Is PRICKLE2 p.Ser337Thr (c.1010G>C) pathogenic?

PRICKLE2 p.Ser337Thr (c.1010G>C) is classified Uncertain significance in PRICKLE2 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-01-21). AlphaMissense: ambiguous (0.3949); Very rare (popmax 0.00133%, afr); Associated with Progressive myoclonic epilepsy type 5.

What condition is associated with PRICKLE2 p.Ser337Thr (c.1010G>C)?

PRICKLE2 p.Ser337Thr (c.1010G>C) is associated with Progressive myoclonic epilepsy type 5 (ClinVar).

How common is PRICKLE2 p.Ser337Thr (c.1010G>C) in the general population?

PRICKLE2 p.Ser337Thr (c.1010G>C) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about PRICKLE2 p.Ser337Thr (c.1010G>C)?

AlphaMissense predicts ambiguous (score 0.3949) — an in-silico prediction, not a clinical call.

PRICKLE2 p.Ser337Thr

c.1010G>C · rs750388947 · VCV940564

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3949 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

Progressive myoclonic epilepsy type 5

Computational evidence

Protein change
AlphaMissense	0.3949	ambiguous
REVEL	0.259	benign-leaning
SaProt	LLR -6.97	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 5, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 49 kb · p 0.078 · regional, not allelic
Overall
CADD	25.4	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 0.00133% African / African-American · 1/74,944 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000248% 4/1,614,132 alleles · very rare exomes 3/1,461,876 · genomes 1/152,256 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	74,944
European (non-Finnish)	0.000254%	393,355

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.Ser337Thr
Coding: c.1010G>C
MANE Select: NM_198859
dbSNP: rs750388947
Type: single nucleotide variant
Location: chr3:64147480 (GRCh38)
Gene constraint: LOEUF 0.34 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 56.41
Residue 337: 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.Ser337Asn Uncertain significance ★ ⚠ same residue
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

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-ser337thr (accessed [today's date]).

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