Is PRICKLE2 p.Ala149Ser (c.445G>T) pathogenic?

PRICKLE2 p.Ala149Ser (c.445G>T) is classified Uncertain significance in PRICKLE2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-11-05). AlphaMissense: ambiguous (0.3742); Ultra-rare (popmax 0.0453%, nfe); Associated with Progressive myoclonic epilepsy type 5.

What condition is associated with PRICKLE2 p.Ala149Ser (c.445G>T)?

PRICKLE2 p.Ala149Ser (c.445G>T) is associated with Progressive myoclonic epilepsy type 5, progressive myoclonus epilepsy (ClinVar).

How common is PRICKLE2 p.Ala149Ser (c.445G>T) in the general population?

PRICKLE2 p.Ala149Ser (c.445G>T) is ultra-rare (popmax 0.0453%, nfe) (gnomAD).

What do computational predictors say about PRICKLE2 p.Ala149Ser (c.445G>T)?

AlphaMissense predicts ambiguous (score 0.3742) — an in-silico prediction, not a clinical call.

PRICKLE2 p.Ala149Ser

c.445G>T · rs202025796 · VCV448122

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

ambiguous

0.3742 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0453%, nfe)

Conditions

Progressive myoclonic epilepsy type 5

Computational evidence

Protein change
AlphaMissense	0.3742	ambiguous
REVEL	0.518	indeterminate
SaProt	LLR -10.16	damaging
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.7	GERP 2, phastCons 1
Regional constraint	o/e 0.69	unconstrained · MANE · 51 kb · p 7.7e-10 · regional, not allelic
Overall
CADD	22.2	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 0.0453% European (non-Finnish) · 534/1,180,036 alleles

Filtering AF 0.042% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0408%

Overall 0.0348% 561/1,613,810 alleles · ultra-rare exomes 526/1,461,594 · genomes 35/152,216 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0453%	2,210
African / African-American	0.0174%	5,763
Remaining individualsnot grpmax-eligible	0.0128%	7,808
Admixed American	0.005%	20,003
Finnishnot grpmax-eligible	0.00312%	32,010
South Asian	0.0011%	91,064

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.Ala149Ser
Coding: c.445G>T
MANE Select: NM_198859
dbSNP: rs202025796
Type: single nucleotide variant
Location: chr3:64157317 (GRCh38)
Gene constraint: LOEUF 0.34 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 56.41
Residue 149: the lim zinc-binding 1 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

Also linked: progressive myoclonus epilepsy

Similar variants

PRICKLE2 p.Ala149Thr Uncertain significance ★ ⚠ same residue
PRICKLE2 p.Ala149= Likely benign ★ same residue
PRICKLE2 c.*4330A>T Uncertain significance ★★ same condition
PRICKLE2 p.Ala143Thr Uncertain significance ★★ ⚠ same condition
PRICKLE2 p.Ala146Val 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

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-ala149ser (accessed [today's date]).

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