive myoclonus epilepsy (ClinVar).

How common is PRICKLE2 p.Pro350Ser (c.1048C>T) in the general population?

PRICKLE2 p.Pro350Ser (c.1048C>T) is ultra-rare (popmax 0.0716%, amr) (gnomAD).

What do computational predictors say about PRICKLE2 p.Pro350Ser (c.1048C>T)?

AlphaMissense predicts likely benign (score 0.0675) — an in-silico prediction, not a clinical call.

PRICKLE2 p.Pro350Ser

c.1048C>T · rs771168722 · VCV346475

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0675 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0716%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

progressive myoclonus epilepsy

Computational evidence

Protein change
AlphaMissense	0.0675	likely benign
REVEL	0.042	moderately benign-leaning
SaProt	LLR -5.46	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 1.5	GERP 1.7, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 49 kb · p 0.078 · regional, not allelic
Overall
CADD	9.4	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 0.0716% Admixed American · 43/60,014 alleles

Filtering AF 0.0546% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0486%

Overall 0.00273% 44/1,614,136 alleles · ultra-rare exomes 40/1,461,882 · genomes 4/152,254 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0716%	1,396
Remaining individualsnot grpmax-eligible	0.0016%	62,490

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.Pro350Ser
Coding: c.1048C>T
MANE Select: NM_198859
dbSNP: rs771168722
Type: single nucleotide variant
Location: chr3:64147442 (GRCh38)
Gene constraint: LOEUF 0.34 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 56.41
Residue 350: the 'disordered' region

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

Disease context

progressive myoclonus epilepsy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PRICKLE2 c.*4330A>T Uncertain significance ★★ same condition
PRICKLE2 p.Ala149Ser Uncertain significance ★★ same condition
PRICKLE2 p.Ala698Thr Uncertain significance ★★ ⚠ same condition
PRICKLE2 p.Arg390Gln Uncertain significance ★★ ⚠ same condition
PRICKLE2 p.Arg521Cys Uncertain significance ★★ ⚠ same condition
PRICKLE2 p.Gly512Asp Uncertain significance ★★ ⚠ same condition
PRICKLE2 p.His445Pro Uncertain significance ★★ ⚠ same condition
PRICKLE2 p.His738Arg 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-pro350ser (accessed [today's date]).

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