Is PRICKLE1 p.Ser622Pro (c.1864T>C) pathogenic?

PRICKLE1 p.Ser622Pro (c.1864T>C) is classified Uncertain significance in PRICKLE1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-03-29). AlphaMissense: ambiguous (0.4395); Very rare (popmax 0.000508%, nfe).

How common is PRICKLE1 p.Ser622Pro (c.1864T>C) in the general population?

PRICKLE1 p.Ser622Pro (c.1864T>C) is very rare (popmax 0.000508%, nfe) (gnomAD).

What do computational predictors say about PRICKLE1 p.Ser622Pro (c.1864T>C)?

AlphaMissense predicts ambiguous (score 0.4395) — an in-silico prediction, not a clinical call.

PRICKLE1 p.Ser622Pro

c.1864T>C · rs773978081 · VCV2280199

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4395 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000508%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.4395	ambiguous
REVEL	0.106	moderately benign-leaning
SaProt	LLR -8.81	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 9.3	GERP 1.7, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 13 kb · p 1.5e-10 · regional, not allelic
Overall
CADD	23.6	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 0.000508% European (non-Finnish) · 6/1,179,952 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000372% 6/1,613,996 alleles · very rare exomes 6/1,461,838 · genomes 0/152,158 · joint denominator

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.Ser622Pro
Coding: c.1864T>C
MANE Select: NM_153026
dbSNP: rs773978081
Type: single nucleotide variant
Location: chr12:42460441 (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

Similar variants

PRICKLE1 p.Ser622= Likely benign ★ same residue
PRICKLE1 c.1639+4C>T Uncertain significance ★★ same type
PRICKLE1 c.384+6C>A Uncertain significance ★★ same type
PRICKLE1 p.Ala142Thr Uncertain significance ★★ ⚠ same type
PRICKLE1 p.Ala145Val Uncertain significance ★★ ⚠ same type
PRICKLE1 p.Ala34Thr Uncertain significance ★★ ⚠ same type
PRICKLE1 p.Ala34Val Uncertain significance ★★ ⚠ same type
PRICKLE1 p.Ala492Thr Uncertain significance ★★ ⚠ same type

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-ser622pro (accessed [today's date]).

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