Is PRICKLE1 p.Pro697Ser (c.2089C>T) pathogenic?

PRICKLE1 p.Pro697Ser (c.2089C>T) is classified Uncertain significance in PRICKLE1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-02). AlphaMissense: likely benign (0.0834); Ultra-rare (popmax 0.022%, sas); Associated with epilepsy, progressive myoclonic, 1B.

What condition is associated with PRICKLE1 p.Pro697Ser (c.2089C>T)?

PRICKLE1 p.Pro697Ser (c.2089C>T) is associated with epilepsy, progressive myoclonic, 1B (ClinVar).

How common is PRICKLE1 p.Pro697Ser (c.2089C>T) in the general population?

PRICKLE1 p.Pro697Ser (c.2089C>T) is ultra-rare (popmax 0.022%, sas) (gnomAD).

What do computational predictors say about PRICKLE1 p.Pro697Ser (c.2089C>T)?

AlphaMissense predicts likely benign (score 0.0834) — an in-silico prediction, not a clinical call.

PRICKLE1 p.Pro697Ser

c.2089C>T · rs781672373 · VCV537245

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0834 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.022%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

epilepsy, progressive myoclonic, 1B

Computational evidence

Protein change
AlphaMissense	0.0834	likely benign
REVEL	0.143	moderately benign-leaning
SaProt	LLR -5.07	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.4	GERP 0.83, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 13 kb · p 1.5e-10 · regional, not allelic
Overall
CADD	16.84	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 0.022% South Asian · 20/91,082 alleles

Filtering AF 0.0145% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0121%

Overall 0.00136% 22/1,613,974 alleles · ultra-rare exomes 21/1,461,876 · genomes 1/152,098 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.022%	4,554
Remaining individualsnot grpmax-eligible	0.0016%	62,480
European (non-Finnish)	8.47e-05%	1,180,034

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: PRICKLE1
Protein: p.Pro697Ser
Coding: c.2089C>T
MANE Select: NM_153026
dbSNP: rs781672373
Type: single nucleotide variant
Location: chr12:42460216 (GRCh38)
Gene constraint: LOEUF 0.279 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 55.55

Full PRICKLE1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

epilepsy, progressive myoclonic, 1B — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PRICKLE1 p.Pro697= Likely benign ★ same residue
PRICKLE1 c.1639+4C>T Uncertain significance ★★ same condition
PRICKLE1 c.384+6C>A Uncertain significance ★★ same condition
PRICKLE1 p.Ala142Thr Uncertain significance ★★ ⚠ same condition
PRICKLE1 p.Ala145Val Uncertain significance ★★ ⚠ same condition
PRICKLE1 p.Ala34Thr Uncertain significance ★★ ⚠ same condition
PRICKLE1 p.Ala34Val Uncertain significance ★★ ⚠ same condition
PRICKLE1 p.Ala492Thr 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/prickle1-p-pro697ser (accessed [today's date]).

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