Is PRICKLE2 p.Arg705Pro (c.2114G>C) pathogenic?

PRICKLE2 p.Arg705Pro (c.2114G>C) is classified Uncertain significance in PRICKLE2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-04-20). AlphaMissense: likely benign (0.1952); Ultra-rare (popmax 0.0148%, afr); Associated with Progressive myoclonic epilepsy type 5.

What condition is associated with PRICKLE2 p.Arg705Pro (c.2114G>C)?

PRICKLE2 p.Arg705Pro (c.2114G>C) is associated with Progressive myoclonic epilepsy type 5 (ClinVar).

How common is PRICKLE2 p.Arg705Pro (c.2114G>C) in the general population?

PRICKLE2 p.Arg705Pro (c.2114G>C) is ultra-rare (popmax 0.0148%, afr) (gnomAD).

What do computational predictors say about PRICKLE2 p.Arg705Pro (c.2114G>C)?

AlphaMissense predicts likely benign (score 0.1952) — an in-silico prediction, not a clinical call.

PRICKLE2 p.Arg705Pro

c.2114G>C · rs760877594 · VCV1521335

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1952 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0148%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Progressive myoclonic epilepsy type 5

Computational evidence

Protein change
AlphaMissense	0.1952	likely benign
REVEL	0.378	indeterminate
SaProt	LLR -7.45	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 49 kb · p 0.078 · regional, not allelic
Overall
CADD	24.6	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 0.0148% African / African-American · 11/74,116 alleles

Filtering AF 0.00824% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00639%

Overall 0.000821% 13/1,584,186 alleles · ultra-rare exomes 3/1,431,954 · genomes 10/152,232 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0148%	6,738
Admixed American	0.00345%	28,955

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.Arg705Pro
Coding: c.2114G>C
MANE Select: NM_198859
dbSNP: rs760877594
Type: single nucleotide variant
Location: chr3:64099472 (GRCh38)
Gene constraint: LOEUF 0.34 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 56.41
Residue 705: 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.Arg705Cys Uncertain significance ★ ⚠ same residue
PRICKLE2 p.Arg705His 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

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-arg705pro (accessed [today's date]).

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