Is PRICKLE2 p.Ser740Pro (c.2218T>C) pathogenic?

PRICKLE2 p.Ser740Pro (c.2218T>C) is classified Uncertain significance in PRICKLE2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-10). AlphaMissense: likely benign (0.0698); Very rare (popmax 0.00537%, afr); Associated with Progressive myoclonic epilepsy type 5.

What condition is associated with PRICKLE2 p.Ser740Pro (c.2218T>C)?

PRICKLE2 p.Ser740Pro (c.2218T>C) is associated with Progressive myoclonic epilepsy type 5 (ClinVar).

How common is PRICKLE2 p.Ser740Pro (c.2218T>C) in the general population?

PRICKLE2 p.Ser740Pro (c.2218T>C) is very rare (popmax 0.00537%, afr) (gnomAD).

What do computational predictors say about PRICKLE2 p.Ser740Pro (c.2218T>C)?

AlphaMissense predicts likely benign (score 0.0698) — an in-silico prediction, not a clinical call.

PRICKLE2 p.Ser740Pro

c.2218T>C · VCV3664618

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0698 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00537%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Progressive myoclonic epilepsy type 5

⚠ Built without this gene's context — gene constraint and dosage, protein structure, pathways, panels and related-variant links were not looked up for this page. why

Computational evidence

Protein change
AlphaMissense	0.0698	likely benign
REVEL	0.184	benign-leaning
SaProt	LLR -7.51	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 2.5	GERP -1.8, phastCons 0.97
Regional constraint	o/e 0.93	unconstrained · MANE · 49 kb · p 0.078 · regional, not allelic
Overall
CADD	15.1	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

Grpmax group 0.00537% African / African-American · 4/74,494 alleles

Filtering AF 0.00175% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.000435% 7/1,609,764 alleles · very rare exomes 3/1,458,374 · genomes 4/151,390 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00537%	18,623
Remaining individualsnot grpmax-eligible	0.00482%	20,739

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.Ser740Pro
Coding: c.2218T>C
MANE Select: NM_198859
Type: single nucleotide variant
Location: chr3:64099368 (GRCh38)

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

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-ser740pro (accessed [today's date]).

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