Is P2RY2 p.Pro366Ala (c.1096C>G) pathogenic?

P2RY2 p.Pro366Ala (c.1096C>G) is classified Uncertain significance in P2RY2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-03-22). AlphaMissense: likely benign (0.0515); Very rare (popmax 0.00135%, afr).

How common is P2RY2 p.Pro366Ala (c.1096C>G) in the general population?

P2RY2 p.Pro366Ala (c.1096C>G) is very rare (popmax 0.00135%, afr) (gnomAD).

What do computational predictors say about P2RY2 p.Pro366Ala (c.1096C>G)?

AlphaMissense predicts likely benign (score 0.0515) — an in-silico prediction, not a clinical call.

P2RY2 p.Pro366Ala

c.1096C>G · rs769478974 · VCV2279353

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0515 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00135%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0515	likely benign
REVEL	0.09	moderately benign-leaning
SaProt	LLR -6.00	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 -0.032	GERP -3
Regional constraint	o/e 1.10	unconstrained · MANE · 1,130 bp · p 0.024 · regional, not allelic
Overall
CADD	0.249	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 0.00135% African / African-American · 1/74,172 alleles

Filtering AF 0.000771% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000611%

Overall 0.00101% 16/1,589,160 alleles · very rare exomes 12/1,436,906 · genomes 4/152,254 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00135%	74,172
European (non-Finnish)	0.00128%	77,880

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: P2RY2
Protein: p.Pro366Ala
Coding: c.1096C>G
MANE Select: NM_002564
dbSNP: rs769478974
Type: single nucleotide variant
Location: chr11:73235255 (GRCh38)
Gene constraint: LOEUF 1.917 · pLI 0.14 (gnomAD)
Structure: AlphaFold pLDDT 79.11 · 3 PDB
Residue 366: the 'disordered' region

Full P2RY2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

P2RY2 p.Ala176Thr Uncertain significance ★ ⚠ same type
P2RY2 p.Ala252Thr Uncertain significance ★ ⚠ same type
P2RY2 p.Ala287Val Uncertain significance ★ ⚠ same type
P2RY2 p.Ala309Pro Uncertain significance ★ ⚠ same type
P2RY2 p.Ala80Thr Uncertain significance ★ ⚠ same type
P2RY2 p.Ala94Asp Uncertain significance ★ ⚠ same type
P2RY2 p.Ala94Val Uncertain significance ★ ⚠ same type
P2RY2 p.Arg143Cys 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/p2ry2-p-pro366ala (accessed [today's date]).

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