Is PRICKLE2 p.Ser693Cys (c.2078C>G) pathogenic?

PRICKLE2 p.Ser693Cys (c.2078C>G) is classified Uncertain significance in PRICKLE2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-06). AlphaMissense: likely pathogenic (0.6354); Very rare (popmax 0.00111%, sas); Associated with Progressive myoclonic epilepsy type 5.

What condition is associated with PRICKLE2 p.Ser693Cys (c.2078C>G)?

PRICKLE2 p.Ser693Cys (c.2078C>G) is associated with Progressive myoclonic epilepsy type 5 (ClinVar).

How common is PRICKLE2 p.Ser693Cys (c.2078C>G) in the general population?

PRICKLE2 p.Ser693Cys (c.2078C>G) is very rare (popmax 0.00111%, sas) (gnomAD).

What do computational predictors say about PRICKLE2 p.Ser693Cys (c.2078C>G)?

AlphaMissense predicts likely pathogenic (score 0.6354) — an in-silico prediction, not a clinical call.

PRICKLE2 p.Ser693Cys

c.2078C>G · rs922368735 · VCV2777622

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6354 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00111%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Progressive myoclonic epilepsy type 5

Computational evidence

Protein change
AlphaMissense	0.6354	likely pathogenic
REVEL	0.457	indeterminate
SaProt	LLR -8.59	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 49 kb · p 0.078 · regional, not allelic
Overall
CADD	28.5	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 0.00111% South Asian · 1/90,374 alleles

Overall 0.000125% 2/1,599,590 alleles · very rare exomes 2/1,447,232 · genomes 0/152,358 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00111%	90,374
European (non-Finnish)	8.55e-05%	1,168,938

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.Ser693Cys
Coding: c.2078C>G
MANE Select: NM_198859
dbSNP: rs922368735
Type: single nucleotide variant
Location: chr3:64099508 (GRCh38)
Gene constraint: LOEUF 0.34 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 56.41
Residue 693: the 'disordered' region

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.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
PRICKLE2 p.Ala707Thr 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-ser693cys (accessed [today's date]).

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